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Although caregivers of patients with multiple myeloma (MM) play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking. We conducted a cross-sectional, multisite study of patients undergoing treatment with MM and their caregivers. Eligible caregivers were enrolled to 1 of 3 cohorts based on lines of therapy. Caregivers completed validated questionnaires to assess their QOL, psychological distress, and perceptions of prognosis. We enrolled 127 caregivers of patients with MM (newly diagnosed [n = 43], 2-3 lines of therapy [n = 40], and ≥4 lines of therapy [n = 44]). Caregiver QOL and psychological distress did not differ by line of therapy. The rate of clinically significant anxiety, depression, and posttraumatic stress disorder symptoms were 44.1% (56/127), 15.8% (20/127), and 24.4% (31/127), respectively. When examined in dyads, caregivers reported higher rates of clinically significant anxiety (44.4% [55/124] vs 22.5% [28/124]) compared with patients with MM. Most caregivers (84.2%, 101/120) reported that the oncologist had informed them that the patient’s cancer was incurable; however, only 50.9% (58/114) and 53.6% (59/110) of caregivers acknowledged the patient’s cancer was terminal and incurable, respectively. Caregivers of patients undergoing treatment for MM experience substantial psychological distress across the disease continuum, particularly anxiety. The majority of caregivers of patients with MM report that knowing the patient’s prognosis is extremely important and report that the oncologist told them that the patient was incurable. Nevertheless, a significant portion of caregivers believe that the patient’s MM is curable.

Key Points Defibrotide is associated with encouraging responses in the real world, including VOD/SOS after MAC as well as RIC allogeneic HSCT.Early diagnosis, prompt initiation of defibrotide, and minimization of dosing interruptions may be key to successful treatment of VOD/SOS., Visual Abstract, Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Defibrotide is the only medication approved by the US Food and Drug Administration for the management of severe VOD/SOS after HSCT. We report our center’s experience with commercially available defibrotide as treatment of patients with VOD/SOS. We retrospectively identified 28 cases of VOD/SOS, based on the European Society for Blood and Marrow Transplantation criteria, from March 2016 through June 2019. The median day of VOD/SOS onset was 25 days (range, 8-69 days), and defibrotide was initiated on day of diagnosis in 71% of patients. Complete resolution of VOD/SOS occurred in 75% of patients. Day 100 survival was 64% for all HSCT patients and 53% for those with very severe VOD/SOS. Response rates and survival were similar in patients with VOD/SOS after myeloablative or reduced-intensity chemotherapy HSCT. Therapy-related adverse events were mild and included hematuria (43%), epistaxis (18%), and hypotension (11%). Severe hemorrhagic adverse events occurred in 2 patients (pulmonary hemorrhage and upper gastrointestinal hemorrhage; 7%) and both in the setting of progressive VOD/SOS. Early diagnosis, prompt initiation of defibrotide, and minimization of dosing interruptions may be key to successful treatment of VOD/SOS.

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (

Background: Patients with RRMM receive multiple lines of therapy in their disease course and often become refractory to or are intolerant of newer approved therapies (eg, IMiDs, anti-CD38 monoclonal antibody [mAb] therapy, proteasome inhibitors [PIs]), limiting effective treatment options (Kumar et al. Leukemia. 2017; 31:2443). Efficacy outcomes decrease with each line of therapy, showing a need for agents with novel mechanisms of action to improve treatment responses and survival outcomes (Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the phase 2 HORIZON study (OP-106; NCT02963493), melflufen plus dexamethasone demonstrated encouraging efficacy in heavily pretreated patients with RRMM refractory to pomalidomide and/or an anti-CD38 mAb (overall response rate [ORR], 29%; median progression-free survival [PFS], 4.2 months; median overall survival [OS], 11.6 months) with a clinically manageable safety profile characterized primarily by hematologic adverse events (Richardson et al. EHA 2020. Abs. EP945). A contemporary representative control cohort is often used to indirectly compare outcomes of patients in clinical trials versus real-world data. The retrospective MAMMOTH study investigated the natural history and outcomes of patients with RRMM refractory to anti-CD38 mAb therapy after treatment with conventional agents (Gandhi et al. Leukemia. 2019;33:2266), providing a benchmark for the evolving state of the RRMM treatment landscape. Outcomes in clinical studies of novel agents in RRMM have been compared with MAMMOTH previously (Costa et al. ASH 2019. Abs. 3125), but not specifically in patients with RRMM refractory to anti-CD38 mAb therapy. To contextualize the clinical benefit of melflufen plus dexamethasone compared with conventional agents for patients with RRMM refractory to anti-CD38 mAb therapy, an analysis was conducted evaluating efficacy outcomes in HORIZON versus MAMMOTH. Methods: HORIZON patients with RRMM refractory to anti-CD38 mAb in the last line of therapy in the intention-to-treat population at final analysis (data cutoff date, 14 Jan 2020) were included in this analysis (N=63). Patients received melflufen 40 mg (intravenously on day 1 of each 28-day cycle) plus dexamethasone 40 mg weekly until disease progression or unacceptable toxicity. The MAMMOTH dataset included patients who progressed while on anti-CD38 mAb therapy (N=275) and were subsequently treated (N=249). ORR was assessed by the investigator per the International Myeloma Working Group criteria. PFS was defined as the time between the first dose of therapy and disease progression or death. OS was defined as the time from refractoriness to anti-CD38 mAb therapy to death from any cause in contrast to clinical studies in which OS is generally measured from first dose of subsequent therapy. Results: Patients in HORIZON and MAMMOTH had similar baseline median age and profile of daratumumab and isatuximab refractoriness (Table). Patients in HORIZON were more heavily pretreated than those in MAMMOTH (median number of prior therapies [range], 5 [2-10] versus 4 [1-16]). Patients in MAMMOTH were often treated with triplet therapy as first subsequent therapy after anti-CD38 mAb therapy failure (Table). ORR for HORIZON patients who failed last-line therapy with an anti-CD38 mAb (N=63) was 35% versus 31% for all anti-CD38 mAb therapy-refractory patients who received conventional agents in MAMMOTH. Median PFS was 4.6 months (95% CI, 3.7-6.4) versus 3.4 months (95% CI, 2.8-4.0), and median OS from last line was 15.4 months (95% CI, 12.0-25.6) versus 9.3 months (95% CI, 8.1-10.6) for these patients in HORIZON and MAMMOTH, respectively. Conclusion: This indirect comparison of patients with RRMM refractory to anti-CD38 mAb therapy in HORIZON and MAMMOTH suggests longer survival outcomes with melflufen plus dexamethasone (median PFS and OS of 4.6 and 15.4 months, respectively) versus those with conventional agents, despite HORIZON having more heavily pretreated patients. This analysis underscores the high burden of disease and unmet needs for patients with RRMM and the feasibility of novel combination therapy in this setting. Disclosures Blade Creixenti: Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Mateos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larocca:GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodríguez-Otero:Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Abbvie: Consultancy; Kite: Consultancy; Sanofi: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company; Oncopeptides: Consultancy. Leleu:GSK: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; AbbVie: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Oncopeptide: Honoraria. Nadeem:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Adaptive: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Touzeau:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding. Amor:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Maisel:Takeda: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Karyopharm: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Mazumder:The Oncology Institute: Current Employment; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria. Zavisic:Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Harmenberg:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Medivir AB: Current equity holder in publicly-traded company; Ultupharma AB: Current equity holder in private company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. OffLabel Disclosure: This is an indirect comparison of clinical studies, including a phase 2 investigational study of melflufen in RRMM

Introduction: The BOSTON study is a Phase 3 trial comparing the novel triplet regimen of once weekly oral selinexor with once weekly bortezomib and dexamethasone (SVd) versus standard twice weekly Vd in patients with multiple myeloma (MM) after 1-3 prior therapies. The SVd regimen conferred a 47% increase in median progression-free survival (PFS) and time to next therapy (TTNT), higher overall response rates (ORR) and deeper responses compared to Vd. Furthermore, this is the first trial of a bortezomib-based triplet therapy (i.e., SVd) that showed lower rates of overall and Grade ≥2 peripheral neuropathy (PN) compared with doublet Vd while conferring a longer PFS, and the regimen requires ~35% fewer clinic visits than standard twice weekly Vd. This abstract reports analyses of the patient reported outcomes (PROs) in BOSTON to evaluate patterns in therapy-induced PN symptoms, pain and function. Methods: PROs were assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-CIPN20 questionnaires. The QLQ-CIPN20 assesses patients' experience of symptoms and functional limitations related to chemotherapy induced PN (CIPN) and has 3 subscales: sensory, motor, and autonomic. The QLQ-C30 includes several functional and symptom scales and focuses on physical functioning, role functioning, and pain subscales as pre-specified domains of interest. Mixed effects repeated measures models were fit to the longitudinal data to estimate differences over time. Meaningful change thresholds derived using anchor- and distribution-based methods or estimated from the literature were used to identify patients who had experienced a meaningful worsening of symptoms or deterioration in functioning. Time to definitive deterioration was defined as the time from randomization to the first occurrence of meaningful deterioration that was not followed by subsequent improvement. Cox proportional hazard models compared the hazard rates between arms adjusted for baseline questionnaire score, randomization stratification factors (prior PI therapy, number of prior anti-MM regimens, R-ISS stage at MM) and prior bortezomib exposure. Results: A total of 402 patients were enrolled in the trial; 388 completed a baseline QLQ-CIPN20 assessment and are included in these analyses. Based on the mixed model repeated measures analysis (Table 1), a benefit was demonstrated for SVd in change from baseline to Day 106 for sensory (-5.3 points difference, p=0.0006) and pain (-6.6, p=0.007) scores. Patients in the SVd arm had a greater increase in autonomic symptom scores (+5.0, p=0.022). The number of patients with definitive deterioration in QLQ-CIPN20 sensory symptoms was greater in the Vd arm (86 patients, 45.7%) compared to 52 (27.7%) patients in the SVd arm (Table 2). The median time to deterioration was 20.7 months (95% confidence interval [CI]: 15.4, not estimable [NE]) in the SVd arm compared to 12.5 months (95% CI: 7.8, 19.9) in the Vd arm. The adjusted hazard ratio (HR) comparing time to deterioration in sensory scores between SVd and Vd arms was 0.53 (95% CI: 0.38, 0.75; p = 0.0004). Worsening of motor symptoms also trended in favor of SVd with a HR = 0.72 (p=0.052). Roughly half of the patients in each treatment arm experienced worsening autonomic symptoms (54.6% and 48.4%, SVd and Vd respectively) with no significant difference between arms (HR=1.14, p=0.37). While not statistically significant, fewer SVd patients had definitive deteriorations in pain and physical function compared to Vd patients, with similar or extended time to deterioration (Table 2). Conclusions: In the setting of a significant increase in PFS and TTNT, patients with MM after at least one prior therapy who received weekly SVd reported lower sensory symptom and pain scores but higher autonomic symptom scores. Further, patients treated with twice weekly Vd experienced a more rapid rate of sensory symptom worsening and a trend to more rapid worsening of motor symptoms, compared to patients treated with SVd. The improved pain scores in patients treated with SVd may be related to superior disease control. The reduction in PN-related pain and sensory symptoms observed with SVd in the setting of increased PFS and TTNT supports a potentially improved patient experience and decreased health care burden and long term morbidity. Disclosures Leleu: Janssen: Honoraria; BMS-celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Oncopeptide: Honoraria; AbbVie: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria. Beaumont:Clinical Outcomes Solutions: Current Employment; Karyopharm Therapeutics: Consultancy. Yu:Clinical Outcomes Solutions: Current Employment; Karyopharm Therapeutics: Consultancy. Hudgens:Clinical Outcomes Solutions: Current Employment; Sierra Oncology: Consultancy; Karyopharm Therapeutics: Consultancy. Auner:Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Quach:Sanofi: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria. Delimpasi:Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; GENESIS: Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Hajek:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria. Levy:Karyopharm,Takeda, BMS: Consultancy, Honoraria, Speakers Bureau. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chai:Karyopharm Therapeutics Inc: Current Employment. Ma:Karyopharm: Current Employment, Current equity holder in private company. Tang:Karyopharm Therapeutics: Current Employment. Leong:AbbVie: Ended employment in the past 24 months; Karyopharm Therapeutics: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Coronavirus disease 2019 (COVID-19) is a heterogeneous clinical condition caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The initial stage of infection occurs at the time of respiratory viral invasion through angiotensin-converting enzyme 2 (ACE2) receptors in alveolar pneumocytes and macrophages. In the second stage of established pulmonary disease without and with hypoxia, viral multiplication and localized inflammation occurs. The third stage COVID-19 is the most severe, characterized by systemic hyperinflammation, acute respiratory distress syndrome (ARDS) and generalized microangiopathy, with significantly elevated biomarkers including IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1α, tumor necrosis factor-α, C-reactive protein, ferritin, D-dimer, von Willebrand factor (vWF) and thrombomodulin (TM). Evidence suggests that endothelial damage and activation play a key role in the pathobiology of the disease, and thus protecting endothelium and reversing endotheliitis may be a key therapeutic goal (Teuwen et al,Nat Rev Immunol2020). Defibrotide (DF), a complex mixture of poly-deoxyribonucleotides extracted from porcine mucosa, modulates expression of thrombogenic and inflammatory mediators produced in response to endothelial cell injury and/or leukocyte activation. DF increases tissue plasminogen activator (t-PA) and TM expression, thereby enhancing the enzymatic activity of plasmin to hydrolyze fibrin clot, while also decreasing vWF and plasminogen activator inhibitor-1 (PAI-1). Platelet adhesion is inhibited via increases in nitric oxide (NO), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) (Falanga A et al,Leukemia 2003). Anti-inflammatory properties via inhibition of p38 MAPK pathway have been demonstrated with DF, attenuating the release of inflammatory mediators including IL-6, thromboxane A2, leukotriene B4, tumor necrosis factor-alpha, and reactive oxygen species (Mitsiades et al,Clin Cancer Res2009). Additionally, DF inhibits both the expression and activity of heparanase, which in turn modulates heparan sulfate, a vital moiety for viral infection (Richardson et al,Blood Adv2018; Koganti et al,Cell Mol Life Sci2020). DF also modulates endothelial cell injury in murine models by down-regulating the expression of endothelial cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), that are critical to leukocyte adhesion and migration, and by increasing the endothelial cell release of anti-inflammatory cytokines, conferring survival benefit (Garcia-Bernal et al,J Cell Mol Med2020). DF is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) complicating stem cell transplantation and has demonstrated efficacy and safety in critically ill patients with multi-organ failure, underpinned by vasculopathy, endotheliitis, immune activation and hemorrhagic risk (Richardson et al,Blood2016). This multi-target and pleiotropic approach makes DF an attractive candidate for the treatment of advanced stage COVID 19 and the systemic endothelial complications underpinning both its pathobiology and ensuing mortality (Figure 1). Various clinical studies in Spain, Italy, Ireland, the UK and USA are underway, with the larger randomized placebo-controlled prospective phase 2 study in Spain (clinicaltrials.gov: NCT04348383) leading in accrual with promising early results, demonstrating safety to date with potential efficacy, as reflected by favorable outcome in a subset of intubated patients as part of an ongoing multi-center trial. Other studies within the group have focused on safety and particularly the therapeutic role of DF in advanced disease, including those patients requiring extracorporeal membrane oxygenation (ECMO) and full dose systemic anticoagulation. These trials include common in-depth biological correlatives, assessing biomarkers including heparanase, inflammatory cytokines, immune cell sub-populations, vWF and soluble TM, as well as other novel markers and pharmacokinetics. In aggregate, these studies will hopefully help demonstrate the effects of DF on the proposed targets in COVID-19 and successfully correlate these effects with improved clinical outcome. Disclosures Moraleda: Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis, Sandoz, Takeda:Honoraria;Gilead:Honoraria, Other: Travel expenses.Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca:Honoraria;Boehringer Ingelheim and Sanofi:Consultancy;ADC Therapeutics and Rhizen Pharmaceuticals:Research Funding.Jara Rubio:Edwards Lifesciences, Getinge:Honoraria.Diaz-Ricart:Jazz Pharmaceuticals:Honoraria, Research Funding;German Jose Carreras Leukaemia Foundation:Research Funding.Carreras:Jazz Pharmaceuticals:Research Funding, Speakers Bureau;German Jose´ Carreras Leukaemia Foundation:Research Funding.Mo:Celgene/BMS:Membership on an entity's Board of Directors or advisory committees.Cooke:Jazz Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.Soiffer:Be the Match/ National Marrow Donor Program:Membership on an entity's Board of Directors or advisory committees;alexion:Consultancy;Celgene:Membership on an entity's Board of Directors or advisory committees;Juno:Membership on an entity's Board of Directors or advisory committees;Novartis:Consultancy;VOR Biopharma:Consultancy;Mana Therapeutics:Consultancy;Precision Bioscience:Consultancy;Cugene:Consultancy;Rheos Therapeutics:Consultancy;Gilead:Consultancy;Kiadis:Membership on an entity's Board of Directors or advisory committees.Baron:Genetech:Consultancy;Merck:Consultancy.Pagliuca:Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm:Research Funding. OffLabel Disclosure: Defibrotide used for the treatment of endotheliitis complicating SARS-Cov-2 infection

Background: Advances in therapy have improved outcomes in multiple myeloma (MM), but enhancement in overall survival (OS) has resulted in patients living with the burden of symptoms and complications of relapsed/refractory MM (RRMM) and prior lines of therapy (Vogl et al. Leuk Lymphoma. 2018;59:398; Kumar et al. Leukemia. 2017;31:2443). Elderly patients represent a particularly difficult-to-treat population with RRMM due to the additional presence of comorbidities, reduced fitness level, and treatment with concomitant medications (Larocca et al. Leukemia. 2018;32:1697). There is an unmet need for efficacious and convenient treatment options with manageable side effects to optimize tolerability for elderly patients with RRMM. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the phase 2 HORIZON study (OP-106; NCT02963493), melflufen plus dexamethasone (dex) demonstrated encouraging efficacy and a clinically manageable safety profile in patients with heavily pretreated RRMM (Richardson et al. EHA 2020. Abs. EP945). This analysis examines the efficacy and safety of melflufen plus dex in the subset of patients aged ≥75 years in the HORIZON study. Methods: Patients with RRMM must have received ≥2 prior lines of therapy, including an IMiD and a proteasome inhibitor, and been refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Pts received melflufen 40 mg intravenously on day 1 and dex 40 mg per week (20 mg in patients aged ≥75 years) during each 28-day treatment cycle until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥ partial response [PR]; investigator-assessed per International Myeloma Working Group criteria). Secondary endpoints included progression-free survival (PFS), OS, duration of response (DOR), and safety. An analysis was conducted in the intention-to-treat population for patients aged ≥75 years. Results: As of the data cutoff date (January 14, 2020), 157 patients were enrolled and treated; 25 (16%) were aged ≥75 years. Baseline characteristics for older patients were generally similar to that of the overall population and were indicative of a heavily pretreated population with a poor prognosis. Among patients aged ≥75 years, the median age was 77 years (range, 75-86); 32% had International Staging System stage 3; and 24% had extramedullary disease. Patients had received a median of 5 prior lines of therapy (range, 2-8), and 76% had triple-class-refractory MM. Efficacy results were consistent with those of the overall population and were not affected negatively by advanced patient age. ORR was 32% and 29% in patients aged ≥75 years and in the overall population, respectively (Table). In responding patients, median DOR was not reached in patients aged ≥75 years and was 5.5 months in the overall population. In patients aged ≥75 years and the overall population, median PFS was 5.6 months and 4.2 months, respectively, and median OS was 13.5 months and 11.6 months, respectively. In patients aged ≥75 years and the overall population, respectively, grade 3/4 AEs occurred in 96% and 89% of patients, most commonly neutropenia (44% and 53%), white blood cell count decrease (44% and 26%), thrombocytopenia (40% and 57%), and anemia (40% and 43%); the most common nonhematologic grade 3/4 AEs were pneumonia (20% and 10%), hypertension (12% and 2%), febrile neutropenia (12% and 6%), and hypophosphatemia (12% and 5%). Serious AEs occurred in 40% of patients aged ≥75 years and in 49% of the overall population, most commonly, pneumonia (16% [4 events] and 9% [14 events]); all other serious AEs in patients aged ≥75 years were observed in 1 patient each (4%). There were no treatment-related deaths. Conclusion: Melflufen, once monthly infusion, plus weekly dex demonstrated clinically meaningful efficacy and a manageable safety profile in older patients with heavily pretreated RRMM. In patients aged ≥75 years, treatment resulted in durable responses, with a safety profile consistent with that in previous reports. Further study is warranted to confirm these results suggesting that melflufen may be an efficacious, convenient, and tolerable therapy for elderly patients with RRMM who have limited treatment options. Disclosures Larocca: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Oriol:Janssen: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodríguez-Otero:Janssen, BMS: Other: Travel, accommodations, expenses; BMS, Janssen, Amgen: Honoraria; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding. Leleu:Amgen: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Oncopeptide: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; BMS-celgene: Honoraria. Nadeem:Adaptive: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hassoun:Celgene: Research Funding; Takeda: Research Funding; Novartis: Consultancy. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Amor:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maisel:Takeda: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Karyopharm: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau. Mazumder:Celgene: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Thuresson:Statisticon: Current Employment; Oncopeptides: Consultancy, Current equity holder in publicly-traded company. Harmenberg:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Ultupharma AB: Current equity holder in private company; Medivir AB: Current equity holder in publicly-traded company. Gustavsson:PiezoMotor AB: Current equity holder in publicly-traded company; Sangus Jazz AB: Current equity holder in private company; Bristol-Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months; XSpray AB: Divested equity in a private or publicly-traded company in the past 24 months; Vinnova: Honoraria; Episurf AB: Current equity holder in publicly-traded company; Nanexa AB: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Mateos:GlaxoSmithKline: Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM.

Background: In patients with relapsed/refractory multiple myeloma (RRMM), 29%-59% have high-risk (HR) cytogenetic abnormalities that are associated with poor treatment outcomes (Kumar et al. Leukemia. 2017;31:2443; Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Melflufen plus dexamethasone (dex) showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated and poor-risk RRMM in the phase 2 HORIZON study (OP-106; NCT02963493; Richardson et al. EHA 2020. Abs. EP945). The overall response rate (ORR) was 29%, median progression-free survival (PFS) was 4.2 months, and median overall survival (OS) was 11.6 months. The most common nonhematologic grade 3/4 adverse event (AE) was pneumonia (10%). This is an analysis of the cytogenetic profile and a comparison of the efficacy for patients with and without HR cytogenetic abnormalities in the HORIZON study. Methods: Patients with RRMM had received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Patients received melflufen 40 mg (intravenously on day 1 of each 28-day cycle) and dex 40 mg/wk until progressive disease or unacceptable toxicity. The primary endpoint was ORR (≥ partial response [PR]; investigator-assessed per International Myeloma Working Group criteria); secondary endpoints included PFS, OS, duration of response (DOR), and safety. At screening, cytogenetics were evaluated using plasma cells from bone marrow aspirate by interphase fluorescence in situ hybridization and by conventional karyotyping. HR cytogenetic abnormalities were classified by the presence of t(4;14), t(14;16), t(14;20), del(17/17p), or gain(1q) (Sonneveld et al. Blood. 2016;127:2955). Results: Of the 157 patients enrolled and treated (data cutoff date, January 14, 2020), 59 (38%) had HR cytogenetic abnormalities at screening. Cytogenetic status was missing/unknown in 31 patients (20%). Among patients with HR cytogenetics, gain(1q) was seen in 41 (69%), del(17p) in 31%, t(4:14) in 31%, t(14:16) in 7%, and t(14:20) in none. Although baseline characteristics were generally similar between patients with and without HR cytogenetics (Table), fewer patients with HR cytogenetics had triple-class-refractory MM (69%) than those without HR cytogenetics (80%). The ORR (95% CI) was 20% (11-33) in patients with HR cytogenetics and 35% (25-45) in patients without HR cytogenetics. Among responding patients with HR cytogenetics (n=12), 4 achieved a very good PR and 8 a PR, with a median DOR of 6.7 months (95% CI, 3.0-not evaluable). Median DOR was 5.1 months (95% CI, 3.9-7.5) in patients without HR cytogenetics (n=34). Median PFS was 3.1 months (95% CI, 2.1-5.4) and 4.4 months (95% CI, 3.8-5.1), respectively, and OS was 11.5 months (95% CI, 8.5-13.6) and 13.2 months (95% CI, 8.1-17.6), respectively, in patients with and without HR cytogenetics. Among patients with HR cytogenetics, the ORR was 24% (95% CI, 11-40) in patients with 1 HR cytogenetic abnormality (n=38) and 14% (95% CI, 3-36) in patients with ≥2 HR cytogenetic abnormalities (n=21). Median PFS was 2.9 months (95% CI, 1.9-7.6) and 4.4 months (95% CI, 1.9-6.5), and OS was 11.6 months (95% CI, 7.7-21.1) and 11.5 months (95% CI, 4.5-13.9) in patients with 1 and ≥2 HR cytogenetic abnormalities, respectively. In patients with HR cytogenetics (n=59) and the overall population (N=157), grade 3/4 AEs were reported in 92% and 89%, respectively; the most common grade 3/4 AEs were thrombocytopenia (51% and 57%), neutropenia (47% and 53%), and anemia (36% and 43%); the most common nonhematologic grade 3/4 AE was pneumonia (17% and 10%). Serious AEs occurred in 54% of patients with HR cytogenetics and in 49% of patients in the overall population, most commonly pneumonia (17% and 9%, respectively). Conclusions: In the HORIZON study, melflufen plus dex also showed efficacy in patients with HR cytogenetics. The safety profile of melflufen plus dex in patients with HR cytogenetics was consistent with that of the overall population. Taken together, these data support further evaluation of melflufen plus dex in RRMM with HR cytogenetics. Disclosures Mateos: GlaxoSmithKline: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodríguez-Otero:Kite: Consultancy; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy; Abbvie: Consultancy; Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company; Oncopeptides: Consultancy. Leleu:BMS-celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; GSK: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Novartis: Honoraria. Nadeem:Adaptive: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Touzeau:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Amor:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Maisel:Texas Oncology: Current Employment; Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau. Mazumder:Takeda: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau. Harmenberg:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Medivir AB: Current equity holder in publicly-traded company; Ultupharma AB: Current equity holder in private company. Gustavsson:Vinnova: Honoraria; XSpray AB: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months; Bristol-Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Sangus Jazz AB: Current equity holder in private company; PiezoMotor AB: Current equity holder in publicly-traded company; Episurf AB: Current equity holder in publicly-traded company; Nanexa AB: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. OffLabel Disclosure: This is a phase 2 investigational study of melflufe in RRMM.

Background: Pts with RRMM are a very sick population due to disease symptoms, comorbidities, side effects from treatments, and age-related fragility (Chim et al. Leukemia. 2018;32:252). Pts often experience adverse events (AEs) that affect their quality of life and reduce treatment compliance; hematologic AEs are frequent. Inpatient services for the management of AEs are often necessary and a major cost driver, with costs rising per AE episode (highest for hematologic AEs; Felber et al. ASH 2019. Abs. 4725). Additionally, a real-world study suggested that >50% of pts with hematologic AEs require readmittance to the hospital after initial treatment (Yeaw et al. ISPOR 2020. Abs. PCN78). Published data to date come from real-world evidence, with limited reports from clinical trials. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the pivotal, phase 2, HORIZON study (OP-106; NCT02963493), melflufen plus dex showed clinically meaningful efficacy and a safety profile consisting primarily of clinically manageable hematologic AEs in pts with heavily pretreated RRMM (Richardson et al. EHA 2020. Abs EP945). This analysis aids to further elucidate the healthcare resource utilization of pts with RRMM treated with melfulfen in a clinical trial by evaluating the impact of AEs on hospitalizations in HORIZON. Methods: Pts with RRMM who had received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody were treated with melflufen and dex as described (Richardson et al. EHA 2020. Abs EP945). Data for specific AEs potentially related to the study drugs (melflufen and/or dex; TRAEs) requiring hospitalizations >24 h were compared with all potential TRAEs and within each preferred term with >1 event reported regardless of hospitalization. AEs were classified as TRAE if reported as related or possibly related to either study drug by the treating physician. Results: At the data cutoff date (14 Jan 2020), 157 pts were enrolled and had received ≥1 dose of study treatment; 35 (22%) had been hospitalized due to a TRAE. Pts hospitalized due to TRAEs had a median age of 63 y (range, 43-84); 31% had International Staging System stage 3 disease; 49% had high-risk cytogenetics; and 77% had triple-class-refractory MM. In the overall population (N=157), the most frequent grade 3/4 treatment-emergent AEs (TEAEs) were thrombocytopenia (57%), neutropenia (53%), and anemia (43%). Serious AEs occurred in 49% of pts, most commonly pneumonia (9%) and febrile neutropenia (5%). Of all 3713 TEAEs, 118 (3.2%) led to hospitalization. Of 2688 TRAEs, 58 (2.2%) resulted in hospitalization. Pneumonia and febrile neutropenia TRAEs resulted in the most hospitalizations, with 11 events (78.6% of pneumonia TRAEs; 0.41% of all TRAEs) and 10 events (83.3% of febrile neutropenia TRAEs; 0.37% of all TRAEs), respectively (Table). Grade 3/4 hematologic TRAEs resulting in hospitalization included thrombocytopenia (9 hospitalizations; 1.4% of thrombocytopenia TRAEs; 0.33% of all TRAEs) and neutropenia (2 hospitalizations; 0.3% of neutropenia TRAEs; 0.07% of all TRAEs). All TRAEs that resulted in hospitalization were grade 3/4 except for 2 events (1 pyrexia [grade 1]; 1 pneumonia [grade 2]). For 3 of 9 thrombocytopenia events and 1 of 2 neutropenia events, it was unclear whether the hospitalization was >24 h; however, they were included in current analysis. Conclusion: Within this heavily pretreated pt population, most TRAEs could be managed without the need for hospitalization. Hematologic AEs were common but led to few hospitalizations overall. Although 11 cases (78.6%) of TRAEs of pneumonia required hospitalization, these events represent only 0.41% of all TRAEs, and infections are normally expected in advanced RRMM (Blimark et al. Plasma Cell Disorders. 2015;100:107). Use of inpatient services are a major driver of economic burden in RRMM and have been shown to be highly utilized in less heavily pretreated populations than HORIZON (Yeaw et al. ISPOR 2020. Abs. PCN7; Felber et al. ASH 2019. Abs. 4725). Results of this analysis suggest limited use of inpatient services for TRAEs with melflufen plus dex. Further analyses of real-world data on melflufen are warranted to confirm the results presented from this analysis. Disclosures Nadeem: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Mateos:Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Larocca:GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Rodríguez-Otero:Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company; Oncopeptides: Consultancy; Abbvie: Consultancy; Kite: Consultancy; Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Leleu:Oncopeptide: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Amgen: Honoraria; Novartis: Honoraria; BMS-celgene: Honoraria; AbbVie: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Janssen: Honoraria. Hassoun:Novartis: Consultancy; Takeda: Research Funding; Celgene: Research Funding. Touzeau:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Amor:GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Maisel:Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Mazumder:Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment. Raptis:UPMC: Current Employment; INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Puig:BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Sandberg:Oncopeptides AB: Current Employment; Novo Nordisk AS: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Pelaez:Märsta Läkarhus AB: Ended employment in the past 24 months; Oncopeptides: Consultancy. Jaques:Pharma Biotech Consultants: Consultancy; Oncopeptides: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Consultancy; Morphosys AG: Consultancy; Oncopeptides: Ended employment in the past 24 months. Orre:Oncopeptides: Current Employment. Cavo:GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: This is phase 2 investigational study of melflufen in RRMM.

Introduction Selinexor is a first-in-class, oral, potent selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, leading to cancer cell apoptosis. Selinexor has demonstrated antimyeloma activity in triple class refractory multiple myeloma (MM) [Chari et al. NEJM 2019]. Selinexor synergizes with proteasome inhibitors (PIs) in PI-sensitive and -resistant cell lines and produces high response rates in patients with PI refractory and non-refractory MM (Bahlis et al. Blood 2018). In the phase 3 BOSTON study, the combination of once weekly (QW) selinexor, QW bortezomib, and dexamethasone (SVd) in patients who had received 1-3 prior therapies led to a significantly longer (47%) median progression-free survival (PFS) of 13.93 vs 9.46 months, with a hazard ratio of 0.70 (P=0.0075) compared to standard twice weekly bortezomib and dexamethasone (Vd). In addition, SVd regimen produced higher response rates and deeper responses (ORR: 76.4% vs 62.3% and ≥CR 16.9% vs 10.2%) compared with Vd. The benefit with SVd was observed across all efficacy endpoints and was associated with lower incidence and severity of bortezomib-induced peripheral neuropathy. Here we analyzed the effect of prior PI therapy (bortezomib, carfilzomib, ixazomib) on the efficacy and safety of SVd compared with Vd. Methods BOSTON is an open-label, randomized phase 3 study in patients with MM comparing SVd (QW oral selinexor 100 mg, QW subcutaneous bortezomib 1.3 mg/m2, and BIW oral dexamethasone 20 mg), versus Vd (BIW bortezomib 1.3 mg/m2 and QIW dexamethasone 20 mg). Patients previously treated with a PI must have had at least a partial response (PR) to the PI and 6 months since the last PI regimen. The study primary end point was PFS. Here we report subgroup analysis of treatment outcomes based on prior PI treatment. Results Subgroups consisted of PI naïve patients (n=95; 24%) and patients with prior PI treatment (n=307; 76%). Both the subgroups and study arms were comparable for baseline patient demographic and disease characteristics. However, those with prior PI treatment more frequently had a previous stem cell transplant (38% vs 24%) or 3 lines of prior anti MM therapy (21% vs 13%). Median PFS was improved with SVd compared with Vd in both the PI naïve group (PFS not reached (NR) vs 9.7 months; HR 0.2585 [95% CI, 0.1116-0.5988]; P=0.0003) and in the PI treated group (11.7 vs 9.4 months; HR 0.7839 [95% CI, 0.5791-1.0612]; P=0.06). Other efficacy endpoints are shown in the table. Peripheral neuropathy ≥grade 2 (a secondary study endpoint) was less frequent in the SVd compared with the Vd arm (PI naïve: 25.5%, Vd 43.8%, P=0.0302; PI treated: SVd 19.6%, Vd 31.4%, P=0.0092). Adverse events of ≥grade 3 occurred in 71% of patients in the PI naïve group (SVd 77%, Vd 65%) and 74% of patients in the PI treated group (SVd 88%, Vd 60%). Thrombocytopenia was more frequent in patients in the SVd arms (PI naïve: SVd 32%, Vd 13%; PI treated: SVd 42%, Vd 19%) as was anemia (PI naïve: SVd 15%, Vd 6%; PI treated: SVd 16%, Vd 12%), and fatigue (PI naïve: SVd 15%, Vd 2%; PI treated: SVd 13%, Vd 1%). Conclusions The once-weekly SVd combination was associated with significant clinical benefit and reduced peripheral neuropathy as compared with standard twice-weekly Vd in patients with MM and 1-3 prior therapies, regardless of prior therapy with a PI. However, the benefits of SVd over Vd were more pronounced in patients who had never been treated with a PI (PFS HR 0.26), suggesting that selinexor could be an optimal partner for combining with weekly bortezomib as the first PI-containing MM regimen. Figure 1 Disclosures Mateos: Roche: Honoraria; Seattle Genetics: Honoraria; EDO Mundipharma: Honoraria; Adaptive Biotechnologies: Honoraria; GlaxoSmithKline: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Auner:Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Leleu:AbbVie: Honoraria; GSK: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Oncopeptide: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria. Hajek:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Delimpasi:GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Kryachok:Janssen, Bayer, Karyopharm, MSD, Acerta, AvbbVie, Debiopharm: Research Funding; Takeda, Janssen: Consultancy; Takeda, MSD, AbbVie, Ro: Other: Travel, accommodations, expenses; Takeda, Janssen, Novartis, Roche, MSD, Bayer: Consultancy, Research Funding. Sinha:Dr Reddys Lab, Intas Pharmaceuticals, Karyopharm Therapeutics: Honoraria. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Quach:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Moreau:Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Honoraria. Levy:Karyopharm,Takeda, BMS: Consultancy, Honoraria, Speakers Bureau. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Anderson:Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Bahlis:Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Chai:Karyopharm Therapeutics Inc: Current Employment. Arazy:Karyopharm Therapeutics Inc.: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Background: With advances in therapy, outcomes have generally improved for pts with MM; however, pts with late-stage RRMM have limited treatment options and poor outcomes (Kumar et al. Leukemia. 2017;31:2443; Gandhi et al. Leukemia. 2019;33:2266). Pts with late-stage RRMM, often older and having comorbidities, require efficacious and tolerable therapies to maintain HRQoL (Richardson et al. Blood. 2019;134[suppl 1]:3487). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the pivotal, phase 2, HORIZON study (NCT02963493) melflufen plus dex showed an overall response rate of 29%, median progression-free survival of 4.2 months, median overall survival of 11.6 months, and a manageable safety profile (N=157; Richardson et al. EHA 2020. Abs EP945). A previous baseline (BL) HRQoL analysis concluded that the HORIZON population is representative of RRMM populations, with a poor overall HRQoL relative to other populations with advanced cancers (Richardson et al. ASH 2019. Abs 3487). This analysis evaluates HRQoL in pts with RRMM throughout treatment with melflufen plus dex in the HORIZON study. Methods: Eligible pts received melflufen 40 mg on d1 of each 28-day cycle plus dex 40 mg/wk (20 mg in pts aged ≥75 y). HRQoL was added as a secondary endpoint as an amendment to the HORIZON protocol, which allowed collection of data from a subset of pts using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 V.3 (EORTC QLQ-C30) and the EuroQOL 5 Dimension-3 Level (EQ-5D) questionnaires. EORTC QLC-C30 evaluates functional domains and symptoms on a scale from 0-100 (higher functional scores = better function; higher symptom scores = more symptomatology/problems). The EQ-5D index is evaluated on a scale from 0 (death) to 1 (perfect health) and the EQ-5D VAS is evaluated on a scale from 0 (death) to 100 (perfect health). Questionnaires were administered before dosing at BL (cycle [C] 1) and predose at intervals throughout the study. Descriptive data for pts with post-BL assessments at C2, C4, and C6 are presented herein. Pts with only BL questionnaire assessments were excluded from this analysis. Select EORTC QLQ-C30 and EQ-5D results are presented. This analysis is ongoing. Results: At HRQoL data cutoff (May 28, 2020), of the 64 pts with post-BL HRQoL assessments, 19 remained on therapy. Among 64 pts in the HRQoL subgroup, median age was 67 y (range, 46-84); 17% had International Staging System stage 3 disease; and 36% had high-risk cytogenetics at study entry. Pts had received a median of 5 prior lines of therapy (range, 2-10). At C2, C4, and C6, 97.9%, 98.9%, and 99.4% of pts with ongoing treatment completed HRQoL assessments. Mean EORTC QLQ-C30 summary score and mean EQ-5D scores were relatively constant from BL through C6 (Figure). EORTC QLQ-C30 global health status/QoL and emotional functioning had mean scores of 58.6 and 78.4, respectively, at BL and 63.0 and 83.7, respectively, at C6 (Table). Mean symptom scores at BL and C6 for pain were 39.1 and 29.0, respectively, and for fatigue were 39.4 and 38.2, respectively. The EQ-5D VAS and EQ-5D index scores were generally consistent throughout treatment, with mean scores of 61.4 and 0.75, respectively, at BL and 62.3 and 0.74, respectively, at C6. Among pts with HRQoL data and the overall population (n=64 and N=157, respectively; Jan 14, 2020 data cutoff date), 92% and 89% had ≥1 grade 3/4 AEs, respectively; most common AEs were white blood cell count decreased (42% and 26%), thrombocytopenia (41% and 57%), and anemia (39% and 43%); most common nonhematologic grade 3/4 AEs was pneumonia (14% and 10%). SAEs occurred in 47% of pts in the HRQoL group and 49% of patients overall, most commonly pneumonia (14% and 9%); there were no treatment-related deaths. Conclusion: The EORTC QLQ-C30 global health status/QoL score and EQ-5D VAS and index scores were consistent from BL throughout treatment, suggesting that melflufen plus dex preserves HRQoL in pts with RRMM. The safety profile of melflufen plus dex consisted primarily of clinically manageable hematologic AEs in the overall pt population. No new safety signals were observed in the HRQoL-evaluable population. These findings are encouraging as treatment-related AEs may negatively affect HRQoL in RRMM. Data should be interpreted with caution due to the attrition of pts over time. Disclosures Oriol: Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Mateos:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; GSK: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cavo:GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodríguez-Otero:Abbvie: Consultancy; Kite: Consultancy; Amgen: Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Oncopeptides: Consultancy; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company. Nadeem:Adaptive: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Touzeau:Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Honoraria, Research Funding. Amor:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Maisel:Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Mazumder:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; THE BINDING SITE: Consultancy, Honoraria. Strang:Karolinska Institutet: Current Employment; Oncopeptides: Consultancy. Sandberg:Novo Nordisk AS: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Oncopeptides AB: Current Employment. Jaques:Pfizer: Consultancy; Morphosys AG: Consultancy; Oncopeptides: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pharma Biotech Consultants: Consultancy; Oncopeptides: Ended employment in the past 24 months. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Orre:Oncopeptides: Current Employment. Leleu:GSK: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; BMS-celgene: Honoraria. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM.

Introduction Selinexor is a first-in-class, oral, potent selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, leading to cancer cell apoptosis. Selinexor has demonstrated antimyeloma activity in triple class refractory multiple myeloma (MM) [Chari et al. NEJM 2019]. Selinexor synergizes with proteasome inhibitors (PIs) in PI-sensitive and -resistant cell lines and produces high response rates in patients with PI refractory and non-refractory MM. (Bahlis et al. Blood 2018). In the phase 3 BOSTON study, the combination of once weekly (QW) selinexor, QW bortezomib and dexamethasone (SVd) in patients who had received 1-3 prior therapies led to a significantly (47%) longer median progression-free survival (PFS) of 13.93 versus 9.46 months (HR 0.70; P=0.0075) compared to standard twice weekly bortezomib and dexamethasone (Vd). In addition, SVd regimen produced higher response rates and deeper responses (ORR: 76.4% vs 62.3% and ≥CR 16.9% vs 10.2%) compared with Vd. The benefit with SVd was observed across all efficacy endpoints and was associated with lower incidence and severity of bortezomib-induced peripheral neuropathy. Here we present subgroup analyses according to number of prior lines of therapy and prior treatment with lenalidomide (LEN). Methods BOSTON is an open-label, randomized phase 3 study in patients with MM comparing SVd (QW selinexor 100 mg, QW subcutaneous bortezomib 1.3 mg/m2, and 20 mg twice weekly [BIW] dexamethasone), versus Vd (1.3 mg/m2 bortezomib BIW and dexamethasone 20 mg 4 x weekly [QIW]). Patients previously treated with a PI must have had at least a partial response (PR) to the PI and 6 months since the last PI regimen. The study primary end point was PFS. Results Of the 402 patients in the BOSTON study, 198 (49%) had 1 prior line versus 204 (51%) with 2-3 prior lines. In addition, 154 (38%) comprised the LEN treated subgroup, versus 248 (62%) in the LEN naïve subgroup. Of note, 41% patients received prior thalidomide, which is consistent with most of the BOSTON study patients being treated in the EU. Baseline demographic and disease characteristics were well balanced between treatment arms across subgroups. A very good partial response (VGPR) or better to most recent prior line anti-MM therapy was more frequent in patients with 1 prior line of therapy (63% vs 41%) versus those with 2-3 prior lines of therapy. Patients with prior LEN therapy were more likely to have had 2-3 prior therapies (72.1%) compared with LEN naive patients (37.5%). As shown in the table, SVd was associated with longer PFS compared with Vd in all subgroups. Overall response rates (ORR) and times-to-next-treatment (TTNT) were statistically greater with SVd compared with Vd in all subgroups. Rates of very good partial response or better (VGPR) were statistically greater for SVd vs Vd in the LEN-naïve group and 1 prior treatment group. Grade ≥2 peripheral neuropathy (a key secondary endpoint prespecified in the study) occurred less frequently across all SVd subgroups compared with Vd: LEN treated (21% SVd, 37% Vd, P=0.0166); LEN-naïve (21% SVd, 33% Vd, P=0.0252), 1 prior line (21% SVd, 33% Vd, P=0.0501); 2-3 prior lines (21% SVd, 36% Vd, P=0.0107). Adverse events of ≥grade 3 were more commonly reported in the SVd treatment arm than in the Vd arm, LEN treated (83% SVd, 57% Vd), LEN-naïve (76% SVd, 55% Vd), 1 prior line (77% SVd, 56% Vd), 2-3 prior lines (81% SVd, 56% Vd), and were mostly managed with dose modification and/or supportive treatment. Pneumonia occurred at comparable rates between treatment arms. There were no differences between subgroups in grade 3 adverse events. Conclusions In the BOSTON study, once-weekly SVd significantly improved PFS, ORR, TTNT and reduced rates of ≥grade 2 peripheral neuropathy compared with Vd regardless of number of prior treatments or whether patients were previously treated with LEN. Adverse events were managed with dose modification and treatment-related discontinuation rates did not differ between the 2 regimens for any subgroup. The PFS of 16.6 months with SVd after 1 prior therapy, and the HR of 0.63 in patients with prior LEN treatment support the use of once-weekly SVd for the second line treatment of MM following a LEN-containing regimen. Table Disclosures Mateos: Takeda: Honoraria; Abbvie: Honoraria; GlaxoSmithKline: Honoraria; EDO Mundipharma: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Jagannath:Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria. Delimpasi:GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Kryachok:Takeda, Janssen, Novartis, Roche, MSD, Bayer: Consultancy, Research Funding; Janssen, Bayer, Karyopharm, MSD, Acerta, AvbbVie, Debiopharm: Research Funding; Takeda, MSD, AbbVie, Ro: Other: Travel, accommodations, expenses; Takeda, Janssen: Consultancy. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Auner:Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Leleu:BMS-celgene: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria. Sinha:Dr Reddys Lab, Intas Pharmaceuticals, Karyopharm Therapeutics: Honoraria. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Quach:Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Moreau:Novartis: Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Levy:Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment; Takeda: Consultancy, Honoraria, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Anderson:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Bahlis:Genentech: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Chai:Karyopharm Therapeutics Inc: Current Employment. Arazy:Karyopharm Therapeutics Inc.: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs >75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients >75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

IF 15.132 (2017); International audience; The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (

Proteasome inhibitors bortezomib, carfilzomib and ixazomib (approved by the US Food and Drug Administration [FDA]) induce remissions in patients with multiple myeloma (MM), but most patients eventually become resistant. MM and other hematologic malignancies express ubiquitous constitutive proteasomes and lymphoid tissue–specific immunoproteasomes; immunoproteasome expression is increased in resistant patients. Immunoproteasomes contain 3 distinct pairs of active sites, β5i, β1i, and β2i, which are different from their constitutive β5c, β1c, and β2c counterparts. Bortezomib and carfilzomib block β5c and β5i sites. We report here that pharmacologically relevant concentrations of β5i-specific inhibitor ONX-0914 show cytotoxicity in MM cell lines similar to that of carfilzomib and bortezomib. In addition, increasing immunoproteasome expression by interferon-γ increases sensitivity to ONX-0914 but not to carfilzomib. LU-102, an inhibitor of β2 sites, dramatically sensitizes MM cell lines and primary cells to ONX-0914. ONX-0914 synergizes with all FDA-approved proteasome inhibitors in MM in vitro and in vivo. Thus, immunoproteasome inhibitors, currently in clinical trials for the treatment of autoimmune diseases, should also be considered for the treatment of MM.

The treatment landscape for multiple myeloma has been transformed by the introduction of novel agents, including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. These have been shown to be more effective and generally better tolerated than conventional chemotherapy, with their introduction into clinical practice leading to improved survival. Furthermore, a better understanding of disease biology, improved diagnostic criteria, and the development of sensitive and specific tools for disease prognostication have contributed to better outcome. Treatment in the younger patient can now be individualized based on host and disease features with enhanced monitoring of response and use of high-sensitivity techniques for evaluating residual disease. The current standard of care has been significantly enhanced by novel agents with a paradigm shift toward optional or delayed autologous stem cell transplant as a reasonable choice in selected patients. Conversely, extended treatment with induction of remission followed by maintenance strategies is now a standard of care, conferring prolonged disease control with more manageable toxicities in both the short and long term, as well as improved quality of life.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; P = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.

Introduction: Treatment of relapsed and refractory multiple myeloma (RRMM) continues to evolve as most patients are lenalidomide (LEN) refractory at the time of first relapse with its widespread use in both induction and maintenance therapy. Pomalidomide, bortezomib and dexamethasone in RRMM has demonstrated significant activity and improvement in progression-free survival in LEN-refractory patients (Richardson et al Lancet Oncol 2019 Jun;20(6):781-794). Ixazomib is a novel oral proteasome inhibitor (PI) that is currently approved in combination with LEN and dexamethasone in RRMM. Ixazomib is administered on a once weekly schedule and its oral route of administration is particularly attractive, not least in the context of the current COVID-19 pandemic. Twice weekly dosing of ixazomib has been studied in combination with LEN demonstrating promising activity in NDMM (Richardson et al, Br J Haematol. 2018 Jul;182(2):231-244). Moreover, safety and efficacy has been shown in RRMM as twice weekly monotherapy on this schedule (Richardson et al, Blood 2014 Aug 14;124(7):1038-46). We hypothesized that a twice weekly ixazomib schedule in combination with pomalidomide and dexamethasone will lead to enhanced efficacy and comparable safety in RRMM. Methods: This is a phase I/II multicenter, single-arm, open label study evaluating the combination of twice weekly ixazomib with pomalidomide and dexamethasone in RRMM. Primary objective for phase I portion is to determine safety and the maximum tolerated dose (MTD) of this combination using a standard 3+3 dose escalation design. Ixazomib is studied at doses of 3mg or 4mg on days 1, 4, 8, 11, pomalidomide at a dose of 2mg, 3mg and 4mg on days 1-14 and dexamethasone is administered at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21 day cycle (Table 1). Patients were included if they received 2 prior lines of therapy, but 1 prior line was allowed if first line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy. Patients who received prior ixazomib were excluded. Results: At the time of data cutoff, 12 patients have been enrolled across cohorts 0, 1 and 2 and enrollment in the final cohort 3 is ongoing. Median age at the time of enrollment was 70 years old with slight male predominance (58%). ISS stage at diagnosis was II or greater in 75% of patients and 9 out of 12 (75%) patients had high-risk FISH as follows: del 17p (17%), gain 1q (50%), and t(4;14) (8%). Median prior lines of therapy was 2 (range 1-3) with 100% of patients having prior treatment with lenalidomide and 92% with prior bortezomib. Forty-two percent of patients had a prior autologous stem cell transplant. Most common treatment-related toxicities were mainly low grade and included neutropenia (58%), hyperglycemia (42%), fatigue (33%), anemia (25%), thrombocytopenia (25%), and rash (25%). Grade 3 or greater toxicities included neutropenia (17%), anemia (8%), bacterial lung infection (8%), and atrial fibrillation (8%). There was 1 dose limiting toxicity (DLT) in cohort 2 due to lung infection necessitating a delay in initiation of cycle 2 and no further DLTs have been noted. Dose reductions occurred in 4 patients and predominantly involved dexamethasone due to weight gain, insomnia, atrial fibrillation and fatigue. There have been no discontinuations due to toxicity and no treatment related mortality at the time of data cutoff. In response evaluable patients, 5 out of 12 patients have demonstrated a partial response or better (42%), with 1 very good partial response (VGPR) and all patients at least achieving stable disease. Conclusions: Twice weekly ixazomib in combination with pomalidomide and dexamethasone is a generally well-tolerated regimen with promising early activity in a high-risk RRMM cohort. Maximal tolerated dose and recommend phase II dose has not yet been reached and this study continues to accrue robustly, reflecting in part the convenience and safety of an all oral approach in the current era of COVID-19. Moreover, the ability to perform remote laboratory testing, telemedicine visits and to send medications directly to patients has been an additional value-add to this trial. Updated data will be presented at the meeting. Disclosures Nadeem: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Mo:Celgene: Membership on an entity's Board of Directors or advisory committees. Barth:Sanofi: Membership on an entity's Board of Directors or advisory committees. Sanchorawala:Takeda: Research Funding; Celgene: Research Funding; Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Janssen: Research Funding. Munshi:BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Ghobrial:Celgene: Consultancy, Honoraria; GlaxoSmithKline: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Noxxon Pharma: Consultancy; Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Cellectar: Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GNS Healthcare: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Anderson:Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ∼30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors.

Background: Pomalidomide (POM) is an established agent in relapsed/refractory (R/R) multiple myeloma (MM) with direct cytotoxicity against MM cells and immunostimulatory activities in multiple cell types including T cells and NK cells. CC-92480 is a novel Aiolos/Ikaros degrading cereblon E3 ligase modulator (CELMoD ®) agent is currently being investigated in combination with the proteasome inhibitor (PI) bortezomib (BTZ) and corticosteroid dexamethasone (DEX), or with DEX only in R/R MM (CC-92480-MM-002 and CC-92480-MM-001). Previous results indicate that triplet combination of POM/BTZ/DEX may enhance some T, B and NK cell subpopulations, overcoming immunosuppression when compared to BTZ/DEX-only treated patients (Rao et al, 2019). Mechanisms of action (MOA) of CC-92480- and POM-mediated substrate depletion occurs via ubiquitination and proteasome degradation, where BTZ has been speculated as potentially antagonistic as a PI. Here, we report pre-clinical and clinical observations of an immune MOA of CC-92480 or POM in combination with BTZ. Results: To mimic the clinical pharmacokinetics, BTZ was utilized as a high-dose pulse method alone and in combination with POM or CC-92480, followed by flow cytometric measurements of Aiolos and Ikaros protein abundance in healthy donor (HD) T cells. The addition of BTZ modestly delayed CRBN-dependent substrate depletion compared to single agent POM or CC-92480; however, this effect was only apparent at early time points (1-6 hr) where the effect was negligible by 24 hr. To understand the functional implications of BTZ combination, we conducted CD3-stimulated PBMC-mediated cytotoxicity assay against H929 MM target cells in a co-culture model. The efficiency of POM or CC-92480 induced PBMC-mediated killing in a dose dependent manner (~65% increase compared to DMSO) were similar at a 100-fold lower dose range of CC-92480 compared to POM, with the effect not being altered by co-treatment with BTZ. These data were replicated with a POM or CC-92480 treated supernatant stimulation of purified NK cells co-culture, which induced an 80% reduction in target cell viability with the BTZ combination having no negative effects on CELMoD-mediated activity. Cytokine analysis on PBMC supernatants treated with either POM or CC-92480 in the absence or presence of BTZ-pulse showed a dose-dependent increase in IL-2 (>2.4-fold) and Granzyme B (>3.1-fold), which were not impacted by BTZ co-treatment. As a secondary readout on activation status, we measured multiple signaling molecules and activation markers on the cell surface of T and NK cell subsets in CD3 stimulated HD PBMCs treated with dose-dependent POM or CC-92480 with or without co-treatment of BTZ. Compared to DMSO controls, elevated expression levels of CD25 (IL2RA), CD278 (ICOS), Granzyme B, CD134 (OX40R) and HLA-DR were observed with both POM and CC-92480 on CD4, CD8 and NK cells demonstrating a CELMoD-mediated increase in immune activation. These effects were not impacted by the co-treatment of BTZ. Examination of peripheral blood samples from MM patients enrolled in the CC-92480-MM-001/002 (NCT03374085/NCT03989414) clinical trials revealed that CC-92480 promoted potent immunomodulation when administered in combination with DEX and with BTZ/DEX. These data included increased numbers of activated and central memory T cells, as well as increased Ki67+ proliferating T and NK cell populations compared to samples collected during the screening period before any drugs had been administered, consistent with earlier observation of POM in combination with BTZ/DEX treated patients. Conclusions: Taken together, these data demonstrate that POM and CC-92480 are potent immunomodulatory agents with enhanced induction of PBMC and NK mediated cell killing of MM tumor cells and activation of T and NK cells, at 100-fold lower concentrations of CC-92480 compared to POM. Additionally, we showed that combination with BTZ in preclinical assays and in the clinical setting did not antagonistically affect the immunostimulatory ability of POM or CC-92480. Disclosures Bjorklund: BMS: Current Employment, Current equity holder in publicly-traded company. Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Chiu: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Kang: BMS: Current equity holder in publicly-traded company. Civardi: Bristol Myers Squibb: Current Employment. Katz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Maciag: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hagner: BMS: Current Employment, Current equity holder in publicly-traded company. Pourdehnad: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: No royalty. Bahlis: Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Richardson: Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

Introduction : Despite recent advances, MM remains incurable and new therapeutic options are needed, particularly for pts with RRMM. IBER is a novel, potent oral cereblon E3 ligase modulator (CELMoD ®) compound with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory (IMiD ®) agents. Preclinically, IBER demonstrated marked synergy with DEX and with other standard myeloma treatments. CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating IBER with different treatment combinations in independent cohorts of pts with RRMM; in phase 1, the recommended phase 2 dose of IBER, when given in combination with DEX, was determined at 1.6 mg (Lonial S, et al. Blood 2019;134[suppl 1]:3119). Here we report results from the dose expansion of IBER + DEX in pts with heavily pretreated, triple-class exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) RRMM. Methods : Eligible pts had RRMM; had received ≥ 3 prior lines of therapy, including lenalidomide (LEN), pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb; had experienced disease progression within 60 days of last myeloma therapy; and were refractory to an IMiD agent, a PI, a glucocorticoid, and an anti-CD38 mAb. Pts with central nervous system involvement were not eligible. Pts who had received prior anti-BCMA therapy were excluded, but included in a supportive cohort for safety and preliminary efficacy assessment. IBER (1.6 mg) was given orally on days (D) 1-21, in combination with DEX (40 mg; 20 mg if > 75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. Thrombo-embolism prophylaxis was mandatory for all pts. Primary objective was to determine efficacy expressed as overall response rate (ORR). Secondary endpoints included additional efficacy and safety assessments. Exploratory endpoints included evaluation of health-related quality of life (HRQoL). Results : As of June 2, 2021, 107 pts had received IBER + DEX. Median age was 64 (44-83) years; median time since initial diagnosis was 6.9 (1.6-24.5) years. Extramedullary plasmacytomas were present in 25.2% of pts; 29.9% of pts had high-risk cytogenetics. Median number of prior regimens was 6 (3-23). All pts were triple-class exposed; prior therapies included autologous stem cell transplantation (78.5%), PIs (100%), IMiD agents (LEN [100%] and POM [100%]), and anti-CD38 mAbs (100%); 99.1% of pts were refractory to last myeloma regimen and 97.2% of pts were triple-class refractory. Median follow-up was 7.69 (0.5-17.5) months, with a median number of 4 (1-17) cycles received and 13 (12.1%) pts continuing treatment. Main reason for discontinuation was progressive disease (69.2%). ORR was 26.2%, with 1 (0.9%) stringent complete response, 8 (7.5%) very good partial responses, and 19 (17.8%) partial responses (Table); the clinical benefit rate (≥ minimal response) was 36.4% and disease control rate (≥ stable disease) was 79.4%. Median duration of response was 7.0 (4.5-11.3) months (Table), median progression-free survival was 3.0 (2.8-3.7) months, and median overall survival was 11.2 (9.0-not reached) months. Similar response rates were observed among a cohort of pts also exposed to BCMA therapies (N = 24, Table). Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 88 (82.2%) pts. Most frequent (≥ 20% pts) hematologic Gr 3-4 TEAEs were neutropenia (44.9%; and 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%). Gr 3-4 infections were reported in 27.1% of pts; Gr 3-4 pneumonia and COVID-19 occurred in 10.3% and 4.7% of pts, respectively. Occurrence of other Gr 3-4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.6%), fatigue (2.8%), rash (1.9%). Fifty-six (52.3%) pts and 20 (18.7%) had IBER dose interruptions and reductions due to TEAEs, respectively. Five (4.7%) pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. Conclusions : IBER + DEX demonstrated promising efficacy in pts with heavily pretreated, triple-class exposed and refractory RRMM, as well as in pts who had previously received anti-BCMA therapy; this combination was generally well tolerated and TEAEs were manageable with dose reductions and interruptions. These results support the further development of IBER in MM, including phase 3 trials in combination regimens. Figure 1 Figure 1. Disclosures Lonial: Abbvie: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Janssen and BMS: Other: travel expenses. Hulin: Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; abbvie: Honoraria. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson: Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; AbbVie: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Janssen: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Minnema: Cilag: Consultancy; Janssen: Consultancy; Alnylam: Consultancy; Celgene: Other: Travel expenses; Kite/Gilead: Consultancy; BMS: Consultancy. Badros: J&J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Stadtmauer: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chen: Bristol Myers Squibb: Current Employment. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amin: Bristol Myers Squibb: Current Employment. Kueenburg: Celgene a BMS company: Current Employment. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy.

Background: Clinical data support the combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). Recently, the GRIFFIN study evaluated the addition of the CD38 antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated improved efficacy with an acceptable safety profile. Isatuximab is a newer CD38 monoclonal antibody that binds to a specific epitope of the CD38 receptor. In addition to antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, isatuximab eliminates MM cells via direct apoptosis without the need for crosslinking. Isatuximab enhances immune function by boosting the activation and cytotoxic activity of natural killer cells and by depleting CD38+ immune suppressor cells such as regulatory T cells and inducing clonal expansion of T cells. Isatuximab is approved in combination with carfilzomib and dexamethasone for relapsed, refractory MM based on the results of the IKEMA study. The MANHATTAN study evaluated the 4-drug combination of daratumumab, lenalidomide, carfilzomib, and dexamethasone. The primary end point, minimal residual disease negativity was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%). Building upon these data, our study evaluates the addition of isatuximab to weekly carfilzomib, lenalidomide, and dexamethasone. Study Design and Methods: A phase II, open-label clinical trial is being conducted to evaluate the efficacy of once weekly carfilzomib, lenalidomide, dexamethasone, and isatuximab (Isa-KRd) in 50 patients with newly diagnosed, transplant-eligible MM (NCT04430894). Eligible patients will have NDMM, age ≥18 years, ECOG PS of 0-2, and are deemed eligible for stem cell transplantation (SCT). All patients will receive 4 cycles of induction therapy with Isa-KRd followed by stem cell collection with the option to either proceed to upfront SCT versus deferred SCT. Patients undergoing upfront SCT will receive 4 cycles of therapy followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy then maintenance. Patients deferring SCT following collection will receive 4 cycles of therapy followed by stem cell collection followed by 4 additional cycles of therapy then maintenance. Each 28-day cycle will consist of isatuximab 10 mg/kg IV Q1 week for 8 weeks, then Q2 weeks for 16 weeks, thereafter Q4 weeks; carfilzomib (20 mg/m 2 Day 1 only) 56 mg/m 2 IV on Days 1, 8, 15; lenalidomide 25 mg po on Days 1-21; and dexamethasone 20 mg po day of and day after all doses of carfilzomib (Days 1, 2, 8, 9, 15, and 16) and isatuximab (Cycles 1 and 2 Days 22 and 23). For maintenance, patients will be stratified based on cytogenetics (high-risk cytogenetics include deletion (del) 17p, translocation t(4:14), t(14;16), t(14;20)). Patients with standard-risk cytogenetics will receive lenalidomide 10 mg po Days 1-21. Patients with high-risk cytogenetics will receive carfilzomib 56 mg/m 2 Days 1, 15; lenalidomide 10 mg po Days 1-21; and isatuximab 10 mg/kg IV Day 1. Dexamethasone, 20 mg orally or IV will be administered to patients as a pre-infusion medication prior to isatuximab dosing. Main Outcomes and Measures: The primary end point is complete response (CR + stringent CR) rate after 4 cycles of Isa-KRd as assessed by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include determining safety and tolerability of Isa-KRd, minimal residual disease (MRD) after 4 cycles, at completion of consolidation (post-transplant) or induction (transplant-deferred), and sustained MRD at 24 months, progression-free survival, overall survival rates, and quality of life. Efficacy analysis will be performed both in the intent-to-treat (ITT) population and efficacy evaluable (EE) population. The ITT population will include all treated patients, and the EE population will include all patients who receive at least 1 cycle of study drug. The primary analysis will be based on the EE population, and will use the investigator-assessed response data evaluated according to consensus recommendations based on the IMWG criteria. CR (CR+sCR) rate after 4 cycles of Isa-KRd will be reported with 90% confidence interval. Support: Amgen and Sanofi Figure 1 Figure 1. Disclosures O'Donnell: Oncopeptide: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Mo: Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol Myer Squibb: Consultancy. Branagan: Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; CSL Behring: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

Background: Clinical data support the combination of an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). The combination of lenalidomide, bortezomib, and low-dose dexamethasone is a very active, well-tolerated standard of care in the transplant-ineligible NDMM population. Ixazomib, an oral proteasome inhibitor is approved by the US Food and Drug Administration in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Given that ixazomib has improved binding kinetics and pharmacologic profile compared with bortezomib, it is expected that these differences will translate into similar, if not improved, efficacy and safety profiles in the upfront setting. A phase l/ll study of lenalidomide, ixazomib, and dexamethasone in previously untreated patients with MM demonstrated that this combination was well-tolerated and active (NCT01217957). More recently, the GRIFFIN study evaluated the addition of the anti-CD38 monoclonal antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated the ability of daratumumab to improve efficacy of the three-drug combination with an acceptable safety profile. Building upon these data, our study evaluates the addition of daratumumab to the all-oral regimen of lenalidomide, ixazomib, and dexamethasone in transplant-ineligible NDMM. The combination proposed in this study has been evaluated in NDMM irrespective of transplant eligibility and has demonstrated excellent efficacy and tolerability. Responses were rapid with 88% achieving a partial response (PR) or better after 2 cycles (33% very good partial response (VGPR) and 52% VGPR for 29 patients who had completed 4 cycles) with an overall response rate of 95%. 1 In our study, transplant-ineligible NDMM patients will be randomized to receive 12 cycles of induction with lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide alone versus lenalidomide, ixazomib, and daratumumab. Study Design and Methods: A randomized, phase II clinical trial (NCT04009109) is being conducted to assess the impact on progression-free survival (PFS) of the addition of ixazomib and daratumumab to lenalidomide as maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab. In this ongoing trial, eligible patients are randomized 1:1 to Arm A (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy) vs. Arm B (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy). Eligible patients have NDMM requiring treatment, are ≥18 years, have ECOG PS of 0-2, and must have been deemed ineligible for stem cell transplantation. The primary endpoint is PFS. With a sample size of 188 patients (94 patients per arm) enrolled over a 36-month period and followed for a minimum of 24 months after the close of enrollment, a one-sided alpha=0.10 log rank test will have an 85% chance of detecting an increase in median PFS time from 30 months to 48 months (a hazard ratio of 0.625) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with ixazomib, lenalidomide, dexamethasone, and daratumumab. Secondary outcomes of interest include minimal residual disease, overall survival, changes in body composition, quality of life, psychosocial measures of functional status including social activity and support, psychological state, and nutrition using a geriatric assessment tool, and the association of these psychosocial measures with therapy-associated toxicities. 1Kapoor et al. Blood (2019) 134 (Supplement_1): 864. Support: Alliance Foundation Trials; Janssen, Takeda, Celgene; https://acknowledgments.alliancefound.org Figure 1 Figure 1. Disclosures O'Donnell: Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopeptide: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Bristol Myer Squibb: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Yee: Takeda: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; GSK: Consultancy. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

Introduction: Single-agent belantamab mafodotin (belamaf), a B-cell maturation antigen-targeting antibody-drug conjugate, achieved durable responses with a manageable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) in the Phase 2 DREAMM-2 trial (NCT03525678). The DREAMM-5 platform trial (208887; NCT04126200) is evaluating belamaf as combination therapy with other anticancer agents to determine if belamaf's unique multimodal mechanism of action (MoA) is synergistic with MoAs of selected agents to further augment efficacy in RRMM. In this substudy, belamaf is combined with feladilimab (GSK3359609), an inducible co-stimulatory T-cell molecule (ICOS, CD278) agonist (aICOS). Methods: DREAMM-5 is an ongoing Phase 1/2 platform trial. Each platform substudy consists of a dose-exploration (DE) phase to identify effective belamaf combinations followed by a cohort-expansion (CE) phase to compare the combination with a shared single-agent belamaf control arm. The primary and secondary objectives of the DE phase are to determine the safety/tolerability and preliminary efficacy, respectively, of the combination therapy as well as to establish the recommended Phase 2 dose (RP2D) for the CE phase based on these data. A preliminary analysis of safety, pharmacokinetic, biomarker, and efficacy data performed at the end of the DE phase will determine if it should move forward to the CE phase. This is a preliminary analysis of data from patients in the DE phase of the DREAMM-5 belantamab mafodotin and aICOS substudy. Patients are assigned to one of 3 belamaf + aICOS DE cohorts by a predetermined algorithm (N≤10 per cohort): belamaf (1.9 mg/kg or 2.5 mg/kg) + aICOS (8 mg) or belamaf (2.5 mg/kg) plus aICOS (24 mg). In cohort A, the starting dose of belamaf (1.9 mg/kg) and aICOS (8 mg) is administered to 3 patients, starting with a sentinel patient and expanding to the second and third patient consecutively over the course of at least 10 days. Cohort B (belamaf 2.5 mg/kg and aICOS 8 mg) and cohort C (belamaf 2.5 mg/kg and aICOS 24 mg) are only evaluated after the lower doses for each treatment clear the dose-limiting criteria for the first 3 patients. Results: A total of 23 patients treated with belamaf + aICOS were included in this preliminary analysis. The median (range) of prior lines of therapy was 5 (3-10). The majority of patients (21 [91%]) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 and the remainder (2 [9%]) had an ECOG PS of 2. Thirty percent of patients (n=7) had high-risk cytogenetics, and no patients had extramedullary disease. The preliminary overall clinical response rate for the total population was 48% (n=11; 95% CI: 26.8-69.4), with 26% of patients (n=6) achieving a very good partial response or better (Table). Nineteen patients (83%) of the total population experienced an adverse event (AE) related to study treatment and 12 patients (52%) experienced Grade ≥3 AEs related to study treatment. A total of 16 patients (70%) in the total population experienced any grade ocular AEs while 9 patients (39%) had Grade ≥3 ocular AEs related to study treatment. Only 2 patients (1 each from cohorts A and B) permanently discontinued study treatment due to AEs. Dose reductions and delays were used to manage AEs in several patients (Table). Conclusion: In this preliminary analysis, belamaf combined with aICOS showed encouraging clinical activity along with a safety profile that was manageable through dose modifications in heavily pretreated patients with RRMM. Evaluating the efficacy and safety of belamaf + aICOS combination therapy as well as establishing the RP2D for the CE phase is ongoing in this substudy. Funding: GSK (Study 208887); belamaf drug linker technology licensed from Seagen; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure 1 Figure 1. Disclosures Ribrag: Nanostring: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Epizyme: Honoraria, Research Funding. Richardson: Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Secura Bio: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Nooka: Amgen: Consultancy, Research Funding; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Oncology: Consultancy, Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Other: Travel expenses; Oncopeptides: Consultancy. Song: GlaxoSmithKline: Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Minnema: BMS: Honoraria; Jansen-Cilag: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy; Celgene: Other: Hospitality. Weisel: Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ballas: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Li: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ratia: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Kaisermann: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Holkova: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Trudel: Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Genentech: Research Funding; Amgen Canada: Honoraria; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Introduction : Daratumumab (Dara) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with Dara in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. We present results of our phase II, single arm study of Dara in HR-MGUS and LR-SMM. Methods : Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as 1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio 8. Dara (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results : At the time of data cutoff, a total of 42 patients were enrolled on this study from 2018 to 2020 with participation of 5 sites. The median age for all patients at enrolment was 60 years (range 38 to 76), with 22 males (52.4%) and 20 females (47.6%). Majority of patients enrolled were classified as LR-SMM (n = 37, 88.1%) and the remaining 5 patients had HR-MGUS (11.9%). 41 patients have started treatment and are included in toxicity assessment, and 40 patients have at least completed 16 cycles (range 6-20). Grade 3 toxicities were rare and only experienced in 5/41 patients including diarrhea (n =1/41; 2%), flu like symptoms (n = 1/41; 2%), headache (n=1/41; 2%), and hypertension (n=2/41; 5%). Most common toxicities of any grade included fatigue (n = 24/41, 51%), cough (n = 19/41, 46%), nasal congestion (n = 18/41, 44%), headache (n = 14/41, 34%), hypertension (n = 11/41, 27%), nausea (n = 13/41, 32%), and leukopenia (n = 13/41, 32%). No patients have discontinued therapy due to toxicity. Minimal response or better was observed in 82.9% of patients (34/41) and PR or better was observed in 51.2% of patients (21/41). This included overall CR (n = 4, 9.8%), VGPR (n = 1, 2.4%), PR (n = 16, 39.0%), MR (n = 13, 31.7%), and SD (n = 7, 17.1%). In the 40 patients who completed at least 16 cycles, response rates were as follows: MR or better 85% (34/40), PR or better 52.5% (21/40) and VGPR or better 12.5% (5/40). Median time to VGPR was 7 months. Median overall survival and progression-free survival have not been reached and no patients have progressed to overt multiple myeloma while on study. Conclusion : Dara is very well tolerated among patients with HR-MGUS and LR-SMM with minimal toxicities. Responses are seen in majority of patients. Early therapeutic intervention in this precursor patient population appears promising but longer follow up is required to define the role of single agent Dara in preventing progression to MM, therefore avoiding more toxic interventions in this low-risk patient population. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Zonder: Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Intellia: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy. Rosenblatt: Attivare Therapeutics: Consultancy; Imaging Endpoints: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Wolters Kluwer Health: Consultancy, Patents & Royalties. Mo: AbbVIE: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sperling: Adaptive: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Background: Despite many treatment options, multiple myeloma (MM) remains largely incurable with poor outcomes among patients who progress after treatment with a protease inhibitor, immunomodulatory imide drugs (IMiDs), and/or an anti-CD38 antibody. Multiple targeted therapies have been developed for different subtypes of non-Hodgkin lymphoma (NHL); however, these therapies are typically not curative for patients with relapsed/refractory (R/R) disease. IMiDs are a standard of care for treatment of MM and have shown activity in some NHL subtypes. However, given that many patients treated with these agents frequently develop disease progression, an unmet need remains. CFT7455 is a next-generation IKZF1/3 degrader, which is more potent and catalytically active than other approved agents targeting the cereblon E3 ligase complex that degrade IKZF1/3. CFT7455 is orally bioavailable and selective for IKZF1 (Ikaros) and IKZF3 (Aiolos). Depletion of these targets from malignant B cells result in tumor cell death, and depletion from the tumor microenvironment results in T-cell activation. In i n vitro and in vivo models of MM and NHL, including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma (MCL), CFT7455 demonstrated greater activity than other agents in similar classes. These results provided rationale for a first-in-human, phase 1 study to evaluate CFT7455. Study Design: This is an open-label, multicenter, phase 1 clinical trial with dose escalation and dose expansion phases. The dose escalation phase, beginning with a starting dose of 50 mcg daily, may include single-participant cohorts at initial dose levels, after which 3-6 patients are enrolled per cohort using a Bayesian logistic regression model. After initial exploration of single-agent CFT7455 in a mixed cohort of patients with R/R MM or select NHLs, dose escalation is split to perform dose determination in R/R MM separate NHL. Once a safe dose of CFT7455 in R/R MM is determined, the combination of CFT7455 with dexamethasone will be explored in R/R MM. CFT7455 is dosed orally in 28-day cycles, on a 21-day on, 7-day off schedule, until disease progression or intolerable toxicity. Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned. Primary objectives include: safety and tolerability, randomized phase 2 dose (RP2D)/maximum tolerated dose (MTD) of CFT7455, and estimation of antitumor activity of CFT7455. Secondary objectives include assessment of pharmacokinetics. Exploratory objectives include characterization of target engagement and IKZF1/3 degradation and assessing the immunomodulatory effects of CFT7455. For MM patients, key inclusion criteria include histologically/cytologically-confirmed MM that is R/R. Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Plasma cell leukemia is excluded. For NHL patients, key inclusion criteria include histologically/cytologically-confirmed NHL that is R/R. Patients mustn't be candidates for regimens known to provide clinical benefit, defined as the requisite prior lines of therapy according to an indication-specific basis. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Several lymphoma subtypes less likely to benefit are excluded (eg, Richter transformation, Burkitt lymphoma, Sezary syndrome, and lymphoblastic lymphoma). Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726, enrollment is ongoing. Disclosures Berdeja: Legend Biotech: Consultancy; Incyte: Research Funding; Ichnos Sciences: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Lilly: Research Funding; SecuraBio: Consultancy; EMD Serono: Research Funding; Janssen: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Astex Pharmaceuticals: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Takeda: Consultancy. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Xencor: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy; Medimmune: Research Funding. Horwitz: Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Tubulis: Consultancy; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Vividion Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Celgene: Research Funding; Acrotech Biopharma: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Shoreline Biosciences, Inc.: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Verastem: Research Funding. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Martin: GlaxoSmithKline: Consultancy; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; Janssen: Research Funding. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Richard: Karyopharm, Janssen: Honoraria. Bhutani: Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Yee: Takeda: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Palmer: C4 Therapeutics: Current Employment. Gorman: C4 Therapeutics: Current Employment. Schoenborn-Kellenberger: C4 Therapeutics: Current Employment. Bilic: C4 Therapeutics: Current Employment. Crystal: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mahler: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lonial: Merck: Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding.

Introduction: Despite the availability of many effective agents, multiple myeloma is characterized by repeated cycles of treatment response and relapse, and remains incurable in almost all patients. Efforts to optimize treatment are complicated by variation in disease biology and by the combinatorial complexity inherent in assembling, sequencing and administering multi-agent regimens. Determining which strategies provide maximal therapeutic benefit requires deploying a variety of multi-agent regimens in a range of settings and assessing long-term outcomes; information that cannot be readily discerned from clinical trials. Here we present results from a real-world database that comprehensively tracks all treatments and responses in patients with multiple myeloma. Methods: Since March 2017, All4Cure has hosted an online platform for patients with multiple myeloma, clinicians and researchers that has been initially focused in the Pacific Northwest. Medical records from consenting patients are collected and information regarding all treatments and responses graphically displayed on their de-identified dashboards. A discussion panel allows for asynchronous communication between members of All4Cure's community of patients, clinicians and researchers (currently numbering over 1600 participants). There is no charge to patients who participate in All4Cure, and clinicians and researchers are neither charged nor paid for their participation. A summarized real-world database describes the lines of therapy that each patient has received, treatment start and stop dates, and responses in accordance with International Myeloma Working Group (IMWG) criteria. Results: The overall profile of patients with multiple myeloma enrolled in All4Cure (N=555) was benchmarked against myeloma patients from the National Program of Cancer Registries (NPCR) (diagnosis year 2017; N=25,895). Patients in all 50 States and D.C. were included in the comparison, and those with monoclonal gammopathy of undetermined significance (MGUS) were not considered. Myeloma patients enrolled in All4Cure are younger at diagnosis or start of treatment (median 61 versus between 65 and 69), more likely to be white (90.3% versus 73.5%), and more likely to reside in Washington State (41.2% versus 2%) compared to the NPCR cohort, reflecting participation influenced by geographic location as described above. After enrollment, All4Cure patients are followed longitudinally throughout the entirety of their disease course, with fewer than 2% having been lost to follow up. To gain insights uniquely available from the All4Cure database and to inform the future direction for our research, we focus our exploratory data analysis on the All4Cure cohort of patients who started treatment in June 2015 or later (N=299). Despite the relatively recent start of the All4Cure database, this timeframe allows up to 6 years of observation following the start of treatment, since the survival rates for the first 1-2 years of treatment are generally very high. Consistent with prior knowledge, increasing age and disease stage are associated with increased morality, as are high-risk cytogenetics such as 17p-, t(4:14) and t(14;16). We further explored the potential impact of early lines of therapy on long-term disease control. While the current literature is mixed on the merits of aggressive treatments in early lines of therapy in terms of overall survival, insights from our data suggest that more aggressive front-line therapies (such as SCT) are associated with improved disease control over time, although this is evolving with the impact of novel therapies and in particular the use of triplet and now quadruplet induction regimens and adapting treatment to achieve measurable residual disease (MRD) negativity. Conclusions: Even with the current limitations regarding the size and representativeness of All4Cure's database, these preliminary results support the validity of this approach for gaining insight into the treatments and outcomes of patients with multiple myeloma in real-world settings. Disclosures Blau: Oncopeptides: Other: Oncopeptides is an All4Cure customer. Blau: All4Cure: Current equity holder in publicly-traded company. Richter: Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment; Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Richardson: Secura Bio: Consultancy; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit based on previous studies that included treatment with lenalidomide or lenalidomide and dexamethasone (Mateos et al. N Engl J Med 2013; Lonial et al. J Clin Oncol 2020). Combination therapy with triplets has shown higher rates of deep response and improved outcomes in patients with multiple myeloma, including the combination of ixazomib, lenalidomide, and dexamethasone (Moreau et al. N Eng J Med 2016). We present our results of phase II study of ixazomib, lenalidomide and dexamethasone in HR-SMM. Methods: Patients enrolled on the study met eligibility for high-risk SMM based on the defined criteria proposed by Rajkumar et al. (Blood 2014). The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle was defined as 28 consecutive days for a total of 24 months period. Bone marrow samples of all patients were obtained before starting therapy for baseline assessment for minimal residual disease (MRD) testing, whole-exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle for isolating cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Results: Sixty-one patients have been enrolled in this study from February 2017 to 2020. The median age of the patients at enrollment was 64 years (range, 40 to 84), with 33 males (54.1%). The analysis was conducted on patients who have completed at least 2 cycles of therapy (n=55). Thus far, 42 (69%) patients have completed the planned 24 cycles of therapy. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 14 patients out of the 33 evaluable (42.4%) Interphase fluorescence in situ hybridization (iFISH) results. The median number of cycles completed was 24 cycles (range: 2-24). According to the new IMWG risk stratification model (20-2-20), baseline markers showed that 32 patients (58%) were high risk, 18 (33%) were intermediate risk, and 5 (9%) were low risk. The most common grades 3 or greater toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%). Stem cells were collected from all eligible patients by the end of the induction phase. No patients discontinued treatment due to toxicity. At the time of data cut off, the overall response rate (partial response or better) in participants who completed at least 2 cycles of treatment was 90.9% (50 of 55), with 12 complete responses (CR, 21.8%), 10 very good partial responses (VGPR, 18.2%), 28 partial responses (50.9%), and 4 minimal responses (MR, 7.3%). ORR in patients who completed the induction phase (≥9 cycles) was 92.3% (n= 48 of 52), with 22 (40%) deep remissions including 12 (23.1%) and 10 (19.2%) having achieved a CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. No patients developed progression to overt or active MM while on study therapy. After completion of study therapy, 4 patients progressed to active MM during follow up, 3 additional patients developed biochemical progression and started a new course of therapy but did not meet CRAB criteria and 7 patients confirmed biochemical PD and remain off therapy. Conclusions: The combination of ixazomib, lenalidomide, and dexamethasone is an effective all oral well-tolerated intervention in high-risk smoldering myeloma that demonstrated an ORR of >90% and deep remission in >40% of patients. While no patients progressed to overt MM while on therapy, some developed progression after completion of planned study therapy, indicating the possible need for higher intensification of therapy or maintenance therapy beyond 2 years in this high-risk group of patients. Longer follow-up for disease outcome is ongoing. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AstraZeneca: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Background Focal amplifications and rearrangements drive tumor growth and evolution in cancer. Focally amplified regions often involve the juxtaposition of rearranged segments of DNA from distinct chromosomal loci into a single amplified region and nearly half of these regions can be explained by circular, extrachromosomal DNA (ecDNA) formation. Cancer-associated ecDNA shows a unique circular placing ecDNA at the interface of cancer genomics and epigenetics. As formation of ecDNA represents a manifestation of genomic instability, we have investigated presence and prognostic impact of ecDNA in multiple myeloma (MM). Methods Whole genome (WGS) and transcriptome (RNAseq) sequencing data from CD138 purified MM cells from 191 uniformly-treated newly diagnosed MM patients were used for this analysis. Copy number variants (CNV), single nucleotide variants (SNV) and structural variants (SV) were identified on all WGS samples using Facets, Mutect2 and Manta. Seed data from these CNV results was passed to the AmpliconArchitect tool to determine presence of focally amplified and rearranged segments of DNA. Seed CNV thresholds were set for a minimum CNV size of 100kb and a copy number of equal or greater to 5. Extrachromosomal calls were then annotated using the Amplicon Classifier to determine the presence of ecDNA. Multivariate survival analysis was performed after segregating samples into the conventional myeloma risk classifications including translocations, copy number alterations, ISS, age and mutations associated with risk. Differential expression analysis was performed on transcriptomic data using DEseq2. Results We identified 6.8% of the newly diagnosed patients with ecDNA, 12.5% with complex non-cyclic DNA amplifications and 10.1% with linear amplifications. ecDNA and complex events were targeting MM dependent genes, including MYC/PVT1, IRF4 as well as known driver genes such as CDYL and TRAF2. We further evaluated association between ecDNA, complex rearrangements, linear amplification and patients with none of these amplification types and found that patients with ecDNA had significantly poor PFS (median PFS 22 months vs. 41 months) and OS (median OS 41 months vs. 105 months). Patients having ecDNA in their MM cells did not show any significant enrichment for known translocations, double hit or TP53 mutations. In a multivariate model including ecDNA and all other known MM risk features, ecDNA was found to be an independent predictor of progression free survival.(HR 2.6, CI: 1.26 -5.6, p=0.0082) and overall survival (HR 7.94 CI:3.5-17.9 p < 0.0001). Patients with ecDNA have higher mutational load probability(8798 vs 6982, effect size = 0.64 , probability is 91.1). However, this was not reflected in heterogeneity by using MATH score. We found that patients with ecDNA are likely to have BRAF mutations (OR= 25.07 [2.57 - 330 95% CI], p value = 0.002), however overall RAS/RAF pathway mutations were similar to other patients. Patients with ecDNA showed fragile DNA with more breaks (median segments 197 vs. 125.5, p value = 0.001). Although ecDNA is defined as copy number gain with fragments having 5 or more copies, overall genomic gain between ecDNA and other patients were similar. However, overall genomic loss in patients with ecDNA were higher than others (7% vs. 4.2%, p = 0.06). By differential gene expression analysis we noted 98 differentially expressed genes in MM cells with ecDNA. The downregulated geneset involved pathways responsible for cell death as well as the RAS pathway. Interestingly, CD38 was upregulated in the ecDNA dataset suggesting greater potential for CD38 targeting therapies in these patients. Conclusions ecDNA, as an unique marker of perturbed genomic integrity, is observed in a subset of patients and is an independent prognostic marker in newly diagnosed MM patients. As patients with ecDNA are not fully captured by other risk features its incorporation in an expanded definition of a high risk group of multiple myeloma should be investigated. Future studies will endeavor to explore the biological mechanism through which ecDNA are formed and influences outcomes in myeloma. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Secura Bio: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Thakurta: Oxford University: Other: Visiting Professor; BMS: Current Employment, Current equity holder in publicly-traded company. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Celgene: Consultancy; Pfizer: Consultancy.

Introduction: Ixazomib is an oral proteasome inhibitor (PI) that is currently approved to be administered once weekly in combination with lenalidomide (LEN) and dexamethasone in RRMM (Moreau et al N Eng J Med 2016; 374:1621-1634). As most patients are LEN refractory at the time of first relapse, pomalidomide-based regimens are commonly utilized due to their proven efficacy in this population. We hypothesized that twice weekly dosing of ixazomib may be more efficacious as this has been previously studied as monotherapy (Richardson et al, Blood 2014 Aug 14;124(7):1038-46) and in combination with LEN demonstrating promising activity and safety (Richardson et al, Br J Haematol. 2018 Jul;182(2):231-244). We present results of our phase I/II trial of twice weekly ixazomib in combination with pomalidomide and dexamethasone in RRMM, including the recommended phase II dose and first report of efficacy of this combination. Methods: This is a phase I/II multicenter, single-arm, open label study evaluating the combination of twice weekly ixazomib with pomalidomide and dexamethasone in RRMM. The primary objective for phase I portion is to determine safety and the maximum tolerated dose (MTD) of this combination using a standard 3+3 dose escalation design and primary objective of the phase II portion is overall response rate (ORR) with secondary outcomes including progression-free survival (PFS) and clinical benefit rate (CBR) Ixazomib is studied at doses of 3mg or 4mg on days 1, 4, 8, 11, pomalidomide at a dose of 2mg, 3mg and 4mg on days 1-14 and dexamethasone is administered at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21 day cycle (Table 1). Patients were included if they received 2 prior lines of therapy, but 1 prior line was allowed if first line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy. Patients who were ixazomib exposed or pomalidomide refractory were excluded. Results: At the time of data cutoff, 22 patients have been enrolled across all cohorts. There were two dose-limiting toxicities (DLT) noted during the dose escalation phase (upper respiratory infection and neutropenia, respectively) establishing the RP2D of 4mg ixazomib and 4mg pomalidomide. Median age at the time of enrollment was 68 years old with ISS stage at diagnosis of I (14%), II (32%), and III (23%). High-risk FISH abnormalities were seen in 43% of patients as follows: del 17p (9%), gain 1q (36%), t(4;14) (5%), t(14;16) (9%). Median prior lines of therapy was 2 (range 1-4) with 100% of patients having prior treatment with lenalidomide and 95% with prior bortezomib. Fifty-nine percent of patients had a prior autologous stem cell transplant. Ten patients have been enrolled at the RP2D at the time of data cut off. The most common treatment-related toxicities were mainly low grade (Grade 1-2) and included neutropenia (45%), lower extremity edema (41%), insomnia (36%), dyspnea (32%) and weight gain (32%). Grade 3 or greater toxicities were noted in 36% of patients and included neutropenia (18%), thrombocytopenia (5%), anemia (5%), atrial fibrillation (5%), dehydration (5%), diarrhea (5%), fall (5%), lung infection (5%), and pneumonitis (5%). Dose reductions occurred in 13 patients and predominantly involved dexamethasone due to weight gain, insomnia, atrial fibrillation and fatigue. There have been no discontinuations due to toxicity and no treatment related mortality at the time of data cutoff. The ORR in all cohorts was 45%, with 9% achieving sCR, 9% VGPR and 86% achieving stable disease or better. At the RP2D, the ORR was 50% with 30% of patients achieving VGPR or better. At the median follow up of 10 months, median PFS was 13 months (95% CI: 11-NR) and median overall survival was not reached. Conclusions: Twice weekly ixazomib in combination with pomalidomide and dexamethasone is a generally well-tolerated regimen with promising activity. The recommended phase II dose has been established at 4mg of ixazomib and 4mg of pomalidomide demonstrating efficacy in a high-risk cohort of RRMM patients. The all-oral nature of this regimen has allowed for robust accrual during the COVID 19 pandemic. Figure 1 Figure 1. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sanchorawala: Celgene: Research Funding; Pfizer: Honoraria; Sorrento: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding. Sperling: Adaptive: Consultancy. Munshi: Janssen: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Legend: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Richardson: AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

Introduction: CC-92480 is a potent, novel CELMoD ® compound designed for rapid and maximal degradation of Ikaros and Aiolos, that has shown immunostimulatory effects and enhanced tumoricidal activity in myeloma cells, including those resistant to lenalidomide (LEN) and pomalidomide (POM). CC-92480 has demonstrated potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) (Wong L, et al. Blood 2019;134[suppl 1]:1815). In pts with RRMM, CC-92480 in combination with DEX demonstrated a manageable safety profile with promising preliminary efficacy (Richardson PG, et al. J Clin Oncol 2020;38[suppl 15]:8500). CC-92480-MM-002 (NCT03989414) is an ongoing phase 1/2 study evaluating CC-92480 in combination with standard treatments in pts with RRMM. Here we report preliminary results from the CC-92480 + BORT + DEX cohort. Methods: Pts with RRMM who had received 2-4 prior regimens, including prior treatment with LEN, and had documented disease progression during or after their last myeloma therapy were eligible. CC-92480, at specified cohort doses (0.3 mg, 0.6 mg, and 1.0 mg), was administered orally on days (D) 1-14 with subcutaneous BORT (1.3 mg/m 2) on D1, 4, 8, and 11 in cycles (C) 1-8 and on D1 and 8 after C8, over a 21-day cycle; DEX (20 mg/day or 10 mg/day if > 75 years of age) was given on D1, 2, 4, 5, 8, 9, 11, and 12 in C1-8 and on D1, 2, 8, and 9 after C8. Primary objectives were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and to evaluate safety and preliminary efficacy. Pharmacodynamics (PD), Ikaros/Aiolos protein levels, and immunophenotyping were also assessed. Results: As of May 26, 2021, 19 pts had received CC-92480 + BORT + DEX. Median age was 66 (50-83) years, median time since initial diagnosis was 4.8 (1.9-17.1) years, and median number of prior regimens was 3 (2-4). Prior therapies included stem cell transplantation (57.9%), BORT (78.9%), carfilzomib (CFZ, 21.1%), LEN (100%), POM (47.4%), and anti-CD38 mAbs (36.8%); 21.1% of the pts had extramedullary disease and 21.1% were triple-class refractory (refractory to immunomodulatory drug, PI, and anti-CD38 mAb). Median follow-up was 8 (1.0-19.2) months, with a median number of 10 (1-28) cycles received and 9 (47.4%) pts continue on treatment. Main reason for discontinuation was progressive disease, reported in 5 pts. All pts experienced ≥ 1 treatment-emergent adverse events (TEAEs) and grade (Gr) 3-4 TEAEs were reported in 18 (94.7%) pts. Most frequent (≥ 10% of pts) Gr 3-4 TEAEs were neutropenia (36.8%, no febrile neutropenia reported), thrombocytopenia (21.1%, no bleeding reported), anemia (10.5%), hyperglycemia (10.5%), and insomnia (10.5%). Gr 3-4 infection was reported in 1 (5.3%) pt. Eight (42.1%) pts had Gr 1-2 peripheral neuropathy. Five (26.3%) pts had serious TEAEs, none considered related to study treatment. Five (26.3%), 7 (36.8%), and 8 (42.1%) pts had dose reductions of CC-92480, BORT, and DEX, respectively; 4 (21.1%) pts had dose reductions due to TEAEs. Two (10.5%) pts discontinued due to TEAEs (dysgeusia and colon neoplasm [pre-existing]). No pt experienced dose-limiting toxicity and the MTD was not reached. Two deaths were reported (due to myeloma progression and colon neoplasm). The overall response rate across all doses per investigator assessment was 73.7% (14/19 pts), including 3 stringent complete responses and 1 complete response. Responses were observed at all dose levels. Median duration of response was 10.4 (5.5-not reached) months and median time to first response was 0.95 (0.7-3.3) months. Plasma exposures of CC-92480 + BORT + DEX were consistent with previous pharmacokinetic (PK) analysis of CC-92480 + DEX. Consistent with CC-92480 mechanism of action, PD studies showed potent degradation of substrates 3-6 hours post treatment and a reduction of mature B cells with CC-92480 + BORT + DEX treatment. Based on safety, efficacy, and PK/PD data, a 1.0 mg dose of CC-92480 was selected as the RP2D. Conclusions: CC-92480 in combination with BORT and DEX appears to be safe and well tolerated with encouraging preliminary efficacy in pts with RRMM. These results support further development of CC-92480 in combination regimens in RRMM. In the CC-92480-MM-002 study, a CC-92480 + BORT + DEX expansion cohort is ongoing at the RP2D, as well as a CC-92480 + CFZ + DEX cohort. Updated data will be presented at the meeting. Disclosures Richardson: Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Ocio: Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy; MSD: Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. White: Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Forus: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sandhu: Celgene/BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Raab: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. LeBlanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Rodriguez: BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau. Trudel: Sanofi: Honoraria; Roche: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Genentech: Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Wäsch: Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Perrot: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria. Bahlis: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Zhou: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lamba: Bristol Myers Squibb: Current Employment; Pfizer: Current equity holder in publicly-traded company. Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Civardi: Bristol Myers Squibb: Current Employment. Katz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Maciag: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Amgen: Honoraria.

Background: SARS-CoV-2 related acute respiratory distress syndrome (ARDS) is associated with endothelial dysfunction and profound dysregulation of the thrombotic/fibrinolytic pathway, with thrombotic complications common in affected patients (pts). Fibrin deposition may be a key feature of the pathobiology, with markedly elevated levels of PAI-1 reported. Defibrotide (DF), a polyanionic naturally-derived polydeoxyribonucelotide with endothelial stabilizing activity, has fibrinolytic, antithrombotic and anti-inflammatory properties, with known activity in reducing PAI-1 levels and inhibiting heparanase. We now report a prospective, open label, safety and tolerability trial of defibrotide for the management of patients with advanced SARS-CoV-2 related ARDS. Patients and Methods: Eligible patients (pts) were ≥18 years in age, with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-Dimer > 2X ULN, and a positive PCR-based assay for SARS-CoV-2. Concomitant use of systemic anticoagulants or fibrinolytics was initially precluded, with the study amended to allow prophylactic doses of systemic heparin in its latter stages. Defibrotide (6.25 mg/kg/dose IV q. 6 hours) was administered for a planned 7-day course, with day 1 defined as the first day of study therapy. Therapy was able to be discontinued prior to day 7 in pts who met the pulmonary response parameter at that earlier timepoint. Patients with a partial response to therapy (> 20% reduction in FiO2) by day 7 were allowed to receive an additional 7 days of therapy (14 days total). Response was defined as complete cessation of supplemental O2 support, or ≥ 2 point reduction in WHO ordinal score for 48 consecutive hours by day 7. Patients were recruited from a single center between October 2020 and March 2021. Results: Twelve pts (median 63 years, range 35-73 years) were treated, with 10 of 12 pts on mechanical ventilation (median FiO2 55%, PEEP 18 mmHg), and six on vasopressor support at the time of study entry. Baseline PaO2/FiO2 ratios ranged from 82 - 200 mmHg. The median D-Dimer was 3.25 mcg/ml (range 1.33-12.3 mcg/ml), and fibrinogen 637 mg/dl (range 250-1208 mg/dl) at study entry. Dexamethasone and remdesivir had been administered prior to DF in all pts, with no other SARS-CoV-2 targeted treatment given during DF therapy. Eleven pts received ≤7 days of therapy, with one pt receiving 14 days. The first 9 pts received DF without other concomitant anticoagulants, with the last 3 pts concurrently receiving prophylactic heparin plus DF. No hemorrhagic or bleeding complications occurred during DF therapy, including the 3 pts receiving concurrent heparin prophylaxis. Likewise, no thrombotic complications developed during study therapy, including the 9 patients in which DF was their sole anti-coagulant. All 12 patients were evaluable for response. Four pts met the day 7 pulmonary response parameter, with 2 pts having a complete cessation of O2 support within this period. Three pts died from progressive pulmonary disease, at 11, 17 and 34 days from study entry. The 3 pts (who died) had the lowest baseline PaO2/FiO2 ratios (82-115 mmHg) of all study subjects. Nine pts (75%) remain alive, 64 to 174 days from study entry, all 9 discharged from their primary hospitalization. Day 30 all-cause mortality was 17% (95%CI: 0-35%). Serial coagulation and fibrinolytic assays were available in 7 patients. Total PAI-1 levels decreased from a median 167 ng/ml (range 105-264 ng/ml) to a median 104 ng/ml (range 55-166 ng/ml) by day 4 of therapy, with all 7 subjects showing a decline in PAI-1 levels at that time point. Total tPA levels increased from a median 3.02 ng/ml (range 0.72 - 36.1 ng/ml) at baseline to 4.5 ng/ml (range 1.1-8.2 ng/ml) by day 4 in study subjects. Allowing for the small sample size, baseline PAI-1, tPA or D-Dimer levels did not impact response. One of two patients with a baseline D-Dimer > 10 mcg/ml responded, while both patients with a baseline D-Dimer Conclusion: The use of DF for the management of SARS-CoV-2-related ARDS proved safe and tolerable in a prospective, open label trial. No hemorrhagic or thrombotic complications were reported during therapy. Outcomes were promising, including an overall survival of 75% in a patient population with a historically high mortality rate. (The study was supported by a research grant from Jazz Pharmaceuticals) Disclosures Yanik: Jazz Pharmaceutical: Research Funding. Pipe: Sangamo Therapeutics: Other: Scientific Advisory Board; ASC Therapeutics: Other: Scientific Advisory Board; Apcintex: Consultancy; Bayer: Consultancy; Biomarin: Consultancy; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; Freeline: Consultancy; Grifols: Consultancy; HEMA Biologics: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy. Sisson: Translatebio: Other: Data Safety Committee member. Richardson: Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Janssen: Consultancy; Secura Bio: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; AbbVie: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Lawrence: MDI Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Defibrotide: Off label use for ARDS

Introduction Vascular endothelial injury related to treatment with proteasome inhibitors (PI) has been previously described. Carfilzomib is an irreversible PI and has been associated with cardiovascular toxicity, suggesting increased risk of endothelial injury. Thrombotic microangiopathy (TMA) has been described in multiple myeloma (MM) patients receiving PIs; more often with carfilzomib. In the pediatric transplant population, increased risk of TMA was related to heterozygous mutation in the alternative complement pathway. The homozygous deletions enable uncontrolled complement activation and was found three times more frequently in TMA population. We hypothesized that MM patients with complement mutation are at increased risk of PI-related TMA. Materials and Methods We identified ten cases of renal TMA in MM patients receiving carfilzomib from two medical institutions in Greece and in the United States. TMA was diagnosed based on either renal biopsy or acute kidney injury, new-onset anemia, thrombocytopenia and increased LDH in the absence of disease progression. We performed targeted sequencing of the twelve genes implicated in TMA: CFH, CFI, MCP, CFB, CFHR5, C3, THBD, DGKE, PLG, ADAMTS13, MMACHC and G6PD genes. Multiplex Ligation-Dependent Probe Amplification (MLPA) was performed for the analysis of the CFH-CFHR5 region. Results Patient characteristics and laboratory values at TMA diagnosis are presented in Table 1. The median age of patients was 68 years (range, 47-73), with slight male predominance (60%). Median laboratory values at diagnosis included hemoglobin 9.35 g/dL, platelet count 26,500 x 10 6/L, LDH 356,5 U/L and creatinine 2.25 mg/dL. Patients were treated with carfilzomib doses ranging 20-70 mg/m 2. Regimens included carfilzomib-dexamethasone (Kd, 7 patients), carfilzomib-lenalidomide-dexamethasone (KRd, 1 patient), carfilzomib-pomalidomide-dexamethasone (KPd, 1 patient), and carfilzomib-daratumumab-dexamethasone (DaraKd, 1 patient). All patients had previously received at least one line of therapy and seven patients had previously undergone autologous stem cell transplant (ASCT), 1-12 years prior to TMA diagnosis. The median time between carfilzomib initiation and TMA diagnosis was 4.5 months (range, 1-60 months). Diagnosis was confirmed with renal biopsy in four cases. Carfilzomib was discontinued in all patients and five patients were treated with plasma exchange (PLEX) while one patient received eculizumab. Seven patients demonstrated clinical improvement and resolution of TMA at 1 year after discontinuation of carfilzomib. Two patients progressed to end stage renal disease (ESRD) requiring intermittent hemodialysis, and one patient developed multiorgan failure. Results of genetic panel are shown in Table 2. Deletions of the CFHR3-CFHR5 region were present in seven cases (70%): two patients carrying a homozygous deletion of CFHR3-CFHR1, four patients with a heterozygous deletion of CFHR3-CFHR1, and one patient with heterozygous deletion of CFHR1-CFHR4. Direct gene sequencing revealed identifiable mutations in CD46 (MCP) and CFHR5 in two distinct patients. The functional correlation and clinical significance are yet to be investigated. Conclusions In our cohort of ten patients of carfilzomib-induced TMA, deletions of CFHR3-CFHR5 occurred frequently (70%). In the setting of carfilzomib use, heterozygous CFHR3-CFHR1 deletion may represent a risk factor for the development of TMA. Our data set the bases for larger studies assessing complement mutation as a predisposing factor for PI-induced TMA. Figure 1 Figure 1. Disclosures Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Dimopoulos: Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Richardson: AbbVie: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Background: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life (QOL), psychological distress, and prognostic awareness by line of therapy are lacking. Methods: We conducted a cross-sectional, multi-site study of patients undergoing treatment for MM (excluding maintenance therapy) between 6/2020-1/2021. To capture the full spectrum of treatment, we conducted purposeful sampling and recruited patients to 3 cohorts based on lines of therapy: 1) newly diagnosed receiving first-line therapy; 2) 2-3 lines; and 3) ≥ 4 lines. Patients completed validated questionnaires to assess their QOL, symptom burden, fatigue, psychological distress, and perceptions of prognosis. We used multivariate linear regression models to examine the association between lines of therapy, QOL, psychological distress, with patient's perception of their prognosis. Results: We enrolled 180 patients with MM (newly diagnosed (n=60), 2-3 lines (n=60), and ≥4 lines of therapy (n=60)). QOL and fatigue scores did not differ by lines of therapy: (QOL: 116.6 (SD=20.6) vs. 112.3 (SD=28.2) vs. 110.6 (SD=29.6); Fatigue: 36.9 (SD=9.9) vs. 35.4 (SD=11.9) vs. 33.7 (SD=12.5). There were also no statistically significant differences in depression, anxiety, or PTSD symptoms by line of therapy. The rate of clinically significant depression, anxiety, and PTSD symptoms were 23.9% (43/180), 23.9% (43/180), and 24.4% (44/180), respectively. Overall, 84% (147/175) of patients reported that it is 'extremely' or 'very' important to know about their prognosis, and the majority (66.1%, 117/177) stated that they had received adequate information regarding their prognosis. Patients reported that prognostic information was 'extremely' or 'very' helpful in making decisions about treatment (93.4%, 155/166), coping with the disease (87.4%, 145/166), and preparing for the future (86.8%, 144/166). Most patients, 84.7% (149/176) reported that their oncologist told them their cancer was incurable but only 30.6% (53/173) acknowledged that they were terminally ill and only 42.0% (73/174) reported that they thought their cancer was incurable . Patients receiving 2-3 lines of therapy were more likely to acknowledge their terminal illness (36.7% vs. 19.6%, p=0.045) and that their MM was incurable (90.0% vs. 75.9%, p=0.047) compared to those receiving 1 st line therapy. QOL and psychological distress were not associated with patient's perception that their MM was incurable. However, patients who acknowledged their terminal illness reported higher depression (B=1.52, P = 0.009), anxiety (B=1.52, P=0.0037), symptom burden (B=7.42, P=0.007), and lower QOL (B=-14.78, p=0.001). Conclusions: MM patients undergoing treatment experience impaired QOL and elevated psychological distress across the disease continuum, irrespective of their line of therapy. Although the majority reported that their oncologist had told them that their cancer is incurable, a substantial proportion still reported that they believed they were curable. Acknowledgement of terminal illness was associated with higher rates of psychological distress and symptoms burden and lower QOL. Interventions are needed to improve patients' QOL, reduce their psychological distress, and cultivate adaptive coping strategies that may help improve the patient experience over the MM disease course. Disclosures O'Donnell: Adaptive: Consultancy; Oncopeptide: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Karyopharm: Consultancy. Nadeem: Bristol Myer Squibb: Consultancy; GSK: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Yee: Adaptive: Consultancy; Bristol Myers Squibb: Consultancy; GSK: Consultancy; Oncopeptides: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Branagan: Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; CSL Behring: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Anderson: Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mo: Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Eli Lilly: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munshi: Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Takeda: Consultancy; Legend: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Adaptive Biotechnology: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Regeneron: Consultancy; Secura Bio: Consultancy; Celgene/BMS: Consultancy, Research Funding; Sanofi: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other.

Introduction: DARA is approved across lines of therapy for multiple myeloma, including in combination with standard-of-care regimens for NDMM. The CXCR4 receptor antagonist plerixafor is used in conjunction with granulocyte colony-stimulating factor (G-CSF) to increase stem cell mobilization for autologous stem cell transplant (ASCT) and can be given by upfront decision or as a rescue strategy. The phase 2 randomized GRIFFIN study (NCT02874742) evaluates frontline DARA in combination with lenalidomide, bortezomib, and dexamethasone (D-RVd) in transplant-eligible NDMM. In the primary analysis, more pts undergoing stem cell mobilization/collection in the D-RVd group received plerixafor compared with the RVd group (69.5% [66/95] vs 56.3% [45/80]) (Voorhees PM, et al. Blood. 2020). The phase 2 MASTER study (NCT03224507) evaluates DARA plus carfilzomib, lenalidomide, and dexamethasone (D-KRd) in transplant-eligible NDMM (Costa LJ, et al. EHA Library. 2020). Here, we present a summary of stem cell mobilization, collection yields, and ASCT data following frontline DARA-based induction therapy in GRIFFIN and MASTER. Methods: Eligible pts had NDMM and were candidates for ASCT. In GRIFFIN, pts were randomized 1:1 to receive D-RVd or RVd. Pts received 4 induction cycles (21 days) of lenalidomide (R; 25 mg PO on Days 1-14), bortezomib (1.3 mg/m 2 SC on Days 1, 4, 8, and 11), and dexamethasone (d; 40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4). After Cycle 4, pts underwent stem cell mobilization with G-CSF ± plerixafor, per institutional standards; if unsuccessful, chemo mobilization was permitted. Pts then received ASCT and subsequently 2 consolidation cycles (21 days) of D-RVd or RVd followed by maintenance therapy with R ± DARA. In the single-arm MASTER study, pts received 4 D-KRd induction cycles, ASCT, and 0, 4 or 8 D-KRd consolidation cycles followed by maintenance therapy with R, based upon achievement of minimal residual disease-negativity. In each 28-day cycle, all pts received carfilzomib (20/56 mg/m 2 IV QW), R (25 mg PO on Days 1-21), d (40 mg PO or IV QW), and DARA (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). Mobilization was with G-CSF ± plerixafor as per institutional standards. Results: In GRIFFIN, among 207 (D-RVd, n=104; RVd, n=103) randomized pts, 91.3% (n=95) of D-RVd pts and 77.7% (n=80) of RVd pts underwent stem cell mobilization; of those mobilized, 98.9% (n=94) and 97.5% (n=78) underwent ASCT, respectively. In MASTER, 123 D-KRd pts enrolled and at last follow-up, 91.1% (n=112) underwent stem cell mobilization; of those mobilized, 98.2% (n=110) completed ASCT. In GRIFFIN, 46.3% (n=81) of mobilized pts received plerixafor upfront (D-RVd, 51.6%, n=49; RVd, 40.0%, n=32), and 18.3% (n=32 pts) received rescue plerixafor (D-RVd, 20.0%, n=19; RVd, 16.3%, n=13). In MASTER, 70.5% (n=79) D-KRd pts received upfront plerixafor and 25.9% (n=29) received rescue plerixafor. Median CD34 + cell yield was 8.3 × 10 6/kg for D-RVd and 9.4 ×10 6/kg for RVd in GRIFFIN, 6.0 ×10 6/kg for D-KRd in MASTER, and was numerically higher for pts who received upfront plerixafor. Median days for stem cell collection was 1 for pts receiving RVd and 2 for those receiving D-RVd or D-KRd. Median transplanted CD34 + cell count was 4.2 ×10 6/kg for D-RVd and 4.8 ×10 6/kg for RVd in GRIFFIN, and 3.2 ×10 6/kg for D-KRd in MASTER. In GRIFFIN, 93.7% of D-RVd pts and 98.8% of RVd pts reached the minimum institutional CD34 + threshold to perform a single ASCT, which was comparable to results in MASTER (95.5% of D-KRd pts) after first mobilization attempt; 85.3% of D-RVd pts, 92.5% of RVd pts, and 79.5% of D-KRd pts collected 2 times the minimum threshold of stem cells. Additional data by upfront and rescue plerixafor strategies are shown in the Table. Conclusion: The addition of DARA to proteasome inhibitor/immunomodulatory drug/dexamethasone-based induction therapy has a modest impact on stem cell mobilization, with a lower yield of stem cells and higher median number of days required for collection. Nonetheless, pts were able to undergo transplantation, and most pts collected sufficient stem cells for 2 transplants. Pts who received plerixafor by an upfront decision had numerically higher stem cell yields than pts who received plerixafor by a rescue strategy. An upfront plerixafor strategy for pts receiving DARA-based quadruplet induction therapy should be considered with allowance for additional days of apheresis as needed. Figure 1 Figure 1. Disclosures Chhabra: GSK: Honoraria. Costa: Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kaufman: BMS: Consultancy, Research Funding; Fortis Therapeutics: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Tecnofarma SAS, AbbVie: Honoraria; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Research Funding. Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy; GlaxoSmithKline: Consultancy. Reeves: Incyte Corporation: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Pharma Essentia: Consultancy, Honoraria. Rodriguez: Karyopharm: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Silbermann: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah: Sutro Biopharma: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; CareDx: Consultancy; Sanofi: Consultancy; Kite: Consultancy; Poseida: Research Funding; Amgen: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; GSK: Consultancy; Precision Biosciences: Research Funding; Teneobio: Research Funding; Oncopeptides: Consultancy; Nektar: Research Funding; Karyopharm: Consultancy. Bumma: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Holstein: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak: BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Orlowski: CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria. Shain: Novartis Pharmaceuticals Corporation: Consultancy; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cowan: Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Harpoon: Research Funding; GSK: Consultancy; Secura Bio: Consultancy; BMS: Research Funding; Nektar: Research Funding. Dholaria: Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau; Pfizer: Research Funding; Janssen: Research Funding. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Cortoos: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Janssen: Current Employment. Bartlett: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Voorhees: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Background: With new standard-of-care and novel treatment options available in MM, outcomes have improved; however, patients (pts) eventually become refractory to multiple drug classes (Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumor cells. In the United States, melflufen + dex received accelerated approval in RRMM based on results from the phase 2 HORIZON study (Richardson et al. J Clin Oncol. 2021;39:757). In the phase 3, randomized, OCEAN study (NCT03151811), melflufen + dex significantly reduced the risk of disease progression vs pom + dex (progression-free survival [PFS]: hazard ratio [HR], 0.79 [95% CI, 0.64-0.98; P=0.031]) in RRMM (Oncopeptides. Press release. July 8, 2021). This subgroup analysis of OCEAN investigates the impact of prior treatments on efficacy outcomes. Methods: Eligible pts received 2-4 prior lines of therapy (LoT) including lenalidomide (len) and a proteasome inhibitor (PI) and were refractory to len (within 18 mo of randomization) and to their last LoT. Stratified by age, number of prior LoTs, and International Staging System score, pts were randomized 1:1 to 28-d cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to d21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, assessed by an Independent Review Committee per International Myeloma Working Group Uniform Response Criteria. Key secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Subgroup analyses by prior therapy received were prespecified prior to the start of the study. Results: At data cutoff (Feb 3, 2021), 495 pts were randomized to receive melflufen (n=246) or pom (n=249). Among these, 125 pts (51%) and 120 pts (48%) had a prior stem cell transplant (SCT), 43 pts (17%) and 43 pts (17%) were on len for PFS and OS by prior therapy received are shown in the Figure. Significant PFS benefit with melflufen (vs pom) was observed in pts without a prior SCT (HR, 0.59 [95% CI, 0.44-0.79]; P Conclusion: In OCEAN, melflufen + dex showed superior PFS, but not OS, compared with pom + dex. PFS benefit with melflufen was consistent across clinically relevant subgroups, primarily in pts without a prior SCT, with ongoing analyses aimed at determining factors driving this benefit. Figure 1 Figure 1. Disclosures Dimopoulos: BeiGene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria. Schjesvold: Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Schain: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Nordics Nanovector: Current holder of individual stocks in a privately-held company; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy; SkyliteDX: Honoraria; Bayer: Consultancy; AbbVie: Honoraria. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Robak: Medical University of Lodz: Current Employment; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria. Hájek: Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson: AbbVie: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Regeneron: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Oncopeptides: Consultancy, Research Funding; Secura Bio: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Lindberg: Affibody: Membership on an entity's Board of Directors or advisory committees; Camurus: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Oncopeptides: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses. Thuresson: Oncopeptides AB: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Larsson: Oncopeptides AB: Current Employment; Alnylam Pharmaceuticals Inc.: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Sonneveld: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Yes, this is a subgroup analysis of a phase 3 investigational study of melflufen in patients with RRMM refractory to lenalidomid.

Background: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Although caregivers of MM patients play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking. Methods: We conducted a cross-sectional, multisite study of patients undergoing treatment with MM (excluding maintenance therapy) and their caregivers between 6/2020-3/2021. Eligible caregivers were identified by the patient as the primary caregiver and enrolled to 1 of 3 cohorts based on lines of therapy: 1) newly diagnosed receiving first-line therapy; 2) 2-3 lines; 3) ≥4 lines of therapy. Caregivers completed validated questionnaires to assess their QOL, psychological distress, and perceptions of prognosis. Patients also completed validated questions to assess their perception of prognosis. We used descriptive statistics to describe caregiver QOL, psychological distress, and perception of prognosis. We then descriptively compared psychological distress and perception of prognosis between patient and caregiver dyads. Results: We enrolled 127 caregivers of MM patients (newly diagnosed (n=43), 2-3 (n=40), and ≥ 4 lines of therapy (n=44)). Median caregiver age was 61.8 years (range 24.0-81.9); 71.7% (91/127) were female; and 68.5% (87/127) were taking care of their spouse/partner. Caregiver QOL and psychological distress did not differ by lines of therapy. The rate of clinically significant depression, anxiety, and post-traumatic stress disorder (PTSD) symptoms were 15.8% (20/127), 44.1% (56/127), and 24.4% (31/127), respectively. When examining dyads, caregivers reported higher rates of clinically significant anxiety symptoms (44.4% vs. 22.5%) compared to MM patients. Caregivers reported less clinically significant depression symptoms (15.3% vs. 24.2%) and similar rates of clinically significant PTSD symptoms (24.2% vs 25.0%). Overall, 89.6% (112/125) of caregivers reported that it is 'extremely' or 'very' important to know about the patient's prognosis and 55.6% (70/126) stated that they had received adequate information regarding the patient's prognosis. Caregivers reported that prognostic information was 'extremely' or 'very' helpful in making decisions about treatment (94.0%, 109/116), preparing for the future (88.6%, 101/114), and coping with the disease (85.2%, 98/115). Most caregivers (84.2%, 101/120), reported that the oncologist had told them the patient's cancer was incurable. In contrast, only 53.6% (59/110) of caregivers reported that they thought the patient's cancer was incurable and 37.9% (58/114) acknowledged that the patient is terminally ill. Caregiver demographics, line of therapy, QOL, and psychological distress were not associated with their perceptions of the patient's prognosis. When examined in dyads, caregivers were more likely to report that the patient is terminally ill (50.1% vs. 30.1%). There was no difference in caregivers' and patients' report that the oncologist said MM is incurable (83.3% vs. 84.2%). Conclusions: Caregivers of patients undergoing treatment for MM experience substantial psychological distress across the disease continuum, particularly anxiety. Supportive care interventions are needed to improve caregivers' QOL and to reduce their psychological distress. Although the majority of caregivers of MM patients report that knowing the patient's prognosis is extremely important and report that the oncologist told them that the patient was incurable, a significant portion of caregivers report that the patient is curable. Interventions are needed to promote effective coping and to enhance caregiver's perception of the patient's prognosis to facilitate informed-decision making. Disclosures O'Donnell: Janssen: Consultancy; Takeda: Consultancy; Oncopeptide: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol Myer Squibb: Consultancy. Nadeem: Takeda: Consultancy; Bristol Myer Squibb: Consultancy; GSK: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy. Yee: Karyopharm: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy. Branagan: Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; CSL Behring: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Anderson: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mo: Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy. Munshi: Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Legend: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AstraZeneca: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; Secura Bio: Consultancy; Sanofi: Consultancy; Regeneron: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other.

Immune therapies including CAR T cells and bispecific T cell engagers are demonstrating remarkable efficacy in relapsed refractory myeloma (MM). In this context, we have recently shown that proteasome inhibitor bortezomib (BTZ) results in immunogenic cell death (ICD) and in a viral mimicry state in MM cells, allowing for immune recognition of tumor cells. Induction of a robust anti-MM immune response after BTZ was confirmed both in vitro and in vivo: treatment of 5TGM1 MM cells with BTZ induced tumor regression associated with memory immune response, confirmed by ELISPOT of mouse splenocytes. We have confirmed the obligate role of calreticulin (CALR) exposure in phagocytosis and the ICD process, since BTZ-induced ICD is impaired in CALR KO MM cells both in vitro and in vivo. We further showed that the therapeutic efficacy of BTZ in patients was correlated with ICD induction: BTZ-induced ICD signature was positively correlated with OS (p=0.01) in patients enrolled in the IFM/DFCI 2009 study. Together, these studies indicate that ICD is associated with long-term response after BTZ treatment. In this work, we reasoned that genomic or transcriptomic alterations associated with shorter survival of MM patients after BTZ treatment may impair activation of the ICD pathway. To this aim, we performed a transcriptomic analysis of purified CD138+ cells from 360 newly diagnosed, clinically-annotated MM patients enrolled in the IFM/DFCI 2009 study. By focusing on genes involved in the ICD process, we found that low levels of GABA Type A Receptor-Associated Protein (GABARAP) were associated with inferior clinical outcome (EFS, p=0.0055). GABARAP gene locus is located on chr17p13.1, a region deleted in high risk (HR) MM with unfavorable prognosis. Remarkably, we found that correlation of low GABARAP levels with shorter EFS was significant (p=0.018) even after excluding MM patients with del17p; and GABARAP is therefore an independent predictor of clinical outcome. GABARAP is a regulator of autophagy and vesicular trafficking, and a putative CALR binding partner. Interestingly, among a panel of MM cell lines (n=6), BTZ treatment failed to induce exposure of CALR and MM cell phagocytosis by DCs in KMS11 cells, which carry a monoallelic deletion of GABARAP. This effect was rescued by stable overexpression of GABARAP. Moreover, CRISPR/Cas9-mediated KO of GABARAP in 3 ICD-sensitive cell lines (AMO1, H929, 5TGM1) abrogated CALR exposure and ICD induction by BTZ. GABARAP add-back by stable overexpression in KO clones restored both CALR exposure and induction of ICD, confirming GABARAP on-target activity. Similarly, pre-treatment of GABARAP KO cells with recombinant CALR restored MM phagocytosis, further confirming that GABARAP impairs ICD via inhibition of CALR exposure. Based on these findings, we hypothesized that GABARAP loss may alter the ICD pathway via CALR trapping, resulting in the ICD resistant phenotype observed in GABARAP null and del17p cells. To this end, we explored the impact of GABARAP KO on the CALR protein interactome, in the presence or absence of BTZ. Importantly, GABARAP KO produced a significant increase of CALR binding to stanniocalcin 1 (STC1), a phagocytosis checkpoint that mediates the mitochondrial trapping of CALR, thereby minimizing its exposure upon ICD. Consistently, GABARAP KO also affected CALR interactome in BTZ-treated cells, which was significantly enriched in mitochondrial proteins. Importantly, co-IP experiments confirmed GABARAP interaction with STC1. These data indicate a molecular scenario whereby GABARAP interacts with STC1 to avoid STC1-mediated trapping of CALR, allowing for the induction of ICD after treatment with ICD inducers; on the other hand, this mechanism is compromised in GABARAP null or del17p cells, and the STC1-CALR complex remains trapped in the mitochondria, resulting in ICD resistance. To functionally validate our findings in the context of the immune microenvironment, we performed mass Cytometry after T cell co-culture with DCs primed by both WT and GABARAP KO AMO1 clones. And we confirmed that treatment of GABARAP KO clones with BTZ failed to activate an efficient T cell response. In conclusion, our work identifies a unique mechanism of immune escape which may contribute to the poor clinical outcome observed in del17p HR MM patients. It further suggests that novel therapies to restore GABARAP may allow for the induction of ICD and improved patient outcome in MM. Disclosures Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Chauhan: C4 Therapeutics: Current equity holder in publicly-traded company; Stemline Therapeutics, Inc: Consultancy. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.