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Background Multiple myeloma (MM) is considered an incurable hematologic malignancy despite a plethora of standard and novel agents. There is no consensus on the optimal sequencing of available therapies in relapsed/refractory MM (RRMM), even in the second line setting. Novel agents such as selinexor (XPOVIO [X]), an oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, or those that target B-cell maturation antigen (BCMA), have shown significant activity in RRMM. X is approved with bortezomib (V) and dexamethasone (XVd) in patients (pts) with at least 1 prior therapy and is not associated with known long-term clinically significant toxicities such as visual loss, cardiac dysfunction, renal failure, neuropathy, irreversible bone marrow suppression, second malignancies, venous thromboembolism, or rash. Currently, BCMA-targeting agents include 1 form each of chimeric antigen receptor T cell (CAR-T cell) and antibody drug conjugate (ADC) therapy approved in RRMM: idecabtagene vicleucel and belantamab mafodotin, respectively. BCMA-refractory MM represents an area of unmet need in MM without known standards for best treatment. Various novel combinations with X have demonstrated strong benefit in RRMM after 1 or more lines of therapy and activity even in CAR-T cell BCMA-refractory MM (N=7): 1 pt stringent complete (sCR), 3 very good partial (VGPR), 2 partial (PR), and 1 minimal (MR) response (Chari BJH 2020). Here we report on the outcomes of heavily pretreated RRMM pts, a majority of whom had received ADC-BCMA, and who were treated with X-containing regimens on the STOMP trial. Methods STOMP (NCT02343042) is a phase 1b/2, multi-arm, open-label trial of various combinations of X with backbone agents for pts with RRMM or newly diagnosed MM. Here we report on all pts in STOMP with prior anti-BCMA treatment who were treated on STOMP with X+pomalidomide +dexamethasone (XPd); XVd; X+carfilzomib+d (XKd); XPVd; and XPd+elotuzumab (E) (XPEd). Results In total, 11 pts with prior anti-BCMA therapy (6 pts with belantamab mafodotin; 1 each with MEDI2228, SEA-BCMA, BCMA BITE; 2 with idecabtagene vicleucel) were treated with 5 X-containing regimens (Table 1): 9 pts were treated with triplets XPd (4), XVd (3), or XKd (2) and 2 pts with quadruplets XPVd (1) or XPEd (1). Median age was 71 years (range 46-85), 7 pts (63.6%) were women, 11 pts were white. Median duration from MM diagnosis to treatment with a STOMP regimen was 6.9 years (range 2.3-12.8). Five pts (45.5%) had high-risk cytogenetics; pts received median of 6 prior therapies (range 4-10). Eight pts (72.7%) received anti-BCMA in their immediate prior line of therapy. Ten pts (90.9%) were previously treated with all backbone drugs of the STOMP treatments (i.e., X was the only new drug). The overall response rate (ORR) and clinical benefit rate (CBR) for the prior anti-BCMA-containing regimens were 40.0% (2 pts VGPR, 2 PR, 5 stable disease [SD], 1 progressive disease, 1 unknown). Median progression free survival (PFS) was 1.8 months (95% CI: 1.5, NE), and the 6-month PFS probability was 12.5% (95% CI: 2.1, 76.2). ORR for the X-based treatments was 54.5% and CBR was 81.8%: 1 pt VGPR, 5 PR, 3 MR, 2 SD. Median PFS was not reached (95% CI: 5.9, NE) and the 6-month PFS probability was 68.6% (95% CI: 40.3, 100.0). Median overall survival was 10.5 months (95% CI: 9.6, NE) and median time to discontinuation was 8.1 months (95% CI: 6.1, NE). The most common treatment-emergent adverse events were nausea and thrombocytopenia. Nausea was Grade (G) 1/2 (n=8, 72.7%); thrombocytopenia G1-4 in 8 pts (72.7%), 4 with ≥G3; there were no concurrent bleeding events. One pt on XPEd died of pulmonary nocardiosis considered to be associated with the 4-drug regimen. No new safety signals or long-term toxicities due to X were reported. Conclusions In this follow-up cohort of heavily pretreated pts, a majority of whom with MM refractory to ADC-BCMA, we demonstrate impressive potency and durability of the X-based treatments, particularly as compared to that of their prior anti-BCMA therapies. These data support the rationale for the development of novel regimens containing X plus immunomodulatory drugs or proteasome inhibitors in earlier lines of therapy, including first relapse, and further suggest their strong value in the emerging BCMA RRMM space. Figure 1 Figure 1. Disclosures Baljevic: Exelixis: Research Funding; Amgen: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen Research: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gasparetto: Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptide: Consultancy, Honoraria, Speakers Bureau. Schiller: Sangamo: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Geron: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; PrECOG: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Genentech-Roche: Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; FujiFilm: Research Funding; Gamida Cell Ltd.: Research Funding; Constellation Pharmaceuticals: Research Funding; Mateon: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Tolero: Research Funding; Samus: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Trovagene: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy. Lentzsch: Sanofi: Consultancy, Research Funding; Celularity: Consultancy; AbbVie: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Monge: Karyopharm: Research Funding; BMS: Consultancy. Kotb: Celgene: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Pfizer: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BMS: Honoraria; Sanofi: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Akcea: Honoraria. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy. White: Forus: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Chen: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sutherland: GSK: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Amgen: Consultancy. Madan: Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Leblanc: Celgene/BMS: Research Funding; BMS/Celgene 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; 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; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag: Janssen: Research Funding; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. 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. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding.

OBJECTIVES: Findings from a brief geriatric assessment (GA) in a cohort of adults with multiple myeloma (MM) are presented, with particular attention to the utility of the GA in identifying important deficits in adults judged to have a normal Karnofsky Performance Status (KPS ≥ 80). MATERIALS AND METHODS: Adults age 18 and older with MM were recruited into an observational study from 2018 to 2020. A modified Cancer and Aging Research Group (CARG) GA was administered at enrollment. Enrollees also completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients Core 30 questionnaire (QLQ-C30), with subscales of physical, social, role, and cognitive functioning (range 0-100; higher values indicate better function). Data were analyzed using descriptive statistics for the full cohort and stratified by concurrent KPS (score < 80 vs ≥ 80). RESULTS: Among 89 adults, the mean age was 69.1 years, 68% were aged ≥ 65 years, and 70% were white. In this cohort, 78% had KPS ≥ 80. Among those with KPS ≥ 80, functional impairments (Timed Up and Go ≥ 14 seconds and dependence in ≥ 1 instrumental activity of daily living) were seen in 30% and 21%, respectively, with 11% reporting ≥ 1 fall in the prior 6 months. At least two GA-identified deficits were detected in 50% of the overall cohort and in 41% of those with KPS ≥ 80. Among those with KPS ≥ 80, self-reported physical impairment on EORTC QLQ-C30 was noted by 34%. CONCLUSION: Using a modified CARG GA and EORTC questionnaire, functional impairments were identified among adults considered to have a good performance status based on a KPS (≥ 80). Future studies should focus on using GA measures for therapy assignment and identifying opportunities for intervening upon GA-identified deficits.

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.

Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

The spectrum of immunoglobulin paraprotein-associated diseases requiring therapy extends beyond multiple myeloma and AL amyloidosis. Awareness of these is essential in ensuring timely accurate diagnosis and appropriate treatment. As most paraprotein-associated diseases are fairly uncommon, therapeutic decisions must often be made in the absence of data from randomized controlled trials. Treatment is generally directed at the underlying clonal cell population. This review focuses on the spectrum of the less common paraprotein-associated disorders. In most instances, the monoclonal immunoglobulin plays a direct role in the pathophysiology of the disease course; in a select few, the paraprotein may be a disease marker.

We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.

There is great variability in life-expectancy, physical, cognitive, and functional domains in cancer patients of similar chronologic age. Nowhere is this more apparent than among middle-aged and older patients. However, even in younger patients of similar age, extensive exposure to environmental stressors can cause great variability in health status. A biomarker that would reflect biologic age and any and all health deficits in a cancer patient at a distinct point in time might help predict long term outcomes related to treatment, especially toxicity and overall survival. p16INK4a (hereafter referred to as p16) expression represents an ideal biomarker that reflects both cellular senescence and biologic aging. In murine models, p16 expression reflects biologic aging in almost all organs. Preliminary findings in patients with cancer support p16 measurement as a marker of physiologic aging and predictor of toxicity in patients treated with chemotherapy. This review describes the role of p16 in cell senescence, the methodology of p16 measurement in humans, preliminary studies of p16 in humans, and the potential clinical utility of p16 in guiding treatment for cancer patients.

PURPOSE: We performed a retrospective chart review on 393 patients with multiple myeloma (MM) to determine the utility of the gamma gap (GG). METHODS: We calculated the difference between a patient’s total serum protein and albumin as a point-of-care test for assessing disease status in MM. RESULTS: GG is highly correlated with the level of M-spike, and the change in GG correlates with myeloma treatment response. In addition, fitted linear models were established that allow for the calculation of M-protein level from the GG within hours from blood draw. CONCLUSION: Our study has important implications in the care of MM, particularly in countries/areas with limited resources.

Objectives As the aging population grows, interest in applying the concept of frailty to older adults with cancer has increased. This study examines the prevalence of frailty in older patients with multiple myeloma using three frailty models. Methods In this secondary analysis of a prospective cohort study, 40 adults aged ≥65 with myeloma completed the Cancer and Aging Research Group geriatric assessment within three months of initial diagnosis. Geriatric assessment data was used to categorize patients' frailty status according to three indices: The International Myeloma Working Group (IMWG) Frailty Index, the Revised Myeloma Comorbidity Index (R-MCI), and the Carolina Frailty Index (CFI). Agreement between the indices was examined using Cohen's kappa. Results Twenty-eight patients were classified as frail by at least one of the models. However, only slight agreement exists on the classification of frailty among the indices, with little concordance among the models (Kappa 0.03–0.12). Only three patients were categorized as frail by all three models. Conclusion In a cohort of 40 older adults with newly diagnosed multiple myeloma, three frailty indices have differing approaches to operationalizing frailty resulting, in different patients being categorized as frail. Little agreement existed between the models. Further studies are needed to explore the utility of these models in predicting treatment toxicity and prognosis.

Selinexor is an oral, small molecule inhibitor of the nuclear export protein exportin 1 with demonstrated activity in hematologic and solid malignancies. Side effects associated with selinexor include nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia. We reviewed 437 patients with multiple myeloma treated with selinexor and assessed the kinetics of adverse events and impact of supportive care measures. Selinexor reduced both platelets and neutrophils over the first cycle of treatment and reached a nadir between 28 and 42 days. Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. The onset of gastrointestinal side effects (nausea, vomiting, and diarrhea) was most common during the first 1–2 weeks of treatment. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannbainoids. Loperamide and bismuth subsalicylate ameliorated diarrhea. The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement. Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to supportive care.

Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma., This work has been supported in part by grants from the Instituto de Salud Carlos III, Spanish Ministry of Health (FIS PI19/00669), Fondo Europeo de Desarrollo Regional (FEDER) and 2017SGR00792 (AGAUR; Generalitat de Catalunya).

Background Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy – Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. Methods FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. Results Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. Conclusion The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach. Trial registration This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.

Preclinical studies demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after 6 patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I / II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days - 4.1 years), median progression-free survival 4.4 months (95% confidence interval [CI]: 3.0 - 18.4) and median overall survival 34.3 months (95% CI: 19.2 - not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM. This article is protected by copyright. All rights reserved.

Introduction Multiple myeloma (MM), relapsed or refractory (R/R) to standard of care therapies, represents a treatment indication with a significant unmet clinical need. Transcriptional activation of c-MYC through bromodomain and extra-terminal (BET) proteins contributes to the malignant phenotype of the disease. RO is a novel thienodiazepine, small molecule, non-covalent inhibitor of the BET family of bromodomains. Preclinical studies with BET inhibitors have demonstrated significant single agent in vivo activity in myeloma, accompanied by down-regulation of MYC and MYC target gene expression. We report results of a monotherapy phase 1b study of RO in R/R MM (NCT03068351). Methods Eligible pts with R/R MM included those treated with at least three prior lines of multiple myeloma therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent. Primary refractory myeloma pts were only allowed in the dose escalation portion of the study. In the dose escalation (part I), pts received subcutaneous (SC) escalating doses of RO (0.30-0.65 mg/kg) in a standard 3 + 3 design on days 1 - 14 of 21-day cycles to determine both the maximum tolerated dose (MTD) and recommended dose (RD). In the expansion cohort (part II), pts received RO as monotherapy at the RD level. Primary endpoint was safety (DLT, MTD, RD) and secondary endpoints included evaluation of pharmacodynamics (CD11b expression) and preliminary efficacy assessments based on IMWG criteria. Results Between June 2017 and April 2019, a total of 24 pts were enrolled in the US, the UK and Australia. 13 pts were enrolled in the dose escalation and 11 pts in the expansion part. The median age of pts was 65.5 years (range: 46 - 82 years). The study population was heavily pretreated with a median of 6 (3-9) prior therapies. Pts were refractory to immunomodulatory drugs (63%), proteasome inhibitors (46%), both (46%), or daratumumab (42%). 57 total cycles were administered, with a median of 2 (1-6) cycles per patient (pt). Two DLTs occurred in one pt in the 0.65 mg/kg cohort (thrombocytopenia grade 4, angina pectoris grade 3). The recommended dose is 0.65 mg/kg. Grade 3 treatment emergent AEs in ≥ 5% of pts were thrombocytopenia (11 pts [45.8%]), anemia (7 pts [29.2%]), fatigue (3 pts [12.5%]), injection site reaction, malaise, decreased appetite, and hyponatremia (2 pts [8.3%] each). 3 pts (12.5%) experienced a total of 4 AEs leading to discontinuation of the study treatment; these AEs were left ventricular dysfunction, fatigue, sepsis, and staphylococcal bacteremia (the latter two AEs occurred in the same pt). A total of 8 deaths (33.3%) were reported in the study, all as a consequence of progressive disease. The best overall response recorded was partial response in 4 pts (16.7 %), 3 of whom having received prior daratumumab. One pt experienced a minimal response, and stable disease was reported in 12 out of 24 (50%). There was no evidence for a dose-related increase in efficacy, though data are very limited (Table). Responses obtained during treatment with RO6870810 were short-lived and lasted for appr. 6 weeks. As evidence of target engagement, pharmacodynamic profiling demonstrated decreases in CD11b levels in peripheral blood mononuclear cells (Figure). Conclusions Treatment of MM pts with the BET inhibitor RO as monotherapy resulted in a high incidence of cytopenias, especially grade 3-4 thrombocytopenia and grade 3 anemia. However, none of these events led to study drug discontinuation. Cytopenias are a known side effect of BET inhibitors, with thrombocytopenia frequently reported as a DLT in various pt populations. Pts with NUT carcinoma, other solid tumors, or diffuse large B-cell lymphoma treated in the First in Man trial of RO had a low rate of cytopenias, indicating that the underlying disease and the extensive pre-treatment in MM may play a role in their occurrence (publication submitted). In this heavily pretreated R/R MM population, we have established 0.65 mg/kg as the recommended monotherapy dose. Pharmacodynamics effects were evident at this dose, but as monotherapy in this R/R MM cohort, response rates were low and less durable. Future drug combination approaches may result in an improved benefit / risk ratio. Disclosures Ramasamy: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria. Nooka:Adaptive Technologies: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding. 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: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Htut:City of Hope Medical Center: Current Employment. Popat:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees. Tuchman:Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Amgen: Research Funding; Janssen: Research Funding; Oncopeptides: Consultancy; Roche: Research Funding; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Hertzberg:Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; BMS: Honoraria; 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Demario:BioNTech SE: Current Employment, Current equity holder in publicly-traded company; Hoffmann-La Roche Ltd.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Nueesch:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Chesne:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Franjkovic:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Lechner:Roche Diagnostics GmbH: Current Employment, Current equity holder in publicly-traded company. Kornacker:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company.

Background Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). Methods The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. Results Thirty-two patients, median prior therapies 4 (range, 1–8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. Conclusions Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

After unprecedented successes in B-cell malignancies, chimeric antigen receptor T cells have recently been investigated for the treatment of multiple myeloma. Chimeric antigen receptor targeting T cells B-cell maturation antigen (BCMA) on malignant plasma cells have led to impressive clinical responses in recent trials. However, BCMA-negative relapses have been observed, supporting the need for complementary treatment strategies. Here, we explored the feasibility of targeting CD138 (syndecan-1), a surface marker expressed on both normal and malignant plasma cells. We showed that T cells from both healthy donors and from multiple myeloma patients, when transduced with a CD138-specific chimeric antigen receptor, can eliminate tumor cell lines and primary myeloma cells both in vitro and in vivo. CD138 is also expressed by putative myeloma stem cells identified by Hoechst staining, and these cells can be eliminated by CD138-specific chimeric antigen receptor T cells. Preclinical analyses did not identify any on target off tumor cytotoxicity against normal epithelial or endothelial cells, further supporting the rationale for the use of adoptively transferred CD138-specific chimeric antigen receptor T cells for the treatment of patients with relapsed/refractory multiple myeloma.

Background/objectives The incidence of myeloma in older adults is increasing, yet little is known about geriatric impairments in these patients. We aimed to examine the prevalence of geriatric impairments in older adults with myeloma and the association between geriatric assessment and autologous stem cell transplant eligibility. Design Prospective cohort study. Setting Two academic medical centers. Participants A total of 40 adults 65 years and older with newly diagnosed myeloma were enrolled. Measurement Participants completed a primarily self-administered geriatric assessment, including measures of functional status, comorbidities, polypharmacy, psychosocial status, social support, quality of life, cognition, and physical performance. Outcomes were autologous stem cell transplant eligibility and receipt. Results Forty patients enrolled; their mean age was 71 years. Geriatric impairments were common: 62% reported dependence in one or more instrumental activities of daily living (IADL), 76.9% had polypharmacy (four or more medications), and 47.5% had one or more comorbidities. Median time on the Timed Up and Go was 13.3 ± 4.9 seconds. Those considered candidates for autologous stem cell transplant (N = 26) were younger, with fewer comorbidities, better performance status, and faster performance on the Timed Up and Go test. Factors independently associated with receiving autologous stem cell transplant (N = 21) included age and IADL dependence. Conclusion Impairments in geriatric domains are common in this population, even among those considered to have a good performance status. Geriatric assessment domains are associated with both transplant eligibility and receipt. J Am Geriatr Soc 67:987-991, 2019.

OBJECTIVE: Multiple myeloma (MM) is a cancer of older adults with a median age at diagnosis of 70 years. Our study aimed to understand the changes that occurred in geriatric domains and quality of life parameters as older adults underwent treatment for MM over 6-months following initial diagnosis. METHODS: This was a secondary analysis of a prospective cohort study of 40 adults aged ≥65 with newly-diagnosed MM who completed the Cancer and Aging Research Group geriatric assessment and the Functional Assessment of Cancer Therapy (General and subscale Gynecologic Oncology Group-Neurotoxicity) quality of life tool at baseline and at 6 months following treatment initiation. RESULTS: Thirty-six participants completed 6-months of follow-up. There was no significant change in geriatric domains, including dependence in instrumental activities of daily living (IADLs). Compared to baseline, mental health improved at 6-months of follow-up (Mental Health Inventory-17 score, median 77.1 versus 84.3 at baseline and 6-months respectively, p

Background Serum free light chain (FLC) immunoglobulins are key biomarkers that aid in the diagnosis, prognosis and assessment of treatment response in patients with plasma cell disorders (PCD). Here we investigated the transference of manufacturer's reported κFLC, λFLC and κ to λ FLC reference intervals (RI) and established de novo FLC RI and diagnostic ranges on four instruments at three academic medical centers. In addition, we also compared the classification of patient FLC results using manufacturer's versus established RIs and diagnostic ranges. Methods CLSI EP28-A3C protocol was applied to investigate transference and establishment of FLC reference intervals on the cobas (Roche), Immage (Beckman), Optilite and SPA Plus (Binding Site). Serum κ FLC and λ FLC were measured in reference sera (N = 126) with estimation of central 95% RIs and FLC ratio diagnostic range (total range). Frequencies (%) in patient FLC results (N > 380 per institution) classified above, below or within manufacturer's versus established FLC RI were compared. Results Three of four instrument platforms did not exhibit acceptable transference of manufacturer's reported κ FLC RI. The manufacturer's reported FLC total diagnostic range did not encompass all values observed in reference sera for any of the four platforms evaluated. Established FLC ratio diagnostic ranges reduced the frequency of patient results classified above range for three of four platforms evaluated. Conclusions Transference of manufacturer's reported FLC RIs may be inappropriate for select instrument platforms. De novo establishment of FLC RIs specific to instrument platform is highly recommended in order to assure correct patient result classification.

Background With the expanding armamentarium of therapeutic agents for multiple myeloma (MM), it is important to identify any undertreated patient populations to mitigate outcome disparities. Materials and Methods We extracted the data for all plasma cell myeloma cases (International Classification of Disease for Oncology, third revision [ICD-O-3] code 9732) in the Surveillance, Epidemiology, End Results (SEER)–Medicare database from 2007 to 2011. The ICD-O-3 histologic code 9732 captures both active MM and smoldering/asymptomatic myeloma. We defined active MM as either claims indicating receipt of treatments approved for MM or ICD-9 codes for MM-defining clinical features, referred to as the CRAB criteria (calcium [elevated], renal failure, anemia, bone lesions). Multivariate logistic regression was performed to determine the variables that were independently associated with receipt of no treatment. Results Of the initial 4187 patients included in the present study, 373 had no claims indicating receipt of treatments approved for MM and had no ICD-9 codes associated with the CRAB criteria and were excluded from the analyses. Of the 3814 patients with active MM, 1445 (38%) did not have any claims confirming that they had received systemic treatment. Older age, poor performance indicators, comorbidities, African-American race, and lower socioeconomic status, including enrollment in Medicaid, were statistically significant factors associated with the receipt of no systemic treatment. Conclusions In the present retrospective study of data from the SEER–Medicare database, we found that age, health status, race, and socioeconomic status were associated with receipt of MM treatment. These factors have previously been linked to reduced usage of specific treatments for MM, such as stem cell transplantation. To the best of our knowledge, however, ours is the first study to show their association with the receipt of any MM therapy.

Introduction Physically frail older adults with hematological malignancies experience greater treatment-related toxicity, higher rates of treatment non-completion, increased utilization of health care services, and shorter overall survival than younger and fitter patients. For frail adults, living in areas of high social vulnerability may also place them at disproportionately higher risk of experiencing poor health outcomes. Yet, the association between community-level social vulnerability and physical frailty among patients with hematological malignancies has not been previously described. Methods We used a previously developed frailty index [Carolina Frailty Index (CFI)] (Guerard et al., 2017) of accumulated health deficits, derived from geriatric assessment data of participants enrolled in the Carolina Senior Registry (CSR) (ClinicalTrials.gov identifier: NCT01137825) at the University of North Carolina at Chapel Hill or the Registry for Adults with Plasma Cell Disorders (ClinicalTrials.gov identifier: NCT03717844). In this cross-sectional study, we examined the association between county-level social vulnerability [Centers for Disease Control Social Vulnerability Index (CDC SVI)] (https://www.atsdr.cdc.gov/placeandhealth/svi/data_documentation_download.html. Accessed on July 1, 2021) and physical frailty in adults with hematological malignancies enrolled in the registries. In a cohort of 338 patients (CFI score range, 0-1), patients with a CFI score of 0.2 or above were considered frail. Social vulnerability was measured using participant residential zip codes and county locations linked to the overall SVI and each of the four domains: 1, socioeconomic status; 2, household composition & disability; 3, minority status & language, and 4, housing & transportation, that comprise the overall SVI (score range 0-1, with 1= most vulnerable). We used cut points of 0.2, 0.4, 0.6, and 0.8 to stratify the level of social vulnerability. Associations were made using Jonkherre-Terpstra tests for trends. All analyses were performed using SAS version 9.4 (SAS Institute, Inc). All tests were 2-sided, and p < 0.05 was considered statistically significant. Results Among 338 patients [51% male, 70% aged ≥ 70 years (median age 72.5 years) 84% White], multiple myeloma was the most common cancer type (45%), followed by lymphoma (30%) and leukemia (23%). Overall, 52% (n=177) of patients were considered frail. Just over half of the sample (53%, 179/338) lived in a county with an SVI Conclusion Among older adults with hematological malignancies, those residing in areas of high social vulnerability were more likely to be physically frail. These findings suggest that external, contextual factors significantly influence an individual's overall health and highlight the need for further work in this area. Future research should examine community social vulnerability as a risk factor for physical frailty development in adults; information could then be leveraged to identify those at greatest risk for functional losses and frailty onset. Through early identification of this subset of patients, preventative strategies and interventions could be developed, and resources allocated to help those considered most vulnerable. Figure 1 Figure 1. Disclosures Rubinstein: Sanofi: Consultancy; Roche: Consultancy. Wildes: Sanofi: Consultancy; Seattle Genetics: Consultancy; Carevive: Consultancy; Janssen: Consultancy. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy.

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.

Background: Once multiple myeloma (MM) becomes refractory to αCD38 mAb, pts have limited effective treatment options and poor prognoses. With standard therapies, overall response rate (ORR) to the first regimen after refractoriness to an αCD38 mAb is 31%, median progression-free survival (PFS) - 3.4 months and median overall survival (OS) - 9.3 months (Gandhi et al, Leukemia, 2019). Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins. XPO1 is required for MM cell growth, is associated with poor prognosis and mediates resistance to standard MM and other anticancer therapies. Selinexor (SEL) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound approved for patients (pts) with previously treated MM as well as DLBCL. The doublet SEL-dexamethasone (Xd) achieved ORR ~26% in triple-class (Immunomodulatory drug [IMiD], proteosome inhibitor [PI], αCD38 mAb) refractory MM and improved OS over matched cohorts in community (Richardson et al, eJHaem, 2021) and academic (Cornell et al, AJH, 2020) settings. Hence, SEL-based triplets could be more effective in this triple class-treated population. We analyzed the efficacy and safety of SEL-containing triplets in pts in the STOMP study who were previously treated with regimens containing αCD38 mAb. Methods: STOMP is a multi-arm, open-label, Phase 1b/2 study evaluating SEL in various combinations (NCT02343042). Here, we analyzed ORR, clinical benefit rate (CBR), duration of response (DOR), PFS, OS, and treatment-emergent adverse events (TEAEs) of pts who received Xd plus pomalidomide (XPd, n=23) or carfilzomib (XKd, n=23) after prior therapy with αCD38 mAb. Results: Among 46 pts treated, median age was 64 yrs (XPd), 70 yrs (XKd), females 57% (XPd) and 39% (XKd), median time from diagnosis was 5 yrs, and median number of prior regimens 4 (range, 2-10). All pts were previously treated with a PI and IMiD and αCD38 mAb; 78% (XPd) and 52% (XKd) had triple refractory MM. Prior treatment with αCD38 mAb included daratumumab (XPd: 91%, XKd: 100%) and isatuximab (XPd: 9%); 52% (XPd) and 74% (XKd) had αCD38 mAb in their most recent prior regimen. Refractoriness to daratumumab was documented in 87% (XPd) and 96% (XKd); isatuximab in 9% (XPd). Median durations from end of most recent αCD38 mAb therapy to first dose of study treatment were 8 weeks (XPd), 4 weeks (XKd). Among evaluable pts, ORR and CBR were 52% and 76%, respectively in the XPd arm (n=21; 2 pts were not efficacy evaluable) and 65% and 74%, respectively in the XKd arm. In the XPd arm median PFS was 8.7 months (95% CI: 7.6, NE), median DOR was 7.9 months (95% CI: 3.9, NE), and median OS was 21.8 months (95% CI: 8, NE). In the XKd arm median PFS was 15 months (95% CI: 12.0, NE), median DOR was 13.1 months (95% CI: 10.2, NE), and median OS was 33.0 months (95% CI: 20.4, NE). Among the evaluable pts, response to SEL-containing triplets compared favorably to the prior αCD38 mAb-containing regimen used at least 1 line earlier: XPd arm (n=21), ORR 52% vs 58% for prior regimen, CBR 76% vs 58%, median PFS 8.7 months (95% CI: 7.6, NE) vs 10.2 months (95% CI: 5.2, 20.5); XKd arm (n=23), ORR 65% vs 52%, CBR 74% vs 57%, median PFS 15.0 months (95% CI: 12.0, NE) vs 8.5 months (95% CI: 5.9, 17.3). The most common hematological TEAEs (total; grade≥3) were thrombocytopenia (XPd: 35%; 30%; XKd: 78%; 39%), anemia (XPd: 57%; 39%; XKd: 57%; 22%), and neutropenia (XPd: 57%; 48%; XKd: 35%; 4%). Other common TEAEs (total; grade≥3) were nausea (XPd: 74%; 0; XKd: 74%; 4%), fatigue (XPd: 61%; 4%; XKd: 52%; 4%) and decreased appetite (XPd: 48%; 4%; XKd: 48%; 4%). No cases of severe bleeding with thrombocytopenia occurred. Three pts (13%, all XPd) had febrile neutropenia (the outcome of which was fatal in 1 pt, deemed related to SEL and pomalidomide). TEAEs were managed with standard supportive care and dose modifications. Summary/Conclusion: XPd and XKd administered to pts with heavily pretreated MM, including prior αCD38 mAb therapy, exhibit tolerability and comparable effectiveness to that of the prior αCD38 mAb-containing regimen. These results suggest that the use of SEL-containing triplets, implementing the novel XPO1 inhibition mechanism, can provide prolonged disease control with good tolerability rather than recycling previously utilized drugs/mechanisms. The all oral XPd regimen will be evaluated in Study EMN29 against elotuzumab-Pd in patients who have received lenalidomide, a PI and an αCD38 mAb. Disclosures Lentzsch: Janssen: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Oncopeptides: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Bahlis: Takeda: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Sebag: Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Janssen: Research Funding. Sutherland: Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Amgen: Consultancy. Monge: Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Research Funding. Gasparetto: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; Janssen: 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; BMS: Consultancy; Connect Registry: Membership on an entity's Board of Directors or advisory committees. Baljevic: Exelixis: Research Funding; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Janssen Research: Other: Advisory Board; Oncopeptides: Other: Advisory Board; BMS/Celgene: Consultancy; Amgen: Research Funding. Venner: Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; BMS: Honoraria; GSK: Honoraria; Takeda: Honoraria. White: Amgen, Antengene, BMS/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: Consultancy, Honoraria. Kotb: Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Akcea: Honoraria; Pfizer: Honoraria. Chen: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Schiller: Celator: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Tolero: Research Funding; Constellation Pharmaceuticals: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Sangamo: Research Funding; Trovagene: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Cyclacel: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Forma: Research Funding; Daiichi-Sankyo: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Delta-Fly: Research Funding; FujiFilm: Research Funding; Deciphera: Research Funding; Arog: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Regimmune: Research Funding; Ono: Consultancy; Samus: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Madan: Karyopharm: Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Leblanc: Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Amgen 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. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Kauffman: 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) .

Background: Overexpression of the nuclear export protein exportin 1 (XPO1) mediates the functional inactivation of tumor suppressor proteins (TSPs), facilitates the export of oncogene mRNA thus facilitating oncoprotein expression, is associated with poor prognosis in multiple myeloma (MM), and contributes to immunomodulatory drug (IMiD) resistance. Selinexor is an oral, first-in-class, selective inhibitor of nuclear export (SINE) compound that by blocking XPO1 forces the nuclear retention and activation of TSPs and nuclear retention and inactivation of oncoproteins. 1 Selinexor is approved with low-dose dexamethasone ± bortezomib for patients with previously treated MM. Pomalidomide plus dexamethasone (Pd) has an overall response rate (ORR) of ~30% and median PFS (mPFS) of ~4 months in patients with MM refractory to bortezomib and lenalidomide. We hypothesized that selinexor could be safely combined with Pd (XPd) and would improve the combination's efficacy. Methods: In the XPd arm of the multi-arm Phase 1b/2 STOMP study, selinexor was evaluated at 60, 80, or 100 mg in combination with Pd. Study objectives were to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) and to assess the safety and activity of the XPd regimen. The dose of selinexor 60 mg once weekly (QW), pomalidomide 4 mg once daily (days 1-21), dexamethasone 40 mg QW (XPd-60) was the lowest evaluated dose of selinexor in combination with the approved dose of Pd, and in light of the marked efficacy of that dose (ORR 65%), Phase 2 cohorts at a lower (40 mg weekly) dose of selinexor (XPd-40), were evaluated. Of the 19 patients enrolled at XPd-40 and evaluable for efficacy, 12 patients were enrolled into STOMP and 7 patients were enrolled at the same dose level and similar inclusion criteria into a parallel study XPORT-MM-028. Results: As of 14 July 2021, 39 patients were enrolled into the 60 (N=20) and 40 (N=19) mg selinexor dose levels in combination with Pd: 19 males, median age 66.0 years (range 37-85 years), median number of prior lines of therapy 2 (range 1-9). 85% of patients had MM refractory to a proteasome inhibitor (PI; bortezomib or carfilzomib or ixazomib), 79% to an IMiD (thalidomide or lenalidomide or pomalidomide), 33% to an anti-CD38 mAb (daratumumab or isatuximab); 26% had triple class refractory disease. Common hematologic, treatment-emergent adverse events (TEAEs) consisted of (all grades, grade ≥3) neutropenia (72%, 59%; and two cases of grade 3 [G3] febrile neutropenia one in each of the dose levels), and anemia (51%, 15% all G3). Non-hematologic TEAEs were reversible and included fatigue (56%, 10% all G3) and nausea (49%, 0%). On XPd-60, the RP2D (N=20), ORR was 65% (1 stringent complete response [sCR], 5 very good partial responses [VGPR], 7 PR); mPFS was 8.9 months (95% CI, 7.6 - NE, median follow-up 8.3 months). In patients treated at XPd-40 (N=19), ORR was 42% (3 VGPR, 5 PR); mPFS was not reached (95% CI, 5.7 - NE, median follow-up 2.8 months). Among patients who had received anti-CD38 mAb, the ORR was 64% overall and 100% at the RP2D (1 sCR, 2 VGPR, 3 PR). All patients who had MM refractory to pomalidomide (N=3; all at the 60 mg dose level) responded with 1 VGPR and 2 PR. For the 21 responders across both dose levels, median time to response was 1.0 months (95% CI 1.0 - 2.0) and median duration of response was not reached (95% CI: 8.0, NE). Conclusions: Selinexor, once weekly, can be safely combined with Pd in patients with relapsed MM. The all-oral combination of XPd is highly active with an ORR of 65% at XPd-60, the RP2D, and an ORR of 42% at XPd-40 dose level (compared to expected ORR ~30% for Pd). The high ORR that was achieved at the RP2D, including in patients previously treated with anti-CD38 mAb, supports XPd-60 as a promising therapy with no significant cross-resistance to anti-CD38, PIs or lenalidomide. No new safety signals were identified. The most common TEAE, neutropenia, is a common AE of Pd and was managed effectively with standard G-CSF. The regimen leverages the concept of mechanism switching from an anti-CD38 mAb-based regimen to a selinexor-based regimen. These data support the new Phase 3 study (XPORT-MM-031) with an all-oral combination of XPd vs elotuzumab-Pd in patients who have been previously treated with lenalidomide, a PI, and an anti-CD38 mAb. Figure 1 Figure 1. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Forus: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria. Chen: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Baljevic: BMS/Celgene: Consultancy; Exelixis: Research Funding; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Amgen: Research Funding; Janssen Research: Other: Advisory Board; Oncopeptides: Other: Advisory Board. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy. Bahlis: Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria. Schiller: Eli Lilly: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ambit: Research Funding; MedImmune: Research Funding; Cyclacel: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Trovagene: Research Funding; Gamida Cell Ltd.: Research Funding; Bio: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; Deciphera: Research Funding; Regimmune: Research Funding; Delta-Fly: Research Funding; FujiFilm: Research Funding; Tolero: Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Daiichi-Sankyo: Research Funding; Celator: Research Funding; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Elevate: Research Funding; Samus: Research Funding; PrECOG: Research Funding; Constellation Pharmaceuticals: Research Funding; Onconova: Research Funding; Novartis: Consultancy, Research Funding; Ono-UK: Consultancy, Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Sangamo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Pharma: Consultancy; Sanofi: Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Kotb: Akcea: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Amgen: Honoraria; Pfizer: Honoraria; Merck: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; BMS: Honoraria. Sutherland: Celgene: Consultancy; Karyopharm: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy. Bensinger: Amgen, BMS, Janssen, Sanofi: Speakers Bureau; BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding. Madan: Amgen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Sebag: Janssen: Research Funding; Takeda: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Venner: GSK: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria. Leblanc: BMS/Celgene 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; 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; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding. Monge: Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Zhang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. 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. Gasparetto: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Connect Registry: 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.

Background : Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing cell death in cancer cells. SEL 80 mg and dexamethasone (dex) 20 mg, both twice weekly (BIW), received accelerated approval from the FDA for patients (pts) with relapsed refractory multiple myeloma (RRMM). SEL continues to be evaluated in earlier lines of therapy with once weekly administration and in combination regimens. The SVd regimen with once weekly (QW) oral SEL (100 mg), dexamethasone (dex) and QW bortezomib (BOR) had significantly increased progression free survival (PFS) and overall response rate (ORR) with significantly reduced peripheral neuropathy as compared to standard BIW BOR/dex (Vd) in the phase III BOSTON study. The combination of lenalidomide (LEN) and dex (Rd) is an approved regimen in RRMM and newly diagnosed MM (NDMM) with an ORR of 70-76% in RRMM but a low complete response rate. SEL showed synergistic antitumor activity with LEN in a MM xenograft model. Therefore, we hypothesized that the all oral combination of weekly SEL with standard Rd (i.e., SRd) could improve the efficacy compared with Rd in pts with RRMM and NDMM with acceptable toxicity profile. Methods: STOMP is a phase 1b/2 multicenter, open-label, clinical trial with the goals of determining the maximum tolerated dose, the recommended phase 2 dose (RP2D), efficacy and safety of SRd in pts with RRMM or NDMM. For RRMM, SEL was dose escalated in two regimens QW (starting at SEL 80 mg) or BIW (starting at 60 mg), LEN 25 mg PO daily and DEX 20 mg BIW or 40 mg QW. Results: As of June 1, 2020, 24 pts (13 male, 11 female) with RRMM were enrolled. The median age was 67 years (range, 49-84) and the median number of prior lines of therapy was 1.5 (range, 1 - 8). In the 60 mg BIW dosing, 4 pts experienced dose limiting toxicities (DLTs) out of 5 pts dosed (2 thrombocytopenia, 1 anorexia, 1 >25% missed dose due to unrelated QT interval prolongation). In the 80 mg QW dosing, 2 pts experienced DLTs out of 6 pts (both grade 4 thrombocytopenia). In the 60 mg QW dosing, no DLTs were observed. Based on these data, the RP2D of SRd was determined to be: SEL 60 mg QW, LEN 25 mg QD and DEX 40 mg QW. Common treatment related adverse events (TRAEs) (All Grades, ≥3) were thrombocytopenia (71%, 63%), neutropenia (63%, 63%), nausea (58%, 4%), fatigue (54%, 17%), decreased appetite (50%, 8%), and weight loss (42%, 8%). Amongst the 20 pts with RRMM where efficacy was evaluable, previously treated/documented refractory rates were: bortezomib (100%, 45%), LEN (40%, 25%), daratumumab (20%, 20%), and pomalidomide (20%, 20%). Amongst the LEN naïve pts (n=12), the ORR was 92% including 1 stringent complete response [sCR], 4 very good partial responses [VGPR] and 6 partial responses [PR, 2 unconfirmed]). PFS in LEN naïve pts has not been reached with a median follow-up period of 7.8 months. In the pts with prior LEN treatment (n=8), the ORR was 13%. Based on the high levels of activity of SRd in LEN naïve pts, 8 pts (4 males and 4 females) with NDMM were enrolled at the RP2D. The median age was 74 (range: 51-86) years. No DLTs were observed in 5 DLT evaluable pts. Common TRAEs (All Grades, ≥3) were thrombocytopenia (63%, 38%), neutropenia (75%, 75%), fatigue (63%, 50%), nausea (50%, 0%), weight loss (63%, 0%), and decreased appetite (13%, 13%). All 7 efficacy evaluable pts achieved a response, an ORR of 100%, including 1 CR, 4 VGPR, and 2 PR. With a median follow-up of 10.2 months, median PFS has not been reached. Out of these 7 pts, three pts withdrew consent to transit to successful autologous stem cell collection and transplantation. Conclusions: The all oral combination of SRd with once weekly SEL 60 mg, LEN 25 mg QD and DEX 40 mg QW was established as the RP2D for pts with RRMM or NDMM. The safety profile was similar in both settings. All TRAEs were manageable with adequate supportive care and/or dose modification. The all oral combination of SRd has demonstrated ORR of 92% in pts with LEN naïve RRMM and ORR of 100% in pts with NDMM, warranting further investigation of SRd with or without additional anti-MM agents for the treatment of pts with NDMM. Disclosures White: Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Baljevic:NCCN Hematologic Malignancies Congress: Honoraria; MediCom Myeloma CME: Honoraria; Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria. Bahlis:Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Lentzsch:Celularity: Consultancy; Sorrento: Consultancy; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Sanofi: Research Funding; Magenta: Current equity holder in private company; Karyopharm: Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Chen:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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, Research Funding; AbbVie: 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; Sanofi: Research Funding. Lipe:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Tuchman:Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding; Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Kotb:Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in publicly-traded company; Takeda: Honoraria; Celgene: Honoraria; Sanofi: Research Funding; Amgen: Honoraria; Janssen: Honoraria. Sebag:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria; Takeda: Honoraria. Callander:Cellectar: Research Funding; University of Wisconsin: Current Employment. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rossi:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Zhou:Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Kazuharu: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. Schiller:Ariad: Research Funding; Actinium: Research Funding; Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Kaiser Permanente: Consultancy; Trovagene: Research Funding; Tolero: Research Funding; Sangamo: Research Funding; Samus: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; Astellas Pharma: Honoraria, Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Abbvie: Research Funding; Constellation: Research Funding; Ono Pharma: Consultancy; Novartis: Consultancy, Research Funding; Stemline: Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Gilead: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Forma: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding.

Background: Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells. The SVd regimen with once weekly (QW) oral SEL (100 mg), dexamethasone (dex) and QW bortezomib (BOR) had significantly increased progression free survival (PFS) and overall response rate (ORR) with significantly reduced peripheral neuropathy as compared to standard twice weekly BOR/dex (Vd) in the phase III BOSTON study. Pomalidomide (POM) plus dex (Pd) achieved an ORR of 31% and PFS of 4 months in patients (pts) with disease refractory to BOR and lenalidomide (LEN). We hypothesize that the all oral Pd combination with the addition of QW SEL (SPd) would demonstrate improved activity and acceptable tolerability as compared with Pd. Methods: STOMP is a multicenter, open-label, phase 1b/2, dose escalation study with an expansion phase. Pts with RRMM who received ≥ 2 prior therapies including LEN and a proteasome inhibitor (in separate or the same regimens) were eligible for enrollment. Oral SEL was evaluated in 2 different dosing schedules in 28 days cycle: QW 60, 80 or 100 mg or twice weekly (BIW) 60 or 80 mg, with escalating doses of POM 2, 3 or 4 mg (days 1-21), and dex 20 mg BIW or 40 mg QW. The primary objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, ORR and PFS of the combination of SPd in pts with RRMM. Results: As of June 1 2020, 52 pts (28 male and 24 female) were enrolled. The median age was 64 (range: 43-85) years. Pts received a median of 3 (range: 1-10) prior therapies including 44 (84.6%) with autologous stem cell transplantation. During the escalation phase, eight dose limiting toxicities (DLTs) were observed (Table 1). Common hematologic treatment related adverse events (TRAE) included (All Grades, Grades ≥3) neutropenia (62%, 56%), anemia (60%, 37%), and thrombocytopenia (56%, 35%). Common non-hematologic TRAE included nausea (62%, 2%), fatigue (56%, 12%), decreased appetite (48%, 2%), weight loss (42%, 0%), diarrhea (35%, 0%), vomiting (23%, 2%). Rates of ≥ Grade 3 hematological TRAEs were lower in QW vs BIW schedules of SEL: thrombocytopenia (29% vs 44%) and anemia (32% vs 44%). Based on all of the safety data, the RP2D was SEL 60 mg QW, POM 4 mg (days 1-21), and DEX 40 mg QW. Out of 52 pts, 47 were evaluable for response. Previously treated / refractory rates were as follows (N=47 pts evaluable for efficacy): LEN (100% / 96%), BOR (94%, 45%), carfilzomib (38%, 34%), POM (30%, 30%), daratumumab (21%, 21%). Among POM naïve pts (N=33), all pts (100%) received prior LEN and 31 pts (94%) had MM documented LEN refractory. Among pts who were POM naive (N=33), the ORR was 58% (1 CR, 5 very good partial responses and 13 partial responses) and the median PFS and OS were 12.3 and 19.0 months, respectively. Amongst pts who received POM previously (N=14), the ORR was 36% (1 VGPR and 4 PR), and the median PFS and OS were 8.8 and 8.0 months, respectively. Conclusions: The RP2D is SEL 60 mg QW, POM 4 mg QD and dex 40 mg QW. The ORR was 58% in pts in LEN treated or refractory and POM naïve MM compared to previously published data of 31% ORR with Pd in a similar population. The median PFS on SPd of 12.3 months in POM naïve pts is longer than that historically observed with Pd (~4 months). All TRAEs were expected and manageable with appropriate supportive care (eg, G-CSF) and/or dose modifications. The all oral SPd combination appears to confer relatively high ORR with good durability and promising PFS in pts with heavily pretreated MM. Disclosures Chen: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bahlis:Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. Tuchman:Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding. Lipe:Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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. Baljevic:Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; MediCom Myeloma CME: Honoraria; NCCN Hematologic Malignancies Congress: Honoraria. Kotb:Celgene: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in publicly-traded company; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Amgen: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. LeBlanc:Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schiller:Kite Pharma: Research Funding; Ariad: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; DeltaFly: Research Funding; MedImmune: Research Funding; Stemline: Speakers Bureau; Actinium: Research Funding; Abbvie: Research Funding; Jazz Pharmaceuticals: Research Funding; Forma: Research Funding; Novartis: Consultancy, Research Funding; Cyclacel: Research Funding; AstraZeneca: Consultancy; Mateon: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Gamida: Research Funding; FujiFilm: Research Funding; Geron: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Constellation: Research Funding; Genentech-Roche: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Deciphera: Research Funding. Lentzsch:Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sorrento: Consultancy; Celularity: Consultancy; Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Sanofi: Research Funding; Magenta: Current equity holder in private company. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Wang:Karyopharm: Current Employment; Curis: Ended employment in the past 24 months. 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. White:Sanofi: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Background : Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins that cause cell cycle arrest and apoptosis in cancer cells. The combination of SEL with dexamethasone (dex), each administered twice weekly (BIW), received accelerated approval from the FDA in relapsed refractory multiple myeloma (RRMM). Subsequent evaluations of combination regimens have utilized once weekly (QW) SEL. The addition of oral SEL 100 mg QW to bortezomib also QW with dex (SVd) showed superior PFS and ORR with reduced peripheral neuropathy compared with standard BIW bortezomib plus dex (Dimopoulos et al. JCO 2020). SEL sensitized the activity of carfilzomib (CAR) in PI-resistant MM cell lines in vitro and ex vivo in PI-refractory MM cells derived from bone marrow aspirates of patients (pts) with RRMM. SEL and CAR also showed synergistic anti-tumor activity in a NOD-SCID mice xenograft model in vivo. Furthermore, a phase I trial in RRMM pts demonstrated that the combination of SEL and CAR both administered BIW with DEX showed high overall response rates (ORR) in pts with MM refractory to CAR. Carfilzomib QW was recently approved and we hypothesized that the addition of SEL QW to CAR QW plus dex (SKd) would be synergistic and convenient with an acceptable adverse event (AE) profile. Methods: STOMP is a phase 1b/2 multicenter, open-label, clinical trial with the goals of determining the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and the ORR according to the International Myeloma Working Group (IMWG) criteria. The starting SEL dose was 100 mg QW with 20/56 mg/m2 QW CAR (20 mg/m2 only on C1D1 and 56 mg/m2 thereafter, dosed Day 1, 8, and 15, 28 days cycle) with 40 mg QW DEX (Table 1). Eligible pts had MM progressing on study entry that was not refractory to CAR, were ≥ 18 years old, with Eastern Cooperative Oncology Group (ECOG) score of 0-2, WBC ≥ 1,500/mm3,Hb ≥ 8.0 g/dL, and platelet count ≥ 75,000/mm3. Results: The MTD was 20/56 mg/m2 CAR + 80 mg SEL + 40 mg DEX, all given QW. As of May 1, 2020, a total of 24 pts enrolled, of which 17 received the MTD. Median age was 70.5 (range, 50-76) years, 62.5% male, median number of prior therapies 3 (range, 1-8). Median years from initial diagnosis 5.0 (range, 2.7-11.3) years. Prior therapies in the 24 pts included bortezomib 24 pts (100%), lenalidomide 23 pts (95.8%), pomalidomide 15 pts (62.5%), daratumumab 14 pts (58.3%) and 19 (79.2%) stem cell transplantation. Common hematopoietic treatment-related AEs (TRAEs) were thrombocytopenia (70.8% all grades, 54.2% grades 3/4) and anemia (54.2%, 20.8%). Common non-hematological TRAEs were nausea (66.7%, 0%), fatigue (54.2%, 8.3%), anorexia (45.8%, 4.2%), weight loss (37.5%, 0%), and dysgeusia (37.5%, 0%). All TRAEs were expected and manageable with appropriate supportive care (eg, TPO receptor agonists for thrombocytopenia) and/or dose modifications; long term cumulative toxicities have not been observed. ORR was 75.0% including 4 CR (16.7%), 7 VGPR (29.2%) and 7 PR (29.2%). There was 1 MR yielding a clinical benefit rate of 79.2%. Amongst the 14 pts previously treated with daratumumab, 8 pts (57.1%) achieved ≥PR, 9 pts (64.3%) achieved ≥MR. Median time to the first response (≥PR) was 28 days (range, 27-98 days). Median progression free survival has not been reached with a median follow-up of 4.4 months. Conclusions: Weekly SKd (20/56 mg/m2 CAR + 80 mg SEL QW + 40 mg DEX QW) is active with an ORR of 75.0% and deep responses (CR 16.7%, VGPR 29.2%) in pts who had a median of 3 prior lines of therapy including bortezomib and lenalidomide. The ORR of 57.1% in patients previously treated with daratumumab warrants further investigation of this once weekly regimen in 1st or 2nd relapse including among patients with prior daratumumab. Disclosures Lipe: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Tuchman:Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding; Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Lentzsch:Sanofi: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Celularity: Consultancy; Sorrento: Consultancy; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Magenta: Current equity holder in private company; Karyopharm: Research Funding. Baljevic:NCCN Hematologic Malignancies Congress: Honoraria; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Exelixis: Research Funding; MediCom Myeloma CME: Honoraria. Rossi:BMS: 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. Bahlis:Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. White:Sanofi: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Chen:AbbVie: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: 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; Sanofi: Research Funding. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Kotb:Karyopharm: Current equity holder in publicly-traded company; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Research Funding. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Schiller:MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Gilead: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Mateon: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding.

8038 Background: Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins (TSPs), is associated with poor prognosis in MM, and contributes to proteasome inhibitor (PI) and immunomodulatory drug (IMiD) resistance. Selinexor (SEL) is a novel, oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, forcing the nuclear retention and activation of TSPs. SEL in combination with low dose dexamethasone (dex) ± bortezomib (BOR) is FDA approved for previously treated MM. The synergy of SEL with the PI BOR has been confirmed in the phase 3 BOSTON study in MM patients (pts) with 1-3 prior therapies; once weekly (QW) SEL, QW BOR, and dex (XVd) significantly increased progression-free survival (PFS), time to next therapy, and overall response rate (ORR) as compared to standard twice weekly BOR/dex (Vd), despite XVd using 40% less BOR and 25% less dex than standard Vd. We hypothesized that the addition of QW SEL to the PI carfilzomib (CAR)-dex (XKd) would be an active and tolerable regimen in pts with heavily pretreated MM. Methods: In the XKd arm of the multi-arm Phase 1b/2 STOMP study, SEL at 80 or 100 mg QW was evaluated in combination with CAR at 56 or 70 mg/m2 QW plus dex at 40 mg QW in pts with heavily pretreated MM not refractory to CAR. Study objectives were to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) and assess the safety and activity of the XKd regimen. Results: As of 4Jan2021, 27 pts were enrolled: 18 (67%) were male, median age 71 years (range 50-76), and median of 4 (range 1-8) prior lines of therapy. All 27 pts were previously treated with BOR, 26 (96%) lenalidomide (LEN), 19 (70%) pomalidomide (POM), 18 (67%) daratumumab (dara). The majority (67%) of pts were triple-class pretreated (PI, IMiD, and anti-CD38 mAb), and 44% had triple-class refractory MM. Nine pts (33%) had MM quad-refractory to BOR, LEN, POM, and dara. Common hematologic treatment-related adverse events (TRAEs) (total, grade ≥3) included thrombocytopenia (74%, 56%), anemia (59%, 19%), and neutropenia (30%, 7%). Non-hematologic TRAEs included nausea (67%, 4%), fatigue (52%, 7%), and anorexia (52%, 4%). RP2D was identified as SEL 80 mg QW, CAR 56 mg/m2 QW, and dex 40 mg QW. As of 3Feb2021, ORR was 78% (21/27) with 5 pts reaching CR (19%), 8 VGPR (30%), and 8 PR (30%). Median PFS was 23.7 months. Among 18 pts pretreated with dara, ORR was 67% and median PFS 23.7 months. In 9 pts whose MM was refractory to BOR, LEN, POM, and dara, ORR was 67% with 4 VGPR (44%). Conclusions: In pts with heavily pretreated MM, weekly XKd is highly active with an ORR of 78% and deep responses (≥VGPR 48%) with an overall PFS of 23 months. All AEs including grade 3/4 thrombocytopenia can be managed with appropriate supportive care and dose modifications. These data support further investigation of XKd in pts with previously treated MM including those previously treated with dara.

e20004 Background: Multiple myeloma (MM) and immunoglobulin light chain (AL) amyloidosis are clonal plasma cell disorders (PCDs) of aging, with median ages at diagnosis of 69 and 76 years, respectively. The care of adults with these disorders is often challenging due to the higher prevalence of vulnerabilities with advancing age. We examined the prevalence of physical or cognitive impairments and associations with quality-of-life (QoL) ratings in a longitudinal cohort of adults with PCDs. Methods: Adults undergoing treatment for PCDs were recruited to a longitudinal observational study (NCT03717844) from 2018 to 2020. A modified Cancer and Aging Research Group (CARG) geriatric assessment (GA) was administered at enrollment. Patients also completed the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30), which provided subscales of physical function, cognitive function, and global QoL (range 0-100; higher values indicate better function or QoL). Univariate linear regression was used to evaluate associations at the time of enrollment. Results: Among 121 consecutive adults, the mean age was 69 years, 65.8% were aged ≥ 65 years, and 71.9% were white. Diagnoses included MM in 73.6%, AL amyloidosis in 14.0%, and both disorders in 7.4%. The remaining 5.0% had another PCD warranting chemotherapy. Time from diagnosis at enrollment was ≤ 6 months for 25.6%, 6 to 24 months for 18.1%, and ≥ 24 months for 56.3%. In this cohort, 80.2% had a clinician-assessed Karnofsky Performance Status (KPS) score ≥ 80. GA-identified impairments (Timed Up and Go ≥ 14 seconds and dependence in ≥ 1 instrumental activity of daily living [IADL]) were seen in 29.8% and 35.6%, respectively, with 13.5% reporting ≥ 1 fall in the prior 6 months. Polypharmacy (≥ 5 medications) was identified in 80.0%. Self-reported physical and cognitive impairments on QLQ-C30 were described by 48.7% and 20.2%, respectively. Patients with functional deficits had worse EORTC QoL scores compared to those without deficits: dependence in ≥ 1 IADL (mean QoL score 66.3 vs. 79.9, p = 0.0009), ≥ 1 fall (56.7 vs. 76.8, p = 0.0009), self-reported physical impairment on QLQ-C30 (64.0 vs. 84.5, p < 0.0001), and self-reported cognitive impairment on QLQ-C30 (61.2 vs. 77.7, p = 0.0012). Conclusions: Using a modified CARG GA and the EORTC QLQ-C30, we identified physical and cognitive impairments among adults undergoing treatment for PCDs. GA-identified impairments in physical function were more prevalent than clinician-assessed KPS would suggest. Patients with physical and cognitive impairments had worse QoL scores than those without deficits. Future research involving this cohort will investigate the longitudinal trajectory of physical and cognitive functioning, evaluate trends in QoL measurements, and test the feasibility of implementing GA-guided interventions for this population.

8018 Background: Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins (TSPs), is associated with poor prognosis in MM, and contributes to proteasome inhibitor (PI) and immunomodulatory drug (IMiD) resistance. Selinexor (SEL) is a novel, oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, forcing the nuclear retention and activation of TSPs. SEL is approved with low-dose dexamethasone (dex) ± bortezomib (BOR) for patients (pts) with previously treated MM. In the Phase 3 BOSTON study, once weekly (QW) SEL, QW BOR, and dex (XVd) significantly increased progression-free survival (PFS) and overall response rate (ORR) with marked reduction of peripheral neuropathy as compared to standard twice weekly BOR/dex (Vd), despite XVd utilizing 40% less BOR and 25% less dex than Vd. Pomalidomide (POM) plus dex (Pd) has an ORR of 31% and median PFS (mPFS) of 4 months in MM pts refractory to BOR and lenalidomide (LEN). We hypothesized that the addition of once weekly SEL to Pd (XPd) would be an active, all-oral combination with an acceptable safety profile in pts with LEN refractory and BOR treated MM. Methods: In the SPd arm of the multi-arm Phase 1b/2 STOMP study, SEL was evaluated at 60, 80, or 100 mg QW or 60 or 80 mg twice weekly in combination with Pd. Study objectives were to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D), and assess the safety and activity of the SPd regimen including in pts receiving the RP2D. Results: As of 4 Jan 2021, 65 pts (33 male) were enrolled with median age of 64 years (range 37-85 years) and median of 3 (range 1-10) prior lines of therapy. Previously treated/refractory rates were LEN 100%/85%, BOR 92%/49%, carfilzomib 43%/37%, POM 31%/29%, and daratumumab (dara) 26%/26%. RP2D was SEL 60 mg QW, POM 4 mg (days 1-21), dex 40 mg QW. Common hematologic, treatment-related adverse events (TRAEs) included (all grades, grades ≥3) neutropenia (63%, 55%), anemia (58%, 32%), and thrombocytopenia (54%, 31%). Non-hematologic TRAEs included nausea (62%, 2%), fatigue (55%, 11%), and decreased appetite (45%, 2%). Among POM naïve or nonrefractory MM pts (N = 44), ORR was 57% (1 sCR, 1 CR, 8 VGPR, 15 PR); mPFS was 12.2 months. In pts treated with RP2D (N = 20), ORR was 65% (1 sCR, 5 VGPR, 7 PR); mPFS was not reached with a median follow-up time of 3.9 months. In POM-refractory pts and those with prior dara, ORR was 44% (7/16) and 60% (9/15), respectively. Conclusions: SEL, once weekly, can be safely combined with Pd in pts with heavily pretreated MM. No new safety signals were identified. The all-oral combination of XPd is highly active with an ORR of 65% at RP2D (compared to expected ORR ≤30% for Pd) and produces durable responses with a mPFS of 12.2 months overall. These data support a planned Phase 3 study with an all-oral combination of XPd vs Pd in pts who have been previously treated with LEN, a PI, and an anti-CD38 mAb. Clinical trial information: NCT02343042.

e18540 Background: Multiple myeloma (MM) is a disease of aging, associated with one of the greatest black-white disparities in incidence and mortality among all US cancer types. Clinical trials provide the critical evidence-base to inform clinical management in all cancers, including MM. However, clinical trial participants are often younger (age < 65 years) and white, limiting the generalizability of published data to real-world MM care. Although geographical and financial barriers to clinical trial participation are well recognized, less is known about the association of county-level social vulnerability with MM trial availability. We examined county-level variation in the number of registered myeloma trials per 10,000 North Carolina (NC) residents age ≥ 65 years as a function of social vulnerability and the presence of a National Cancer Institute Comprehensive Cancer Center (CCC). Methods: We conducted a cross-sectional study using data from ClinicalTrials.gov to identify all registered interventional myeloma trials involving adults age ≥ 65 years with sites in NC. Records were downloaded on January 24th, 2021. This strategy yielded 456 non-unique NC sites for 223 trials. We obtained county locations for all trial sites by matching city, zip code, or institution name. We obtained NC population data for residents age ≥ 65 years (in 2019) from the American Community Survey. The four themes (socioeconomic status, household composition, ethnic and racial minority status/language, housing/transportation) within the Centers for Disease Control Social Vulnerability Index (CDC SVI) (composite score: 0-1, with a higher number indicating more vulnerability) were used to characterize county-level social vulnerability. We performed negative binomial regression and tabulations using R, version 3.6.1. A p-value < 0.05 was considered statistically significant. Results: Across 100 counties in NC, trial site counts by county per 10,000 residents age ≥ 65 years ranged from 0 to 23.2 (mean: 1.5, median: 0; IQR, 0-0.7). Controlling for the 4 SVI themes, counties with CCCs (Durham, Forsyth, Orange) had 77% more trials than those without CCCs [Incidence Rate Ratio (IRR): 7.74; p = 0.05]. We observed a 3.3% reduction in trial counts with each percentile increase in socioeconomic vulnerability (IRR: 0.97; p = 0.008). Counties with higher representation by racial and ethnic minorities had similar trial site counts to counties with lower minority populations (IRR: 1.01; p = 0.08). Sub-group analyses of early-stage studies (phase 1/2 and phase 2; n = 268) and late-stage studies (phase 2/3 and phase 3; n = 168) were similar. Conclusions: Our preliminary results suggest county-level socioeconomic status is associated with the distribution of MM clinical trial sites across NC. Further work is planned to explore whether additional variances in trial distribution could be explained by site- and study-specific characteristics.

Since the early 2000s, treatment options for multiple myeloma have rapidly expanded, adding significant complexity to the management of this disease. To our knowledge, no systematic qualitative research on clinical decision-making in multiple myeloma has been published. We sought to characterize how physicians view and implement guidelines and incorporate novel approaches into patient care. We designed a semi-structured qualitative interview guide informed by literature review and an expert advisory panel. We conducted 60-minute interviews with a diverse sample of oncology physicians in the southeast United States. We used a constant comparative method to code and analyze interview transcripts. The research team and advisory panel discussed and validated emergent themes. Participants were 13 oncologists representing 5 academic and 4 community practices. Academic physicians reported using formal risk-stratification schemas, community physicians typically did not. Physicians also described differences in eligibility criteria for transplantation, community physicians emphasized distance, social support, and psychosocial capacity in making decisions about transplantation referral, the academic physicians reported using more specific clinical criteria. All physicians reported using a maintenance strategy both for post-transplant and for transplant-ineligible patients, however, determining the timing of maintenance therapy initiation and the response were reported as challenging, as was recognition or definition of relapse, especially in terms of when treatment re-initiation is indicated. Practices reported by both academic and community physicians suggest opportunities for interventions to improve patient care and outcomes through optimal multiple myeloma management and therapy selection. Community physicians in particular might benefit from targeted education interventions about risk stratification, transplant eligibility, and novel therapies.

Multiple myeloma (MM) is the second most common hematologic malignancy in the US. It is typically characterized by production of large amounts of defective immunoglobulin (Ig). Diagnosing MM and monitoring treatment response, including eventual relapse, are largely based on sequential measurements of Ig. However, a small subset of MM called non-secretory multiple myeloma (NSMM) produces no detectable Ig. This subset of true NSMM has become even smaller over time, as the advent of the serum free light chain assay has resulted in the majority of NSMM patients being recategorized as light-chain MM - that is, MM cells that produce only the light-chain component of Ig. True forms of NSMM, meaning MM that secretes no monoclonal proteins whatsoever, constitute a distinct entity that is reviewed; definition of NSMM using current detection methods, discuss the biology underpinning NSMM development, and share recommendations for how NSMM should be managed clinically with respect to detection, treatment, and monitoring.

Purpose Lenalidomide, bortezomib, and dexamethasone (RVd) has emerged as a preferred induction therapy in multiple myeloma (MM) in the United States. Due to lenalidomide's teratogenic risk, patients and prescribers must comply with a risk evaluation and mitigation strategy (REMS) program. The REMS program limits dispensing to certain third-party specialty pharmacies, whose average prescription fill times are longer than in-house specialty pharmacies. In practice, a delay in procurement of lenalidomide may mean that patients start therapy with only bortezomib and dexamethasone, delaying the start of more effective triplet therapy. The primary objective of this study is to determine if a delay from start of bortezomib and dexamethasone to start of triplet therapy with lenalidomide impacts rate of achievement of very good partial response (VGPR) after four cycles of RVd. Methods This was a single-center retrospective review of adults with newly diagnosed MM who received RVd induction therapy at University of North Carolina Medical Center between April 2014 and June 2017. Patients who started lenalidomide ≥10 days after bortezomib comprised the “Delay” group, while those who started lenalidomide concurrently with bortezomib or within 1–9 days after bortezomib comprised the “No Delay” group. The primary outcome was VGPR or better response rate after four cycles of RVd. Results Thirty-eight patients met inclusion criteria. Nine patients (23.7%) experienced any delay in initiation of lenalidomide, with a mean delay of 7.8 days (range 1–18). Four patients (10.5%) experienced a delay ≥10 days. No patients in the Delay group were of reproductive potential, compared to 8.8% in the No Delay group ( p = 0.54). VGPR or better response rate did not differ between the Delay and No Delay groups (66.7% vs. 58.8%, p = 0.79). The mean number of lenalidomide prescriptions generated per RVd cycle was 1.35 (range 1–5, SD 0.74). Conclusions This study did not demonstrate an effect on clinical response after delays ≥10 days between bortezomib and lenalidomide initiation. No patients in the delay group were females of reproductive potential, which is the primary target for increased safety behind the REMS program.

Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are plasma cell disorders of aging. The landscape of the diagnosis and management of MM and MGUS are rapidly changing. This article provides an updated understanding of the clinical presentation, evaluation, diagnosis, and management of older adults with MM and MGUS. Because most oncology providers are not formally trained in geriatric medicine, geriatricians play a key role in providing oncologists with a broader understanding of patient health status in the hope of improving outcomes for older adults with MM.

Context: To reduce infusion duration, fixed-volume infusion of isatuximab (Isa), a CD38 monoclonal antibody, was confirmed to be feasible and safe in the primary analysis. Objective: Evaluate efficacy and safety of a fixed-volume infusion of Isa plus pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma (RRMM). Design: This two-part, Phase 1b study ( NCT02283775 ) enrolled RRMM patients who had received ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor, and who demonstrated disease progression. Part A was an Isa dose-escalation study. In Part B, Isa (10 mg/kg) was administered as a fixed infusion volume of 250 mL (mL/h infusion rate) with standard doses of Pd. The primary endpoint for Part B was incidence of Grade (Gr) ≥3 infusion reactions (IRs) during the first 6 Isa infusions. Secondary endpoints included duration of infusion, safety, efficacy, and immunogenicity. Results: Of 47 patients enrolled in Part B, 22 (47%) remained on treatment at data cut-off. Patients were heavily pretreated, with a median of 3 prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks (range, 1–77). IRs were reported in 19/47 (40%) patients, all Gr 2, and occurred only during first infusion. Median duration of the first, second and ≥3 infusions was 3.7, 1.8, and 1.2 hours, respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE). The most common non-hematologic TEAEs were fatigue (64%), IRs, cough, and upper respiratory tract infection (40% each); 6 patients (13%) died within 30 days of final study treatment. The overall response rate was 53% in all patients. Median time to first response was 0.95 months (range, 0.9–3.4). At a median duration of 9.9 months follow-up (range, 0–17.3), median duration of response, progression-free survival, and overall survival were not reached. Conclusions: Efficacy and safety findings were consistent with Part A of this study and the pivotal Phase 3 ICARIA study. Measurements of response were robust. There were no Gr ≥3 IRs, and all occurred during first infusion. These results confirm the safety, efficacy, and feasibility of Isa administered by a fixed infusion volume. Funding for this study was provided by Sanofi.

8530 Background: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with refractory MM. We hypothesize that once weekly (QW) SKd may be an active well tolerated regimen and evaluated this combination in a dose escalation/expansion study. Methods: STOMP is a phase 1b/2 study evaluating various doses and enrolled pts with carfilzomib naive relapsed MM. Oral selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (on days 1, 8 and 15 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), as well as explore the efficacy and safety of SKd. Results: As of January 2020, 18 pts were enrolled. Median age was 71 years (range: 50-76). Median number of prior regimens was 4 (range: 1-8). All pts (n = 18) were previously treated with bortezomib and lenalidomide, and 50% and 56% pts were refractory to bortezomib and lenalidomide respectively. Nine (50%) pts received prior pomalidomide treatment and 8 (44%) pts were refractory. Eleven (61%) pts received prior daratumumab treatment and 9 (50%) were refractory. The MTD was selinexor 80 mg QW, carfilzomib 56 mg/m2 QW and dexamethasone 40 mg QW. The ORR and CBR were 72% and 79% respectively with 4 complete responses, 7 very good partial responses, 2 partial responses, and 1 minimal response. Stable disease was observed in 3 pts. With a median follow-up period of 4.7 (1.8-16.3) months, median progression-free survival has not been reached. Common treatment-related adverse events (total, Grade ≥3) were thrombocytopenia (83.3%, 66.7%), nausea (66.7%, 0%), anemia (55.6%, 11.1%), fatigue (50%, 11.1%), anorexia (44%, 5.6%), weight loss (44%, 0%), and neutropenia (33.3%, 11.1%). Conclusions: Once weekly SKd demonstrated an encouraging ORR of 72% in pts with a median of 4 lines of prior therapy. The majority of responses are deep and predominantly CR and VGPR. The combination is well tolerated with no new safety signal, no Grade ≥3 nausea, vomiting, diarrhea, weight loss or anorexia. The side effects are a function of the dose and schedule and can be managed with dose modification and supportive care. Enrolment is ongoing and supports a phase 3 study of SKd. Clinical trial information: NCT02343042 .

8510 Background: Selinexor is a first-in-class oral Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates exportin 1 (XPO1). Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with relapsed/refractory MM (RRMM). Single agent daratumumab has demonstrated an ORR of 29% in MM reftactory to proteasome inhibitors (PIs)/immunomodulatory drug (IMiDs). We evaluated the safety, tolerability and preliminary efficacy of the combination of Sel-dex and daratumumab (SDd) in pts with MM refractory to PIs/IMiDs. Methods: This is a multicenter, open-label, phase 1b/2 dose escalation and expansion study. Pts were eligible if they had received ≥ 3 prior lines of therapy, including a PI and an IMiD, or whose MM was refractory to a PI and an IMiD. In the expansion phase, pts were required to be anti-CD38 monoclonal antibody-naïve. One dose level was tested at each schedule: selinexor once-weekly (QW at 100 mg) or twice-weekly (BIW at 60 mg) with dexamethasone 40 mg. Daratumumab 16 mg/kg IV was administered per label. Primary objective was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D), and assess safety, tolerability and efficacy of SDd in pts with RRMM. Results: A total of 34 pts were enrolled; 3 in the 60 mg BIW and 31 in the 100 mg QW cohorts. Median age was 69 and median number of prior treatment regimens was 3 (range, 1–10). Out of 34 pts, 62% and 65% were refractory to bortezomib and lenalidomide respectively. Common treatment related adverse events (all grades, grades 3/4) included: thrombocytopenia (71%, 47%), fatigue (62%, 18%), nausea (71%, 9%), anemia (62%, 32%) and neutropenia (50%, 26%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: Grade 3 thrombocytopenia and Grade 2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort (n = 6), no DLTs occured. 32 patients were evaluable for efficacy. The ORR was 73% (11 VGPR, 11 PR) for 30 daratumumab-naïve pts. Median progression-free survival was 12.5 months in both groups. Conclusions: Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dexamethasone 40 mg, administered QW. In pts with PI and IMiD refractory MM, weekly SDd demonstrated promising activity with an ORR of 73% in daratumumab-naïve pts and a median PFS of 12.5 months. This supports further development of a novel non-PI, non-IMiD backbone in earlier lines of therapy. Clinical trial information: NCT02343042 .

Background: Population-based studies suggest that patients with multiple myeloma (MM) have better outcomes when treated at high-volume facilities, but the relative contribution of provider expertise and hospital resources to improved outcomes is unknown. This study explored how treating facility, individual provider volume, and patient-sharing between MM specialists and community providers influenced outcomes for patients with MM. Patients and Methods: A state cancer registry linked to public and private insurance claims was used to identify a cohort of patients diagnosed with MM in 2006 through 2012. Three multivariable Cox models were used to examine how the following factors impacted overall survival: (1) evaluation at an NCI-designated Comprehensive Cancer Center (NCICCC), (2) the primary oncologist’s volume of patients with MM, and (3) patient-sharing between MM specialists and community oncologists. Results: A total of 1,029 patients diagnosed with MM in 2006 through 2012 were identified. Patients who were not evaluated at an NCICCC had an increased risk of mortality compared with those evaluated at an NCICCC (hazard ratio [HR], 1.50; 95% CI, 1.21–1.86; PPPP=.5591). Patients treated by community oncologists had a higher risk of mortality regardless of patient-sharing compared with patients treated by MM specialists (eg, community oncologist with a history of sharing vs NCICCC MM specialist: HR, 1.49; 95% CI, 1.10–2.02; PConclusions: Findings of this study add to the accumulating evidence showing that patients with MM benefit from care at high-volume facilities, and suggest that similar outcomes can be achieved by the highest-volume providers in the community.

Introduction Multiple myeloma (MM) is a malignant plasma cell disease with a median age at diagnosis of 70 years. Geriatric assessment and frailty measures are increasingly being utilized at the time of diagnosis for prognostication. Gait speed at baseline has recently emerged as a powerful prognostic tool which identifies frailty and predicts outcomes independent of performance status among older patients with blood cancers including myeloma (Liu et al, Blood 2019). However, the longitudinal assessment and responsiveness of change in geriatric assessment measures and functional frailty parameters, including physical performance such as gait speed, over time remains unknown. Objectives We conducted a prospective study of patients with newly diagnosed MM aged 65 and older at two institutions. The prevalence of geriatric domains at baseline has been previously published by Wildes et al (JAGS, 2019). We aimed to conduct a secondary analysis to understand the changes in geriatric and frailty assessment including physical performance as older patients underwent treatment for their myeloma. Methods Older patients with newly-diagnosed myeloma underwent a comprehensive geriatric assessment including a gait function using the Timed Up and Go test at baseline and at 6 months between the years 2012-2014. Results At baseline, forty patients were enrolled in the study with a mean age of 71.6 years; 25 (62.5%) were males. Thirty-six patients completed the 6-month follow-up with 18 patients having undergone a stem cell transplant in the interim. Overall, there were no significant change in the measured geriatric domains, including dependence, physical activity, falls, polypharmacy and cognition, at 6 months compared to baseline. Overall mental health well-being, measured with the Mental Health Inventory-17, improved over time (Table I). Physical performance, assessed with the Timed Up and Go test, showed a trend toward improvement as patients underwent treatment (11.0 seconds at the 6-month follow-up versus 12.3 at baseline, p=0.057). Additionally, two out of four individuals who were unable to complete the Timed Up and Go test at baseline were subsequently able to complete it 6 months following treatment. Conclusion Our study suggests that, for older patients with MM, treatment does not significantly lead to geriatric impairment at 6-months of follow-up, as compared to baseline and in fact is associated with improved overall mental health well-being. Additionally, both the incremental change in Timed Up and Go test and the number of individuals able to complete it may in fact improve as patients undergo treatment. This highlights that gait speed may not be static and improve with treatment, suggesting a dynamic model of frailty. Larger studies conducted longitudinally will be required to further evaluate these findings to explore the evolving concept of frailty in myeloma. Disclosures Mian: Amgen: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pond:Roche Canada: Employment, Other: Stock; Takeda (DSMC membership): Other: Honorarium. Tuchman:Alnylam: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Honoraria; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Prothena: Research Funding; Roche: Research Funding. Fiala:Incyte: Research Funding. Wildes:Janssen: Research Funding; Carvive: Consultancy.

Introduction: The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of relapsed/refractory multiple myeloma with an ORR of 60-76%. The STOMP study assessed the efficacy and safety of the all oral combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory and newly diagnosed multiple myeloma. We previously reported the recommended phase 2 dose (RP2D) of once weekly selinexor 60 mg, lenalidomide 25 mg and dexamethasone achieved an ORR of 92% in patients with RRMM who were lenalidomide naive. Here we evaluated once weekly selinexor in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Methods: STOMP is a multicenter, open-label study with a dose escalation (phase 1) and expansion (phase 2) to assess the maximum tolerated dose, RP2D, efficacy and safety of SRd in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma were eligible if they had symptomatic myeloma per the International Myeloma Working Group (IMWG) guidelines with either hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria or myeloma defining events needing systemic therapy. Enrollment in this arm is ongoing. Results: As of July 01 2019, 8 patients (4 males and 4 females ) with newly diagnosed multiple myeloma were enrolled at the starting dose level of selinexor 60 mg on days 1, 8, 15, and 22; lenalidomide 25 mg daily 1-21and dexamethasone 40 mg weekly on a 28 day cycle. The median age was 74 years (range: 51-86 years). No dose limiting toxicities (DLT) were observed in 5 DLT evaluable patients, 3 patients were not DLT evaluable because 1 patient did not finish cycle 1 due to social reasons and 2 patients missed doses due to serious adverse events (SAEs) unrelated to study drugs.. Common treatment related hematologic AEs (Grades 1/2, ≥3) were neutropenia (0%, 75%), anemia (0%, 25%), and thrombocytopenia (0%, 25%). Common non-hematologic AEs were diarrhea (63%, 0%), nausea (50%, 0%), fatigue (0%, 38%) decreased weight (38%, 0%), constipation (25%, 0%), hypokalemia (25%, 0%), and hypomagnesemia (25%, 0%). Among 7 efficacy evaluable patients, 6 patients achieved a response (ORR of 86%) including 1 complete response, 1 very good partial responses, 4 partial responses (2 unconfirmed), and 1 patient achieved a minimal response. With a median follow-up of 6.1 months, median progression-free survival was not reached. Conclusions: The all oral combination of SRd has promising activity with 6 of 7 efficacy evaluable patients achieving an objective response in patients with newly diagnosed multiple myeloma and no new or unexpected safety signals. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Bahlis:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Chen:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Onconova: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding. Tuchman:Karyopharm: Honoraria; Prothena: Research Funding; Roche: Research Funding; Alnylam: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Kotb:Karyopharm: Equity Ownership; Janssen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen: 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, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; J&J: Research Funding; Takeda: Honoraria; Celgene: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study wherein, Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. The presence of high-risk cytogenetic abnormalities is known to have a poor prognosis in multiple myeloma, with transient responses. We performed post-hoc analyses to determine the outcomes in patients with relapsed/refractory myeloma treated with Sel-dex based on the baseline cytogenetic abnormalities. Methods: STORM was a phase 2b, open-label study which enrolled patients with relapsed and refractory myeloma. Selinexor 80 mg in combination with dexamethasone 20 mg was administered orally, twice weekly. The primary endpoint was ORR. For this analysis, we pooled 78 patients (48 quad-refractory and 30 penta-refractory) from STORM, part 1 and 122 patients (penta-exposed and triple class refractory) from STORM, part 2 to compare outcomes between high-risk and standard risk cytogenetics groups. High-risk cytogenetics was defined as having at least 1 of the following abnormalities by fluorescence in-situ hybridization (FISH) at baseline: del(17p), t(4;14), t(14;16), and gain(1q) in >5% of screened plasma cells. The FISH analyses were performed at a central laboratory and used to assess cytogenetic risk status. Results: Of the 200 patients, 122 (61%) had high-risk disease (del(17p): 36%, t(4;14): 18%, t(14;16): 5%, and gain(1q): 36%). The ORR in high-risk patients was 20.5% (very good partial response [VGPR)]: 5.7% and partial response [PR]: 14.8%) and the ORR was 29.5 % (complete response [CR]: 2.6%, VGPR: 3.8%, and PR: 23.1%) in standard-risk patients. The clinical benefit rate (CBR) was 35.2% in high-risk patients compared with 38.5% in standard-risk patients. Median duration of clinical benefit (DOCB) was 4.4 and 6.2 months in the high-risk and standard-risk patients respectively. Median progression-free survival (PFS) was 3.8 and 4.2 months and overall survival (OS) was 8.6 and 9.4 months in the high-risk and standard-risk patients, respectively. Efficacy by specific cytogenetic abnormality is presented in Table 1 below (Due to the small sample size (n=11), data for the t(14;16) subgroup are not presented separately). Conclusions: Sel-dex demonstrated a similar CBR in patients with high risk and standard risk disease and preserved clinical benefit in heavily pre-treated patients who had rapidly proliferative disease and high-risk cytogenetics at baseline. The benefit was maintained across cytogenetic risk subgroups with a higher ORR in the t(4;14) and gain(1q) subgroups. The DOR and OS was similar across all the subgroups. These analyses support the use of Sel-dex in patients with high-risk cytogenetics and warrant further evaluation of selinexor in combination with other anti-myeloma therapies in high-risk disease. Disclosures Nooka: GSK: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation. Yee:Adaptive: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Huff:Karyopharm, Sanofi, MiDiagnostics: Consultancy; Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Chari:Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: 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; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: 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; Pharmacyclics: Research Funding; Oncoceutics: Research Funding. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; alexion: Consultancy; Janssen: Consultancy. Lonial:Genentech: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Genentech: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Tuchman:Karyopharm: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Merck: Research Funding; Prothena: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Alnylam: Honoraria, Research Funding. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Siegel:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: 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, Research Funding. Liu:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jagannath:Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, therefore forcing the nuclear retention and re-activation of cell cycle regulators such as p53, FOXO, IkB, and Rb. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, which induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (TCR-MM). Patients with TCR-MM often present with plasmacytomas along with serological markers of MM. Methods: Here we analyzed the effects of Sel-dex in patients from the STORM study who had baseline plasmacytomas. Results: 122 patients were in enrolled in the STORM study including 27 with a baseline plasmacytoma. The majority of plasmacytomas were soft tissue (22 patients) and 5 patients had soft tissue disease extension from a bone (rib (2), iliac (2), sacral vertebral). The median age of patients with plasmacytomas was 64 years, the median prior therapies were 7 (range 4 - 15), and 8/27 patients with a plasmacytoma had high risk cytogenetics. Of the 27 patients, 11 patients did not have a follow up plasmacytoma assessment: 6 were not evaluable for response as they came off therapy due to clinical progression and/or adverse events, 4 had stable disease (SD) with no evidence of plasmacytoma change, and 1 had progressive disease (PD) on serum M-protein with no evidence of plasmacytoma change. Sixteen of the 27 patients did have follow-up plasmacytoma assessments (methods of measurements included PET, CT, MRI or Clinical). The median days from baseline plasmacytoma evaluation to follow up was 41 days (range 22 - 119). Five patients had objective responses, based upon para-protein and plasmacytoma reductions according to IMWG criteria (1 very good partial response [VGPR], 4 partial responses [PR]) for an ORR of 18.5%. In addition, 2 patients had a minimal response (MR), 4 had SD and 5 had objective PD. Among the 5 patients with ≥PR, 3 plasmacytomas completely resolved, 1 showed near complete resolution, and another showed size reduction with no metabolic activity on PET. Of the 2 patients with a MR, 1 plasmacytoma completely resolved and 1 showed reduced PET uptake. Among the 4 patients with SD, 1 plasmacytomas completely resolved, 1 increased in size and 2 had unknown outcomes as they were assessed clinically. Among the 5 patients with PD, 1 plasmacytomas decreased in size, 1 increased in size, and 3 had unknown outcomes as they were assessed clinically. Conclusions: Of the 16 patients with TCR-MM and a follow up plasmacytoma assessment enrolled on STORM, 9/16 of the plasmacytomas either completely resolved or decreased in size and/or metabolic activity. Effects on plasmacytomas occurred in patients with objective responses (≥PR), as well as in patients with MR, SD and PD. These observations support the finding that Sel-dex is active in patients with plasmacytomas and heavily pretreated TCR-MM. Disclosures Yee: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Huff:Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Chari:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Oncoceutics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding. Vogl:Active Biotech: Consultancy; Janssen: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Nooka:Adaptive technologies: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Moreau:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lonial:Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Genentech: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Tuchman:Prothena: Research Funding; Amgen: Research Funding; Karyopharm: Honoraria; Alnylam: Honoraria, Research Funding; Sanofi: Research Funding; Merck: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Hoffman:Celgene: Speakers Bureau. Costa:Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Biran:Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Takeda: Consultancy, Honoraria. Siegel:Takeda: 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, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: 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. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Picklesimer:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. Li:Karyopharm Therapeutics: Employment, Equity Ownership. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Richardson:Takeda: 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, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy.

Introduction: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (MM). The recommended phase 2 dose (RP2D) of twice-weekly combination of selinexor, carfilzomib, and dexamethasone (SKd) was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg (NCT02199665). The ORR of this regimen in patients with MM refractory to carfilzomib in last line of therapy (n=13) was 62% and clinical benefit response was 77% (Jakubowiak et al. Br J Haematol 2019). This is consistent with data from the combination of selinexor, bortezomib and dexamethasone where a 43% ORR was observed in bortezomib refractory disease. We conducted the STOMP study to assess the safety and preliminary efficacy of SKd combination using once weekly (QW) dosing in patients with relapsed/refractory MM. Methods: STOMP is a multicenter, open-label study. Patients with relapsed/refractory MM that was not refractory to carfilzomib, and who may have had prior proteasome inhibitor exposure were enrolled. Oral Selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (excluding day 22 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose, RP2D and evaluate the efficacy and safety of SKd in patients with relapsed/refractory MM. Results: As of July 01 2019, 12 patients were enrolled in the study. Of these, 5 were male and 7 were female. The median age was 70 years (range: 50-76 years). The median number of prior treatments was 4 (range: 2 - 8). Nine of 12 patients received prior autologous stem cell transplantation. All 12 patients were carfilzomib naïve. Nine of 12 patients had MM refractory to bortezomib; 11 patients had MM refractory to lenalidomide and/or pomalidomide including 5 patients with MM refractory to both; and 7 patients with MM refractory to daratumumab. Four dose limiting toxicities (DLTs) were observed across 3 dose cohorts (Table 1). Common treatment related adverse events (Grade 1/2 , Grade ≥3) included anemia (42%, 17%), thrombocytopenia (17%, 58%), leukopenia (17%, 17%), nausea (67%, 0%), decreased appetite (33%, 0%), insomnia (33%, 0%), hyperglycemia (25%, 17%), fatigue (25%, 8%), vomiting (25%, 8%), and pneumonia (0%, 17%). The ORR was 75% including 3 complete responses, 5 very good partial responses and 1 partial response. Two patients had stable disease and 1 patient had minimal response. As of July 01, 8 patients remain on treatment. Conclusions: The once weekly SKd combination demonstrated encouraging preliminary activity with an ORR of 75% including complete responses and very good partial responses. Most DLTs were thrombocytopenia and all the DLT events occurred in patients with baseline Grade 1/2 thrombocytopenia. This activity and manageable side effect profile with QW selinexor in combination with carfilzomib and dexamethasone is promising. Disclosures Gasparetto: Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Constellation Pharmaceutical: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Tuchman:Roche: Research Funding; Alnylam: Honoraria, Research Funding; Karyopharm: Honoraria; Prothena: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding. Bahlis:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chen:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Other: Internal Review Committee participant. Kotb:Takeda: Honoraria; Amgen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Karyopharm: Equity Ownership. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: 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, Research Funding. Sebag:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Venner:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Research Funding; J&J: Research Funding; Sanofi: Honoraria; Takeda: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding.

Introduction: The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM) and associated with poor prognosis. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, therefore forces the nuclear retention and re-activation of cell cycle regulators such as p53, FOXO, IkB, and Rb. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Pomalidomide/dexamethasone achieved an ORR of 31% and progression-free survival (PFS) rate of < 4 months in patients refractory to prior bortezomib and lenalidomide. We conducted the STOMP study to assess the efficacy and safety of the combination of selinexor, pomalidomide and dexamethasone (SPd) in patients with relapsed/refractory multiple myeloma. Methods: STOMP is a multicenter, open-label, phase 1/2b, dose escalation study with an expansion phase. Patients with relapsed/refractory multiple myeloma who received prior therapies including lenalidomide and a proteasome inhibitor were eligible for enrollment. Oral selinexor was evaluated in 2 different dosing schedules: once-weekly (QW, 60 or 80 mg) or twice-weekly (BIW, 60 or 80 mg), with escalating doses of pomalidomide 2, 3 or 4 mg PO (days 1-21), and low dose dexamethasone 20 mg BIW or 40 mg QW. The primary objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, and preliminary efficacy of the combination of SPd in patients with relapsed/refractory multiple myeloma. Results: As of July 01 2019, 48 patients (26 male and 22 female) were enrolled. The median age was 64 years (range:43-83 years). Patients received a median of 4 (range: 2-13) prior treatment regimens. Forty patients (83%) received prior autologous stem cell transplantation (one patient received prior autologous and allogenic stem cell transplantation). The phase 1 dose escalation enrollment is now complete. Across all cohorts, eight dose limiting toxicities (DLTs) were observed (Table 1). Common hematologic treatment related adverse events (TRAE) included (Grades 1/2, Grades ≥3): neutropenia (8%, 54%), thrombocytopenia (21%, 33%), anemia (17%, 29%) and leukopenia (13%, 15%). Common non-hematologic TRAE included: nausea (56%, 0%), fatigue (40%, 10%), decreased appetite (46%, 0%), weight decreased (33%, 0%), diarrhea (27%, 0%), vomiting (21%, 2%). Lower rates of ≥ Grade 3 thrombocytopenia (27% vs 44%) and anemia (20% vs 44%) were observed in QW dosing vs BIW dosing. Out of 48 patients, 44 were evaluable for response (27 patients lenalidomide refractory/pom naive, 4 patients lenalidomide treated/pom naïve, 13 patients refractory to pomalidomide and lenalidomide, and 19 patients refractory to lenalidomide and bortezomib). Among patients who were pomalidomide naive (N=31), the ORR was 58% (7 very good partial responses and 11 partial responses) and the median PFS was 12.2 months. Among patients refractory to lenalidomide/pomalidomide (N=13) the ORR was 31% (4 partial responses) and the median PFS was 4.2 months. Conclusions: The all oral SPd combination is durable and active with an ORR of 58% in patients with disease that is lenalidomide refractory and pomalidomide naïve compared to previously published data of 31% ORR for pomalidomide/dexamethasone in a similar patient population. The median PFS on SPd of 12.2 months in pomalidomide naïve patients is longer than that observed with pomalidomide/dexamethasone ( Disclosures Chen: Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Bahlis:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Honoraria; Alnylam: Honoraria, Research Funding; Sanofi: Research Funding; Prothena: Research Funding; Roche: Research Funding; Amgen: Research Funding; Merck: Research Funding. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Karyopharm: Other: Internal Review Committee participant; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kotb:Celgene: Honoraria; Karyopharm: Equity Ownership; Merck: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Bensinger:Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant; Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Celgene: Membership on an entity's Board of Directors or advisory committees. Leblanc:Janssen: 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, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Takeda: Honoraria; J&J: Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria. Schiller:Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Astellas: Research Funding; Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. White:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

We retrospectively studied 340 fit patients with multiple myeloma (MM) who underwent autologous stem cell transplantation (ASCT). We hypothesized that progression-free survival (PFS) of older patients was non-inferior to that of younger patients after ASCT. Our null hypothesis was that the PFS hazard ratio (HR) for a 5-year increase in age was ≥1.05; the alternative (non-inferiority) hypothesis was that the HR was ≤1. The observed HR was 0.94 (95% confidence interval [CI] 0.86–1.03); since the CI upper bound was 1.05. Toxicity was similar across ages and transplant-related mortality was minimal. 28% of subjects