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Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.

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

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

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

Background Extensive protein synthesis in multiple myeloma (MM) cells renders them vulnerable to proteasome inhibitors (PI), a cornerstone of anti-myeloma therapy. However, relapse is inevitable and PI resistance remains a major barrier to improving outcomes. Adaptive responses to PI include upregulation of autophagy, another major degradation pathway in cells. We hypothesised that autophagy inhibition increases cell death and impedes recovery of MM cells exposed to Carfilzomib (K), a second generation PI effective in newly diagnosed and relapsed/refractory MM. Methods: Human myeloma cell lines (HMCL) and patient samples were exposed to a 1-hour pulse of K to mimic pharmacokinetics, ± autophagy inhibitors (AI) vacuolar protein sorting kinase 34 inhibitor (VPS34i) or unc-51 like autophagy initiating kinase inhibitor (ULKi). Apoptosis was assessed by Annexin V/Propidium iodide (AnV/PI) flow cytometry (FC) and autophagic flux by western blotting (WB) and FC for light chain 3B (LC3B) ± bafilomycin (B). Cell cycle was examined by FC using KI67/PI. Results: Basal autophagic flux was seen in all HMCL (MM1s, H929, KMS12BM) tested (±B). Autophagic flux increased in response to K: MM1s mean fluorescence intensity (MFI) control (CTL) 318±28 vs K 567±72, (mean±SEM),p=0.01, n=6). Autophagy was inhibited in all 3 HMCL with AI. Combined exposure to K and AI (VPS34i or ULKi) increased time dependent apoptosis in all HMCL tested: MM1s 31±8% (K) vs 58±9% (K+VPS34i), p=0.03, (n=3), and 13±0.4% (K) vs 63±16% (K+ULKi), p=0.03 (n=3), (K 10nM, AI 1uM) 48 hours(h) post K exposure. Basal autophagic flux was detected in all CD138+ primary MM patient samples tested by LC3B FC assay (MFI CTL B- 407±57 vs B+ 1081±125, p K treated MM1s cells were examined for kinetics of ubiquitinated protein build up and autophagic induction by WB. Increased ubiquitinated proteins were detectable up to 24h post K pulse, whilst autophagic flux increased up to 72h but returned to baseline thereafter (n=3). MM1s cells were treated with K±VPS34i for up to 7 days and apoptosis, absolute cell number and cell cycle assessed. In K treated cells, apoptosis was maximal at 72h but declined thereafter. Viable cell numbers fell initially but increased after 96h, indicating cell recovery. However, in MM1s cells treated with K+VPS34i/ULKi, apoptosis was enhanced with a rapid loss of viable cells (Fig 2) and viable cell numbers remained low at all timepoints (Fig 3). Cell cycle assays confirmed persistent G0/G1 arrest in MM1s cells treated with K+VPS34i or ULKi at all timepoints, whilst cell proliferation recovered in K treated cells on day 3, (15±3% cells in S/G2M in K treated cells vs 2±0.4% with K+VPS34i, p=0.02, n=4, 11±3% in S/G2M with K vs 1± 0.7% with K+ULKi, p=0.04, n=3, day 4)(Fig 4). To confirm that effects of AI were mediated via autophagy, KMS28PE (ATG12 null HMCL) were treated with K±VPS34i. These autophagy depleted cells showed limited basal or K induced autophagic flux and addition of VPS34i to K had no effect on apoptosis or cell cycle. Conclusion MM cells displayed active autophagic flux that increased with K treatment. Inhibition of autophagy increased K induced apoptosis, prolonged K-induced cell cycle arrest and prevented MM cell recovery. Addition of AI to K increased cytotoxicity in patient samples and many patients showed sensitivity to AI alone; these effects correlated with basal autophagic flux. These data suggest that autophagy plays a vital role in cell recovery from proteasome inhibition independent of proteotoxic stress. Dual inhibition of the proteasome and autophagosome may therefore help overcome PI resistance, which remains an unmet need in MM. Figure 1 Figure 1. Disclosures Auner: Takeda, Karyopharm: Other: Advisory role; Amgen: Research Funding; Janssen: Speakers Bureau. Khwaja: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yong: Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; GSK: Honoraria; Amgen: Honoraria; BMS: Research Funding; Autolus: Research Funding.

Introduction: Treatment of multiple myeloma (MM) has greatly improved over the last two decades. However, most pts will relapse and develop refractory disease. Most anti-cancer regimens require dose modifications (interruption, reduction, or discontinuation) during the treatment course in order to optimize the therapeutic window; appropriate modifications improve tolerability while maintaining anti-cancer activity. Selinexor, an oral selective inhibitor of XPO1-mediated nuclear export (SINE) compound, enforces the nuclear retention and functional activation of tumor suppressor proteins within the nucleus and prevents the translation of oncoproteins. The combination of once weekly (QW) selinexor, QW bortezomib, and dexamethasone (XVd) is FDA approved for previously treated MM. Compared to standard twice weekly (BIW) bortezomib plus dexamethasone (Vd) and using 40% less bortezomib and 25% less dexamethasone, XVd demonstrated significantly prolonged median progression-free survival (PFS) and time-to-next-treatment (TTNT), increased the overall response rate (ORR), reduced rates of peripheral neuropathy, and showed a trend towards improved overall survival (OS) in the Phase 3 randomized BOSTON study (NCT03110562). The recommended starting dose of selinexor in XVd is 100mg QW, but the median dose administered in BOSTON was 80 mg QW. Here, we analyzed the efficacy outcomes and adverse events (AEs) in pts whose dose was reduced compared to those where it was not. Methods: The BOSTON study consisted of two arms: pts treated with selinexor QW (100mg), bortezomib QW (1.3mg/m 2) and dexamethasone BIW (20 mg) (XVd; n=195 in the intention-to-treat [ITT] population) compared to standard BIW Vd. Results: Of the XVd pts in the BOSTON study, 126 had a dose reduction of selinexor and 69 did not. The median age was 66.0 in both groups (range: with reduction, 47-87; without, 40-84) and the median number of prior therapies was 1.0 (range, 1-3) for both groups (Table 1). The median time to dose reduction in these pts was 68 days (range, 8-561 days). The median duration of study treatment for these pts was 34.5 weeks (range, 3-120 weeks) compared to 20.0 weeks (range, 1-118) in pts with no dose reduction. In the group with dose reduction, the median dose of selinexor received per week was 71.3 mg (range, 29.7, 101.4) compared to 100 mg (range, 33.3, 136.7) in pts with no reduction. Pts who dose reduced had a median PFS of 16.6 months compared to 9.2 months in pts who did not (one-sided p value, The most common adverse events (AEs; dose reduction and without dose reduction) of any grade were thrombocytopenia (69.8% and 42.0%), nausea (55.6% and 40.6%), and fatigue (49.2% and 29.0%). The rate of treatment discontinuation in the dose reduced group was 24.6% and 14.5% without dose reductions. In the dose reduced group, there were 6 (4.8%) deaths and 6 (8.7%) in the group with no dose reduction. As pts with a dose reduction stayed on therapy for a prolonged period of time, to best understand the impact of dose reduction on the AE, we present the duration-adjusted incidence rates of AEs of clinical interest. The duration-adjusted incidence rates of AE were considerably lower after dose reduction of selinexor compared to the rates on or before dose reduction: thrombocytopenia (62.5% vs 47.6%), nausea (31.6% vs 7.3%), fatigue (28.1% vs 9.9%), decreased appetite (21.5% vs 6.4%), anemia (17.9% vs 10.3%), and diarrhea (12.9% vs 5.2) (Table 3). Conclusions: While all pts on XVd initiated therapy at 100mg selinexor QW, and it was associated with very low rates of progressive disease (1 in 195 pts), appropriate dose reductions of selinexor were associated with a longer PFS, DOR, and TTNT, and significantly reduced AE with improved tolerability, highlighting dose reductions as an important tool to personalize and optimize the therapeutic window for pts with RRMM. Figure 1 Figure 1. Disclosures Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Badros: Janssen: Research Funding; GlaxoSmithKline: Research Funding; J&J: Research Funding; BMS: Research Funding. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Moreau: Celgene BMS: Honoraria; Oncopeptides: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Gavriatopoulou: Takeda: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Garg: University Hospital Leicester: Current Employment; Amgen Janssen Novartis Sanofi Takeda: Honoraria; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses. Gironella Mesa: BMS, Janssen: Honoraria. Jurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Radinoff: Janssen, Pfizer, Novartis, Servier etc.: Consultancy, Honoraria; Amgen, Bayer, Takeda, etc.: Research Funding; the Bulgarian Minister of Health: Membership on an entity's Board of Directors or advisory committees. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Quach: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bila: Takeda, AMGEN, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. 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. Richardson: GlaxoSmithKline: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

Introduction: Patients with multiple myeloma (MM) have a high rate of relapse resulting in a need for multiple lines of therapy. In contrast to MM with standard risk cytogenetics (SR-Cyto), high-risk cytogenetics (HR-Cyto) in MM such as del(17p), t(4;14), t(14;16), and gain(1q) (≥3 copies), can result in shorter progression-free survival (PFS) and overall survival (OS) with less durable responses. Treatment regimens that can overcome the negative effect of HR-Cyto abnormalities are required to address this area of unmet medical need. Exportin 1 (XPO1), is overexpressed in many hematologic and solid tumor malignancies including MM, and exports tumor suppressor proteins from the nucleus to the cytoplasm, leading to their inactivation. Elevated levels of XPO1 are correlated with more aggressive MM and resistance to therapy and confers a poor prognosis. The potent oral XPO1 inhibitor, selinexor, has been approved as a triplet combination with bortezomib and dexamethasone for previously-treated MM. In the Phase 3 BOSTON study, treatment with XVd in patients with previously treated MM significantly prolonged median PFS and improved the overall response rate (ORR), with a trend towards a prolonged OS amongst all patients as well as those with HR cytogenetics. Methods: We performed post hoc analyses on patients with previously-treated MM from the XVd arm of the Phase 1b/2 study STOMP (NCT02343042) and the Phase 3 BOSTON (NCT03110562) study to determine the effects of cytogenetic abnormalities on outcomes. The HR-Cyto group included patients with at least one of the following cytogenetic abnormalities at initial diagnosis or screening: del(17p), t(4;14), t(14;16), or gain(1q) (≥3 copies). Efficacy was based on independent review committee. Results: A total of 106 patients with HR-Cyto were identified, including del(17p) (n=25), t(4;14) (n=25), t(14;16) (n=10), and gain(1q) (n=80). There were 131 patients classified as SR-Cyto including those with unknown cytogenetics. Baseline demographics were similar between groups with median age of 66 years old (range 40-87). Patients with HR-Cyto had a median PFS of 12.9 months and patients with SR-Cyto had a median PFS of 16.6 months; PFS on the BOSTON Vd control arm were 8.6 and 9.5 months with HR- and SR-Cyto, respectively. Of the individual abnormalities, a PFS of 13.2 and 13.9 months was observed in the t(4;14) and gain1q subgroups, respectively. Of the HR-Cyto subgroups with more than 10 patients, a similar median OS was observed in comparison to SR-Cyto and ranged from 20.4 months to not reached. The response of XVd treatment was maintained across HR-Cyto risk subgroups, with an ORR of 76.4% overall and the following values for subgroups: del(17p) (72.0%), t(4;14) (88.0%), and gain1q (73.8%). The ORR of the SR group was 69.5%. Of all patients that received XVd, there were 6 CRs (5.7%) and 32 VGPRs (30.2%) in the HR group and 9 CRs (6.9%) and 29 VGPRs (22.1%) in the SR group. The ORRs on the BOSTON Vd control arm were 57.7% and 64.7% for HR- and SR-Cyto, respectively. The rates of the most common treatment emergent adverse events (TEAEs) of any grade were similar across risk groups (HR- vs SR-Cyto): thrombocytopenia (65.1% vs. 54.2%), nausea (53.8% vs. 53.4%), fatigue (47.2% vs. 45.0%) decreased appetite (37.7% vs. 42.0%) and anemia (34.6% vs 40.5%). Rates of AEs of any grade peripheral neuropathy (PN) were 35.8% overall, 40.0% in del(17p), t(4;14) (40.0%), t(14;16) (30.0%), gain(1q) (38.8%), and 23.7% in the SR group. The rates of PN in the HR and SR groups of the XVd arm of the BOSTON and STOMP studies were 37.1% and 29.6% and 11.1% and 15.2%, respectively. The corresponding rates for Vd alone in the BOSTON study were 48.6% and 47.0%. Conclusions: Patients with MM with HR-Cyto treated with XVd demonstrated a comparable ORR and PFS, with a manageable safety profile compared to patients with SR-Cyto, supporting the use of XVd in patients with any cytogenetic profile. These results are consistent with the distinct and broad mechanism of action associated with XPO1 inhibition and the use of the agent in earlier lines of therapy. Further assessment of selinexor in combination with other therapies in patients with MM across the entire cytogenetic spectrum is warranted. Figure 1 Figure 1. Disclosures Bahlis: Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Richard: Karyopharm, Janssen: Honoraria. White: Amgen, Antengene, BMS/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: Consultancy, Honoraria. Chen: Gilead: Research Funding; BMS, Janssen, Abbvie, Novartis, Gilead, AstraZeneca: Consultancy. Delimpasi: Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Sutherland: Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Celgene: Consultancy; Karyopharm: Research Funding. Sebag: Janssen: Research Funding; Bristol Myers-Squibb: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Gavriatopoulou: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria. Lentzsch: Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; Janssen: 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. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kriachok: Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau; Takeda, Roche, Abbivie, Janssen, MSD: Consultancy. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Beigene: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Garg: Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria; University Hospital Leicester: Current Employment. Quach: Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jagannath: Karyopharm Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Badros: J&J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos: Oncopeptides: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Bluebird bio: Honoraria; AbbVie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. 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. Richardson: Secura Bio: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

Introduction: Despite recent advances, there remains an unmet need for novel therapies to improve outcomes and abrogate the adverse effects of high-risk cytogenetics in patients with multiple myeloma (MM). In patients with triple class refractory MM in the Phase 2b STORM study, the clinical benefit of selinexor plus low dose dexamethasone (sel-dex) was preserved across high-risk cytogenetic subgroups, supporting further evaluation of selinexor combined with other anti-MM therapies (Nooka et al. ASH 2019). The phase 3 BOSTON study evaluated the combination of weekly sel-dex with the proteasome inhibitor (PI) bortezomib (SVd) against standard twice weekly bortezomib-dex (Vd) in patients with MM who had received 1-3 prior therapies. SVd significantly improved progression free survival (PFS), time to next therapy (TTNT), overall response rate (ORR) and depth of response (≥VGPR), while inducing less overall and grade ≥2 peripheral neuropathy (PN) compared with Vd. Here, we present the results of prespecified subgroup analyses from the BOSTON study according to cytogenetic risk status. Methods: In the BOSTON study, patients were randomly assigned (1:1) to once weekly oral sel (100 mg) plus once weekly subcutaneous (SC) bortezomib (1.3 mg/m2) and dex (20 mg BIW) in the SVd arm or twice weekly SC bortezomib (1.3 mg/m2) and dex (20 mg QIW) in the Vd arm. Treatment was administered in both arms until disease progression. The primary endpoint was PFS, as assessed by an Independent Review Committee (IRC). Central FISH analyses were performed on CD138+ sorted cells from bone marrow aspirates collected at screening. The high-risk group consisted of patients with at least 1 of the following abnormalities: del(17p), t(4;14), t(14;16), and amplification of 1q21 in ≥10% of screened plasma cells with amp (1q21) requiring ≥3 copies. The standard-risk group consisted of all other patients with available and known baseline cytogenetics. Results: Of the 402 enrolled patients, 192 (48%) had high-risk (SVd=97, Vd=95) and 210 (52%) had standard-risk (SVd=98, Vd=112) cytogenetics. Baseline patient and disease characteristics were well balanced across treatment arms. SVd significantly improved PFS relative to Vd in the high-risk (12.9 vs 8.1 months; HR, 0.67; 95% CI, 0.45-0.98; P=0.0192) and standard-risk (16.6 vs 9.7 months; HR, 0.63; 95% CI, 0.42-0.95; P=0.0131) groups. Time to next treatment was significantly increased with SVd in the high-risk (14.6 vs 8.7 months; P=0.0049) and standard risk groups (NR vs 13.1 months; P=0.0158). The ORR was significantly improved with SVd in the high-risk group (77.3% vs 55.8%; P=0.0008) and numerically improved in the standard-risk group (75.5% vs 67.9%; P=0.11) with comparable rates between the high-risk and standard-risk groups in the SVd arm. Very good partial response or better was achieved in 42.3% patients on SVd versus 24.2% on Vd (P=0.0041) and 46.9% on SVd versus 39.3% on Vd (P=0.13) in the high-risk and standard-risk groups, respectively. Overall survival was 23.5 months in the high-risk group in the Vd arm and was not reached in the other groups. Efficacy by specific cytogenetics abnormalities in the high-risk subgroup is shown in the table below. PFS and ORR were improved with SVd compared with Vd across all subgroups except t(14;16) which was the smallest subgroup (N=18, 4% of the study population). There were 61 deaths in the high-risk group (SVd=27 and Vd=34) versus 48 in the standard-risk group (SVd=20 and Vd=28). The safety profiles of SVd and Vd in the high-risk and standard-risk groups were consistent with the overall population. Rate of grade ≥2 peripheral neuropathy was lower with SVd compared with Vd in both the high-risk (26.8% vs 32.3%; P=0.18) and standard-risk groups (15.3% vs 36.0%; P=0.0003). Conclusions: These prespecified subgroup analyses from the BOSTON study demonstrate that despite utilizing 40% less bortezomib and 25% less dexamethasone during the first 24-weeks of treatment, SVd is superior to Vd in patients with MM including high-risk patients. The PFS benefit was particularly notable in patients with del(17p), t(4;14) and amp(1q21) abnormalities. The ORR was comparable between the high-risk and standard-risk groups in the SVd arm. These data support the use of selinexor, with its novel mechanism of action, in the treatment of patients with early relapsed MM, including those with high risk cytogenetic abnormalities. Figure 1 Disclosures Chari: Secura Bio: Consultancy; Novartis: Honoraria; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy; Adaptive Biotechnology: Honoraria; The Binding Site: Honoraria; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Sanofi Genzyme: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Antengene: Consultancy; Amgen: Consultancy, Research Funding; Array BioPharma: Honoraria; Glaxo Smith Kline: Consultancy. Delimpasi:GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Kryachok:Takeda, Janssen: Consultancy; Janssen, Bayer, Karyopharm, MSD, Acerta, AvbbVie, Debiopharm: Research Funding; Takeda, Janssen, Novartis, Roche, MSD, Bayer: Consultancy, Research Funding; Takeda, MSD, AbbVie, Ro: Other: Travel, accommodations, expenses. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Auner:Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Leleu:Oncopeptide: Honoraria; Incyte: Honoraria; Merck: Honoraria; Carsgen: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; GSK: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; BMS-celgene: Honoraria; Novartis: Honoraria. Hajek:Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding. Sinha:Dr Reddys Lab, Intas Pharmaceuticals, Karyopharm Therapeutics: Honoraria. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Quach:GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Jagannath:Takeda: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Moreau:Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Levy:Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Badros:University of Maryland: Current Employment; Amgen: Consultancy. Anderson:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Bahlis:Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mateos:Janssen-Cilag: Consultancy, Honoraria; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: 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; 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. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chang:Karyopharm Therapeutics Inc: Current Employment. Landesman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chai:Karyopharm Therapeutics Inc: Current Employment. Arazy:Karyopharm Therapeutics Inc.: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Introduction: Treatment of older or frail patients (pts) with multiple myeloma (MM) remains challenging due to impaired organ function, underlying comorbidities, need for convenient regimens and burden of care, all of which impact the tolerability of anti-MM therapies. In the STORM study, selinexor plus dexamethasone (sel-dex) demonstrated anti-MM activity with an ORR of 26.2% and similar safety across all age groups in pts with triple-class refractory MM (Chari et al. NEJM 2019, Gavriatopoulou et al. IMW 2019). In the phase 3 BOSTON study, the combination of weekly sel-dex with once weekly bortezomib (SVd) was superior to standard twice weekly bortezomib and dex (Vd) across all efficacy endpoints in pts with MM who had received 1-3 prior therapies. Furthermore, while conferring a longer PFS and higher ORR than Vd, SVd was associated with significantly reduced rates of peripheral neuropathy (PN), the most clinically relevant toxicity associated with bortezomib that limits long term administration, especially in older and/or frail pts. Here we present results of subgroup analyses of the BOSTON study to evaluate the safety and efficacy of SVd versus Vd based on age and frailty index. Methods: Pts enrolled in BOSTON were assigned (1:1) to once weekly oral sel (100 mg) plus once weekly subcutaneous (SC) bortezomib (1.3 mg/m2) and dex (20 mg BIW) in the SVd arm or to standard twice weekly SC bortezomib (1.3 mg/m2) and dex (20 mg QIW) in the Vd arm. Treatment was administered in both arms until disease progression. The primary endpoint was PFS, as assessed by an Independent Review Committee. For these analyses, pts were assigned to 2 groups based on age ( Results: Of the 402 enrolled pts, 241 (60%) were ≥65 years (SVd=109, Vd=132). Of these, 81 (37%) were ≥75 and 106 (44%) were categorized as frail (SVd=51, Vd=55). Baseline pt and disease characteristics were well balanced between treatment arms in the subgroups. PFS was prolonged in both age groups with SVd compared with Vd. In ≥65, PFS was 21.0 vs 9.5 months (HR, 0.55; 95% CI, 0.37-0.83; P=0.0018) and in Conclusions: In pts with previously treated MM, the once weekly SVd regimen led to prolonged PFS, improved response rates and rates of PN regardless of age and frailty score compared to standard twice weekly Vd. Non-PN AEs were higher with triplet than doublet therapy, but most of the AEs were reversible and treatable. There were fewer deaths on SVd in pts ≥65 and in frail pts compared to Vd. Once weekly SVd is a potent and convenient treatment option for pts with previously treated MM, including those who are ≥65 years and/or frail. Figure Disclosures Auner: Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Delimpasi:GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Leleu:Incyte: Honoraria; Merck: Honoraria; AbbVie: Honoraria; Carsgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria; BMS-celgene: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Oncopeptide: Honoraria. Hajek:Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding. Sinha:Dr Reddys Lab, Intas Pharmaceuticals, Karyopharm Therapeutics: Honoraria. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Quach:Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy. Jagannath:Sanofi: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Moreau:Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Honoraria. Levy:Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Anderson:BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mateos:EDO Mundipharma: Honoraria; Seattle Genetics: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; GlaxoSmithKline: Honoraria; Adaptive Biotechnologies: Honoraria; Takeda: Honoraria; Roche: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chai:Karyopharm Therapeutics Inc: Current Employment. Arazy:Karyopharm Therapeutics Inc.: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

ZBP1 is an inducible nucleic acid (NA) sensor that is activated when pathogen NA bind to its Zα and Zβ domains. ZBP1 is required for TBK1-dependent phosphorylation of the transcription factor IRF3 (pIRF3) followed by its direct activation of type I interferon genes. However, the role, if any, of ZBP1 in tumour biology is not known. By searching for genes selectively expressed in multiple myeloma (MM) we identified ZBP1 mRNA expressed in 29 MM cell lines (MMCL) but not in >1000 other cancer cell lines (CCLE dataset); ZBP1 was expressed in all 766 patient myeloma PC (CoMMpass dataset) but not in normal blood cells (Blueprint) or 53 healthy tissues (GTex). We confirmed expression of ZBP1 mRNA and/or protein in MMCL, primary human and murine germinal centre B (GCB) and plasma cells (PC) as well as in myeloma PC. By inducing T cell-dependent humoral immune responses after ip alum-NP-KLH immunisation, we explored the role of selective and constitutive expression of Zbp1 in GCB to PC transition. We found no differences in the frequency of splenic GCB cells and PC between control WT and Zbp1-/- mice and in GCB cell frequency between immunised WT and Zbp1-/- mice. However, compared to WT, the increase in PC frequency in immunised Zbp1-/- mice was 50% lower (n=10/group, p To explore the function of ZBP1 in MM we depleted by 2 lentiviral shRNAs either isoform 1 (contains both Zα and Zβ domains; shRNA1) or both isoform 1 and isoform 2 (latter lacks Zα domain; shRNA2). Both shRNAs were toxic to all 5 MMCL tested suggesting that isoform 1 but not isoform 2 is essential for myeloma cell survival. This effect was specific because survival of K562 cells, which lack expression of ZBP1, was not affected by either shRNA and exogenous ZBP1 cDNA rescued cell death of ZBP1-depleted myeloma cells. Dox-induced ZBP1 depletion was toxic to MMCL in vitro and significantly inhibited myeloma cell growth in a subcutaneous NSG model of the MMCL H929 and MM.1S. Together, these findings reveal a novel myeloma cell-specific ZBP1 dependency. Transcriptome analysis of ZBP1-depleted H929 and MM.1S cells showed amongst the significantly downregulated genes enrichment for the cell cycle control and DNA repair pathways consistent with a critical role of ZBP1 in promoting myeloma cell proliferation. Flow-cytometric analysis of ZBP1-depleted MMCL as well as of patient-derived myeloma PC revealed cell cycle arrest at the G0/1 phase and increasing apoptosis. Exploring potential links with IRF3, we first observed that unlike in non-malignant cells, IRF3 was constitutively phosphorylated in MMCL. Using protein-co-immunoprecipitation we found that endogenous ZBP1 interacts with IRF3 and TBK1 while upon co-transfection with different ZBP1 deletion mutants, ZBP1-IRF3 interaction required primarily the ZBP1, RHIM domain-containing, C-terminus. Further, while in ZBP1-depleted myeloma cells total IRF3 and TBK1 levels were not altered, pIRF3 and pTBK1 levels decreased thus showing a post-translational dependency of constitutive pIRF3 and pTBK1 on ZBP1. Finally, pharmacological inhibition of TBK1 resulted in decrease of pIRF3 without affecting total IRF3. Importantly, shRNA-mediated IRF3 depletion resulted in cell cycle arrest and death of MMCL. By integrating histone mark and in-house IRF3 ChiP-seq with transcriptome of IRF3-depleted MM.1S cells we identified 770 down- and 330 up-regulated genes predicted to be directly regulated by IRF3. Pathway enrichment analysis confirmed cell cycle as the most highly regulated by IRF3. Notably, we observed no direct or indirect regulation of the interferon genes (e.g., IFNA1, IFNB1) by IRF3. As well as the IRF3 motif, IRF3 cistrome analysis revealed significant enrichment for the distinct IRF4 motif. Integration of the IRF3/IRF4 cistromes identified >80% IRF3 binding regions are co-occupied by IRF4 and co-regulation of cell cycle genes. Further we validated IRF3-IRF4 interaction at the IRF4 super-enhancer by ChIP-re-ChIP. These data show a novel dependency in MM comprising constitutive activation of the ZBP1-IRF3 pathway and regulation of cell cycle and proliferation by IRF3 thus providing opportunities for therapeutic targeting. Disclosures Caputo: GSK: Research Funding. Auner:Amgen: Other: Consultancy and Research Funding; Takeda: Consultancy; Karyopharm: Consultancy. Karadimitris:GSK: Research Funding.

BACKGROUND: The biological basis for the adverse prognosis of chr1q gain/amplification (1q+) present in ~30% of patients with multiple myeloma (MM) remains ill-defined. The transcription factor (TF) Pre-B-cell leukaemia homeobox 1 (PBX1), encoded on chr1q, acts as master regulator of early hematopoiesis and as an oncogene in leukemia and other malignancies. Herein, we hypothesized that PBX1 orchestrates proliferative regulatory networks that underpin the poor prognosis associated with 1q+ in MM. METHODS: We employed qPCR for mRNA quantification, western blotting and immunohistochemistry for protein analysis, lentiviral shRNA-mediated knock-down, Hoechst/Annexin V staining and flow-cytometry for apoptosis and cell cycle analysis, ChIPseq for cistrome and RNAseq after knock-down for transcriptome analysis. Additional data were obtained from MMRF/CoMMpass, Blueprint Consortium and Arkansas datasets. Computational analysis of clinical and "-omics" data was performed using standard bioinformatic work-flows; pathway enrichment analysis using EnrichR and GSEA. RESULTS: Combined genomic (WGS/WES) and transcriptomic (RNAseq) analysis of the CoMMpass dataset identified a subgroup of 1q+ MM patients (60%) characterized by aberrant PBX1 overexpression and amplification (PBX1amp); survival analysis revealed significantly worse outcome of this subgroup compared to 1q+ non-PBX1amp (p Depletion of PBX1 using 2 validated shRNAs was toxic to the 1q+ MM1.S t(14;16) and U266 t(11;14) myeloma cell lines (MMCL) in vitro, revealing a novel myeloma cell addiction to PBX1. Transcriptome analysis of PBX1-depleted cells showed significant de-regulation of genes (MM1.S: 753down/320up; U266: 598 down/288up) highly enriched in cell cycle and proteasome/ER stress response pathways. Flow-cytometric analysis confirmed that PBX1-depleted myeloma cells undergo cell cycle arrest (G0/1 phase) and apoptosis (n=3; p Genome-wide binding profiling of PBX1 identified 7,354 significantly enriched peaks shared between MM1.S and U266 MMCL. These peaks were distributed at active promoters (~50%) and active enhancers (~30%), as defined by ChromHMM maps; the PBX1 consensus binding motif was identified as top hit upon motif enrichment analysis. Transcriptome-cistrome integration identified 728 and 282 genes directly activated or repressed, respectively, by PBX1 in MM1.S cells. Again, pathway enrichment analysis of PBX1 direct targets demonstrated significant over-representation of cell cycle and proliferation pathways, as well as positive regulation of various metabolic processes (oxidative phosphorylation, glycolysis, unfolded protein response). Strikingly, enrichment analysis against public ChIPseq datasets revealed significant overlap with gene targets of FOXM1 (200) and E2F (150) TF, suggesting the presence of a united PBX1-FOXM1-E2F regulatory circuitry. In fact, PBX1 binding was detected at an active FOXM1 enhancer and at the E2F1/2 promoters, while FOXM1 and E2F1/2 mRNA levels decreased significantly upon PBX1 depletion in two MMCL. To further explore the PBX1-FOXM1 interaction, we overlaid the FOXM1-depleted transcriptome with the PBX1 network in MM.1S cells. This identified 160 genes to be co-regulated by PBX1 and FOXM1, including genes previously linked to myeloma cell drug resistance (NEK2, TOP2A, AURKA); however, PBX1 expression was not altered in FOXM1-depleted cells, suggesting that PBX1 is functionally upstream of FOXM1. Additional analysis across 814 primary MM patient CoMMpass transcriptomes confirmed significant co-expression of PBX1 with FOXM1, E2F1/2 and another 67 PBX1-FOXM1 highly expressed, co-regulated gene targets, conferring poor OS (p CONCLUSIONS: We found that genetic amplification and overexpression of PBX1 defines an ultra high-risk subgroup of 1q+ MM with proliferative features. Myeloma cells are addicted to aberrant PBX1 expression. As well as essential metabolic pathways, PBX1 regulates cell cycle progression by direct transcriptional regulation of FOXM1 and of its target genes. These data reveal PBX1 as a critical biological link between chr1q gain/amplification and poor prognosis in a subset of MM patients. Disclosures Auner: Karyopharm: Consultancy; Amgen: Other: Consultancy and Research Funding; Takeda: Consultancy. Caputo:GSK: Research Funding. Karadimitris:GSK: Research Funding.

BACKGROUND: Bone disease, a common source of morbidity in multiple myeloma (MM), is caused by RANKL-induced aberrant activation of osteoclasts (OC). RANKL-induced OC lineage commitment requires repression of an Irf-8 dependent macrophage inflammatory transcriptional programme commensurate with activation of an OC lineage-specific programme. Functional data have shown the requirement for the histone acetylation readers Brd2-4 BET proteins and of cMyc for OC lineage development. However, how Brd2-4 and Myc co-operate genome-wide to regulate transcriptome changes that underpin the very early stages of RANKL-induced OC lineage commitment has not been defined. METHODS: The OC progenitor-like murine RAW264.7 cell line was used for osteoclastogenesis. OC were assayed by TRAP staining. We performed RNA-seq for transcriptome analysis and ChIP-seq against Brd2-4, cMyc, and H3K27Ac mark for epigenomic profiling. The pan-Bet inhibitor IBET151 was used alone or in combination with RANKL. ChIP-seq/RNA-seq data were processed using standard bioinformatics pipelines; downstream analyses (pathway and motif enrichment, factor differential binding) were performed by various tools including EnrichR, R packages ChIPpeakAnno/DiffBind, Rose. RESULTS: Transcriptomic profiling of OC progenitors at 0, 4, 14 and 24h post-RANKL treatment identified 12 distinct clusters of expression trends. The 4h activated cluster includes OC master transcription factors (TFs; cMyc, Nfatc1, Fosl), and is enriched in OC-defining pathways. Notably, by 14h the majority of the genes required for mature OC formation and activation are already highly expressed (e.g. Ctsk, Mmp9). The downregulated clusters include monocyte defining TFs (e.g. Irf8, Mafb and Bcl6). These RANKL-dependent transcriptome changes are completely abrogated by iBET151, highlighting the critical role of Brd2-4 in osteoclastogenesis. Differential chromatin binding analysis upon RANKL induction revealed an overall enhanced Brd2-4 binding at already existing or de novo gained sites. This was more pronounced for Brd2&4 and much less for Brd3, with differentially binding sites (DBS) comprising 50% and 20% respectively of all binding sites in RANKL-treated cells. For Brd2&3, DBS were primarily distributed at promoters and for Brd4 at intergenic, candidate enhancers regions. Notably, nearly all gained DBS were sensitive to and abrogated by iBET151. Combinatorial profiling of Brd2 and Brd4 showed that almost half of Brd2 DBS peaks overlap with Brd4 (47%; 897/1896), while only 24% (766/3234) of Brd4 DBS peaks are co-occupied by Brd2. Transcriptome and Brd2&4 DBS integration in combination with motif enrichment analysis, identified genes that are predicted to be regulated by Brd2 and/or Brd4. EnrichR analysis suggests that enhanced binding of Brd2&4, singly or in combination, is required for activation of the critical OC lineage-specific and repression of the macrophage-defining transcriptional programs highlighting the non-redundant roles of Brd2&4 in OC development. Cell lineage commitment often requires 'commissioning' of cell-specific super-enhancers (SE). Combined analysis of genome-wide Brd4/H3K27ac profiles identified 678 RANKL-induced SE and their respective target genes. Further, 110 of these SE showed enhanced Brd4 binding in 2 peaks: 20/110 were linked to significantly up- and 90/100 to down-regulated genes. The repressed genes were significantly enriched to previously described Irf8, MafB and RunX1 targets, suggesting a critical role of SE in the repression of the monocyte/macrophage inflammatory programme during OC lineage commitment. Strikingly, among top hits, we detected a SE linked to the regulation of cMyc. To further investigate its role in OC development, we obtained the cistrome of cMyc after RANKL induction. We identified 560 binding sites which were highly enriched in cMyc, Max, Fli1, Fosl2 and Irf8 motifs. Cistrome-transcriptome integration suggested direct activation of 141 and repression of 52 genes by cMyc in response to RANKL; these are enriched in ribosome biogenesis pathways and Irf8-dependent targets respectively. CONCLUSIONS: Myc and Brd4 mark SE that repress an Irf8-dependent transcriptional programme, a requirement for OC lineage commitment. The non-redundant roles of Brd2&4 suggest that selective targeting of either could inhibit aberrant OC activation associated with MM. Disclosures Caputo: GSK: Research Funding. Auner:Amgen: Other: Consultancy and Research Funding; Takeda: Consultancy; Karyopharm: Consultancy. Karadimitris:GSK: Research Funding.

Proteasome inhibitors (PIs) form the backbone of multiple myeloma (MM) treatment regimens used at diagnosis and relapse, but their clinical benefit is limited by varying degrees of resistance. The mechanisms that protect MM cells (MMCs) from PI-induced cell death are only partly understood, and experimental resistance studies often rely on the prolonged exposure of MMCs to relatively low levels of PIs. However, patients receive PI doses that result in high but short plasma peaks. Given that each PI dose reduces a patient's MMC load until a plateau is reached, one can assume that each PI dose kills some MMCs by triggering overwhelming stress. This proposition implies that a proportion of MMCs not only survive but also resolve PI-induced stress. We hypothesised that the mechanisms of PI-induced stress recovery require a redistribution of cellular resources, and that this process triggers specific recovery-associated and potentially druggable vulnerabilities. To test this hypothesis, we obtained a global systems-level view of the cellular response to proteasome inhibition by performing a multi-omics 10-day time-course experiment. To mimic in vivo pharmacokinetics and anti-MM effects, RPMI-8226 MMCs were treated with a 1h pulse of carfilzomib (CFZ; 750nmol/L), which reduced the number of viable MMCs to a nadir of approximately 50% on day +2, followed by a return to pretreatment baseline levels of viable cells by day +6. Levels of ubiquitinated proteins as a readout of effective proteasome inhibition peaked on day +1 and returned to baseline levels on day +6. Samples for transcriptome analysis by RNA-seq, proteome analysis by a multiplexed tandem mass tag (TMT)-based approach, and global metabolomic profiling by ultrahigh performance liquid chromatography-tandem mass spectroscopy (LC-MS) were collected 2h prior to the CFZ pulse (day 0) and on days +1, +2, +4, +6, +8, and +10. The results demonstrate extensive and kinetically complex changes of the MMC transcriptome, proteome and metabolome that did not fully return to baseline by day +10. Conventional and advanced computational analyses of RNA-seq data (including biological homogeneity score-validated graph-based clustering of temporal patterns combined with gene enrichment and KEGG/GO pathway analysis) revealed different patterns of involvement of multiple and functionally diverse pathways. Perhaps most notably, RNA-seq data revealed extensive metabolic pathway responses while cells were dying and throughout recovery. Consistently, metabolomic profiling by LC-MS showed wide-ranging metabolite changes. These included rapid intracellular depletion of glucose, which was paralleled by the accumulation of lactate and pyruvate and lasted until day +8. Consistently, the major glucose uptake regulator TXNIP stood out as upregulated during recovery, which was accompanied by the predicted downregulation of the glucose transporter GLUT1. These findings were confirmed by real-time PCR and immunoblotting in RPMI-8226 and other MMC lines. Moreover, pharmacological inhibition of glucose and lactate metabolising enzymes and transmembrane transport enhanced MMC killing by CFZ, confirming profound and druggable changes in glucose and energy metabolism during PI stress recovery. We also observed prolonged depletion of a number of amino acids, including glutamine, which was paralleled by depletion of glutamate and TCA cycle intermediates. Moreover, we found RNA-seq and real-time PCR/immunoblot-based evidence for an amino acid response (AAR) during stress recovery that was driven by the amino acid sensing kinase GCN2 (EIF2AK4). The preclinical GCN2 inhibitor GCN2iB was effective at blocking the AAR and enhanced MMC killing in a panel of CFZ-treated MMC lines. This effect was particularly pronounced during the intermediate stages of recovery, in line with the kinetics of amino acid depletion and the AAR. Thus, our observations define the complex and prolonged cellular responses that characterise the recovery of MMCs from proteasome inhibition. They reveal wide-ranging metabolic changes that persist far beyond immediate stress survival and highlight the dependence of MMCs on the GCN2-driven AAR to overcome PI stress. The findings demonstrate that the mechanisms of PI recovery trigger druggable vulnerabilities, providing the basis for ongoing investigations into sequential therapeutic interventions to enhance responses to PIs. Disclosures Caputo: GSK: Research Funding. Kaiser:Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Auner:Karyopharm: Consultancy; Takeda: Consultancy; Amgen: Other: Consultancy and Research Funding.

Background Triplet combination therapies are the preferred treatment choice for RRMM, however, high-cost-high-cost drug combinations pose significant barriers for health technology assessments (HTA) and access in many public healthcare systems, including the UK. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1), thereby forcing the nuclear retention of key tumour suppressor proteins (TSPs), leading to MM cell death. Recently, the FDA has granted accelerated approval to selinexor for MM on the basis of results from the STORM trial, which tested selinexor in doublet combination with dexamethasone in RRMM. Several trials exploring triplet combinations are ongoing, but most are with high-cost combination partners. In the Myeloma UK Twelve (MUKTwelve) trial Selinexor is combined with low-dose cyclophosphamide and prednisolone in a randomized phase II design, exploring a triplet regimen that could potentially be more accessible for wider patient population. Study design and methods MUKtwelve is a randomized, controlled, open, parallel group, multi-centre phase II trial designed to evaluate clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone (SCP) in patients with RRMM (ISRCTN15028850). The primary objective is to determine whether the addition of selinexor to cyclophosphamide and prednisolone (CP) may lead to increased progression free survival (PFS) compared to historic CP data. A calibration arm of patients will receive CP alone, and will be used to evaluate the validity of the outcome in the experimental arm in comparison to historical control data. Participants who experience disease progression on the CP arm may, if deemed eligible receive SCP. Eligible participants are those with RRMM who have received ≥ 2 prior anti-myeloma treatments including a proteasome inhibitor and lenalidomide. Entry criteria are inclusive to allow for a real-world RRMM population, including GFR >=20, no limitation regarding pre-existing polyneuropathy and allowance of growth factor and transfusion support. A maximum of 60 participants will be recruited (45 participants in the SCP arm, and 15 in the CP arm) from 10 UK NHS hospitals. Participants are randomized on a 3:1 basis to receive either SCP or CP. The trial opened on 20th July 2018 and as of 23rd July 2019 16 patients have been randomized. Trial treatment is as shown in Table 1 (28 day cycle). Metronomic, continuous doses of cyclophosphamide and intermittent doses of prednisolone in conjuncture with proactive, prophylactic side effect management, in particular nausea and kachexia, have been chosen to make the trial more accessible for a wider RRMM population. The primary endpoint is proportion of patients alive and progression-free at 6 months (PFS6m). Secondary endpoints include response, response duration, safety and toxicity, PFS and treatment compliance. A three outcome statistical design is used based on the SCP arm only. The trial is designed to test the hypothesis PFS 6m ≤0.28 vs. PFS 6m ≥0.44 (equivalent to median PFS 3.3 vs. 5.1 months). With 90% power, 1-sided 10% significance level, a total of 45 patients are required in the SCP arm. Cut-off values and conclusions for the three outcome design: ≤14/45 patients PFS6m, SCP does not warrant further study≥17/45 patients PFS6m, sufficient evidence for further study of SCP15 or 16/45 patients PFS6m, decision uncertain and can be based upon other secondary endpoints. This approach provides more realistic decision-making compared to those where success of failure is hinged on a difference of a single primary endpoint event. Discussion The MUKtwelve trial is the first trial to assess the clinical efficacy of selinexor with low-dose cyclophosphamide and prednisolone in RRMM, a triplet regimen that, if found to be effective, is likely to be accessible to a wider patient population. Disclosures Brown: Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Kendall:Karyopharm: Other: Research funding to Institution. Ingleson:Karyopharm: Other: Research funding to Institution. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Auner:Karyopharm: Consultancy; Takeda: Consultancy; Amgen: Other: Consultancy and Research Funding. Boyd:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Garg:Janssen: Honoraria; Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding. Kaiser:Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

In multiple myeloma (MM), a malignancy of the bone marrow plasma cells (BMPC), hyperdiploidy (HY) and oncogene over-expression via chromosomal translocation [including CCND1- t(11;14), MAF- t(14;16), MMSET-t(4;14)] are the primary myeloma initiating events (MIE) that drive distinct transcriptional programs. These are further shaped by secondary SNV and CNV events. This genetic heterogeneity converges, in most cases, to a functionally dichotomous state of CCND1 or CCND2 overexpression. The molecular mechanisms underlying each of the distinct myelomagenic transcriptomes and the CCND1 vs CCND2 dichotomy have not been defined. To address these questions, we obtained highly purified BMPC from 3 healthy donors and 30 MM patients (HY: 15; CCND1: 4; MMSET: 5; MAF: 2; other: 4), either at diagnosis or relapse, and mapped their chromatin accessibility and transcriptome profiles by ATAC-seq and RNA-seq, respectively. In total, we obtained ~300K regions with accessible chromatin in either MM or normal PC. Overall chromatin accessibility increased in myeloma compared to normal PC, particularly in MAF- and MMSET-translocated subtypes. Analysis of combined ATAC-seq/RNA-seq by Multi-Omics Factor Analysis (MOFA) resulted in a clearer samples distinction than either ATAC-seq or RNA-seq alone, with altered chromatin accessibility accounting for more of the variance than expression. Of the top five identified factors, the top two (one transcriptome driven, one accessibility driven) distinguished normal from MM samples, whilst two more separated MMSET, MAF and CCND1 subgroups. Ninety seven, 157, 256 and 348 overexpressed genes in the CCND1, HY, MMSET and MAF subgroups, respectively, were predicted to be regulated by differentially accessible enhancers. Twenty percent (165/858) of these genes were overexpressed in >1 subgroup suggesting a process of chromatin accessibility-based convergence evolution. Enrichment analysis suggested direct or indirect involvement of Polycomb and chromatin remodellers; significant enrichment was also found for genes involved in neurogenesis. ATAC-seq footprinting predicted binding sites for 250 expressed transcription factors (TFs), 116 of which displayed higher binding frequency in myeloma than in normal PC and included both known (e.g., XBP1, RELA, IRF4, PRDM1) and potentially novel regulators of myeloma biology (e.g., CXXC1 and NFE2L1). The remaining 134 TF were predicted to be present in at least one MM subgroup, but absent in normal PC. Amongst them, as expected, MAF was active in the MMSET- and more so in the MAF-translocated subgroups. DepMap database analysis suggested myeloma cell dependency on 181/250 TF (CRISPR/Cas9 CERES score < -0.1 in >3/14 MMCL analysed). In dissecting the regulatory basis of CCND2 vs CCND1 dichotomy, one MOFA factor completely separated MAF from CCND1 samples, placing extreme opposite weights on the expression of CCND2 and CCND1 respectively. Interestingly, the same factor identified open-chromatin clusters upstream of CCND2 and linked them to its over-expression. These clusters were also open in the MMSET group and in CCND2-expressing HY samples. Conversely, no accessibility was detected in the CCND1 group, the CCND1-expressing HY samples or in normal PCs. Further, super-enhancer calling using the H3K27ac histone mark in MAF-translocated JJN3 cells identified the region of interest as a bona fide super-enhancer. Chromatin long range interactions, as assessed by Capture-HiC, demonstrated high frequency interactions of the CCND2 promoter with the constituent elements of the putative super-enhancer. Experimental validation using a CRISPR/Cas9i system confirmed the functional role of all 4 super-enhancer constituents tested in the regulation of CCND2 expression, while TF footprinting predicted MAF binding to the super-enhancer in MAF-translocated PC. In conclusion, we show that distinct oncogenic transcriptomes in MM are underpinned by extensive chromatin changes, accompanied by TF activity 're-wiring' that does not necessarily require transcriptional deregulation of the TF themselves. We identify novel, non-oncogene TF dependencies that suggest therapeutic opportunities in MM and we discover and characterise the critical super-enhancer that drives overexpression of the CCND2 oncogene in MM. Disclosures Auner: Amgen: Other: Consultancy and Research Funding; Takeda: Consultancy; Karyopharm: Consultancy. Hatjiharissi:Janssen: Honoraria. Caputo:GSK: Research Funding. Karadimitris:GSK: Research Funding.

Background: Multiple myeloma (MM) is a remitting-relapsing malignancy with variable clinical outcome. Certain cytogenetic abnormalities, either present at diagnosis or emerged at later stages, predict for poor outcome and highlight the clinical importance of MM genetic heterogeneity. Whole genome and exome sequencing studies reveal a complex intraclonal genetic landscape, organised in linear and branching Darwinian patterns, which evolves in space and time. Clones with a more complex genetic architecture may be more fit to escape treatment and those patients are likely to have a worse clinical outcome. Clinical multicolour flow cytometry (MFC) is routinely used in MM diagnosis and detection of minimal residual disease. Previous studies have shown that MM cell subpopulations with discrete phenotypic features correspond to genetic subclones, therefore it is plausible that MFC data captures clonal heterogeneity. On that basis, we propose that clustering analysis of MM phenotypic subpopulations could be clinically relevant. Methods: We retrospectively analysed clinical MCF data at diagnosis from 44 patients eligible for autologous stem cell transplantation (AutoSCT) and 14 ineligible patients and data from 52 relapsed patients after first AutoSCT. All patients were treated between 2012 - 2018. The 8-colour MCF marker panel included CD138, CD38, CD56, CD45, CD20, CD19, cytoplasmic kappa and lambda light chains (cytLC). Data was analysed in FlowJo software and MM plasma cells were identified as CD38high, CD19-, cytLC+, within their FSC-A/SSC-A physical gate. The gated events were exported in a new fcs file. Clustering analysis was performed in Cytofkit, a R-based Bioconductor package, using the Rphenograph, Cluster-X and FlowSOM algorithms. All fcs files were subjected in the same clustering analysis, but CD56 positive and CD56 negative cases were analysed separately to offset bias from differential CD56 expression. Parameters inserted in the algorithms were FSC-A, CD138, CD38, CD45, CD20 and CD56. The number of clusters was produced by FlowSOM (k=4) and only clusters with size >1% of the total events were accepted. Results: At diagnosis, FlowSOM identified 1 (n=32, 56.1%) or 2 clusters (n=19, 33.3%) in most cases. Three clusters were found only in 5 patients (8.8%) and 4 clusters in 1 patient (1.8%). The number of clusters at diagnosis did not correlate with cytogenetic risk group or ISS. Also, the number of clusters did not predict for depth of response or relapse free survival post AutoSCT. On the contrary, phenotypic patterns at relapse post AutoSCT were more complex, with 1 cluster identified in 2 patients only (3.8%), 2 clusters in 23 (44.2%), 3 clusters in 24 (46.2%) and 4 clusters in 3 patients (5.8%). Patients with >2 clusters (n=27) had a shorter survival post relapse (median 17 months - 95% CI, 7-26.6) compared to those (n=25) with 1-2 phenotypic clusters (median not reached, Log rank p=0.06). A phenotypic cluster characterised by CD138low/- at relapse, was also associated with adverse outcome and higher risk cytogenetics. In 14 patients with available serial samples at diagnosis and relapse we observed 3 patterns of phenotypic evolution: a. sustained pattern, b. change of dominant cluster and c. emergence of completely new subpopulations. These evolving phenotypes resemble changes in clonal composition over time observed in genetic studies. Conclusion: Clinical MCF, in addition to routine diagnostics, can be informative of MM biological and clinical heterogeneity. Particularly in the relapsed setting, complex phenotypic patterns identified by clustering analysis may be of prognostic value. Validation of this preliminary study results in larger patient cohorts or clinical trials, could provide a useful and readily available tool for patient stratification and prognosis. Disclosures Apperley: Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Karadimitris:Celgene: Research Funding; GSK: Research Funding; Gilead: Honoraria.

Background Carfilzomib (K) and bortezomib (V) and have been studied in head-to-head comparison using a K dose of 56mg/m2 in doublet with dexamethasone at relapse (ENDEAVOR), and also at 36mg/m2 in triplet with melphalan and prednisolone in newly diagnosed non-transplant eligible patients. Differing results may relate to dosing and scheduling, as well as to different study populations. Triplet regimens at relapse are commonly used, and combinations with cyclophosphamide and dexamethasone (Cd) are relatively affordable. Aims The MUK five phase 2 study compared the activity and safety of K (36mg/m2 ) and V in triplet combination with Cd for patients at first relapse, or refractory to no more than 1 prior line of therapy, and investigated the benefit of K maintenance following fixed duration KCd. Methods Eligible patients were randomized (R1) 2:1 to receive 6 cycles of KCd or 8 cycles of VCd (Fig 1); patients with ≥SD at the end of KCd were randomized (R2) 1:1 to receive maintenance K (Fig 1) or no further treatment. Patients in the VCd arm did not receive maintenance. Co-primary endpoints were ≥VGPR rates at 24 weeks post R1 (powered for non-inferiority, 90% confidence interval (CI), odds ratio (OR) >0.8), and PFS from R2 (superiority, 80% power, HR 0.67). Disease response was assessed by IMWG criteria, and minimal residual disease (MRD) by multiparameter flow cytometry (10-4). Adverse genetic risk was any one of t(4;14), t(14;16), t(14;20), del(17p) or 1qgain. Results 300 patients were randomized, 201 KCd and 99 VCd. Patient and disease features were balanced between arms (reported ASH 2017). The safety population was 292 patients (KCd, 196; VCd 96). While 81.6% of patients in the KCd arm received all 6 treatment cycles, only 53.5% in the VCd arm received all 8 cycles. Safety data (reported ASH 2017) showed increased treatment emergent neuropathy with VCd (≥G3 or G2 with pain = 19.8% vs 1.5% with KCd), and more cardiac and hypertension ARs with KCd (G3 3.6% vs 0%, 4.1% vs 2.1%). Overall response at 24 weeks KCd vs VCd: ≥PR 84.0% vs 68.1%, OR 2.72, p=0.0014. Maximum response within 12m (with matching adjustment to remove bias of K maintenance) KCd vs VCd: ≥VGPR 53.1% vs 45.4%; ≥PR 91.3% vs 78.9%, diff=12.4%, 90% CI (2.0, 22.6). Maximum response overall KCd vs. VCd: ≥VGPR 53.6% vs 45.4%. In an updated analysis of genetic data (228 patients), 64/152 (42.1%) patients in KCd arm had adverse risk, vs 34/76 (42.1%) in VCd arm. 79.7% and 65.6% patients with adverse risk completed all cycles of KCd and VCd, respectively, compared to 92.9% and 40.0% patients with standard risk. In the KCd arm, 38.1% of adverse risk patients achieved ≥VGPR at 24 weeks vs 33.9% with standard risk. In the VCd arm, ≥VGPR was 22.6% in adverse risk vs 33.3% in standard risk patients (fig 2). PFS comparisons were based on a 10% 1-sided significance level. For the R1 comparison, 100 (51.0%) and 71 (74.0%) patients have progressed/died in the KCd and VCd arms respectively from R1. Median PFS for KCd (patients receiving maintenance censored) was 11.9m (80%CI 11.6, 12.7) vs 10.2m (9.3, 11.3) for VCd, p=0.50 (not powered to detect difference). A Cox multivariate model for PFS including treatment arm, b2m, previous V, previous ASCT and timing of relapse showed independent effect of b2m level and previous ASCT only. OS data are immature, with only 25% events in each arm. Of 141 patients eligible for R2, 69 were allocated to maintenance K. Arms were well balanced for response (≥VGPR: K 58.0%, obs 54.2%) ECOG, ISS, genetic risk and MRD status (MRD-neg: K 11.6%, obs 13.9%) at end of initial treatment. Safety and tolerability of maintenance have previously been reported (EHA 2018). Median follow-up for patients from R2 was 10.5m (0.9-31.3): 44.3% of patients completed 6 cycles K maintenance. 82.1% of patients had a dose modification. K maintenance was associated with a longer PFS from R2, median 11.9m vs 5.6m obs (HR 0.59, p=0.009). The combined PFS of patients receiving KCd induction followed by K maintenance was 18.1 months (80% CI 14.4-18.9). Conclusion In patients with adverse genetic risk, KCd achieves higher ≥VGPR rate compared to VCd. This contributes to the higher ORR seen with KCd. Maintenance K was associated with longer PFS. Use of KCd triplet for fixed duration followed by maintenance K resulted in combined PFS of 18.1m, which is comparable to the median PFS for patients in ENDEAVOR who had 1PL (22m). The effect of genetic risk on survival outcomes will be updated at the meeting. Disclosures Yong: Celgene: Honoraria; Takeda: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau. Williams:Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria, Other: travel support, Speakers Bureau; Takeda: Honoraria, Other: travel support, Speakers Bureau. Cavenagh:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Kaiser:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Other: travel support; Chugai: Consultancy; Bristol-Myers Squibb: Consultancy, Other: travel support; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Rabin:Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Consultancy, Other: Travel support , Speakers Bureau; Janssen: Consultancy, Other: Travel support, Speakers Bureau. Ramasamy:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garg:Novartis: Other: travel support, Research Funding; Amgen: Honoraria, Other: Travel Support; Janssen: Honoraria; Takeda: Other: Travel Grant. Auner:Takeda: Consultancy; Amgen: Honoraria, Research Funding; Novartis: Consultancy; PharMar: Consultancy. Hawkins:Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Bygrave:Celgene: Honoraria, Other: Meeting sponsorship; Janssen: Honoraria, Other: Meeting sponsorship; Takeda: Honoraria, Other: Meeting sponsorship; Novartis: Honoraria. Morgan:Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Davies:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Janssen: Consultancy, Honoraria; MMRF: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel Support; Janssen: Consultancy, Other: Travel support.

Background The benefit of single agent maintenance is largely established from studies in newly diagnosed patients, while extended therapy combination regimens are more commonly used in relapsed disease. Extended therapy on combination protocols may be limited by tolerability and safety, as well as patient compliance. Fixed duration combination treatment followed by single agent maintenance may provide better long term disease control. Such benefit may correlate with depth of response, measured as minimal residual disease (MRD). Prognostic significance of MRD negativity in the relapsed setting is increasingly recognised, but the utility of single agent maintenance in achieving this is unknown. Aims The MUKfive phase 2 trial studied the safety and activity of carfilzomib, cyclophosphamide and dexamethasone (KCd) for patients at first relapse or refractory to one prior line, and compared activity and safety of maintenance K vs observation after fixed duration KCd. Here we provided updated results of the maintenance randomization, including the effect on MRD and interaction with genetic risk. Methods The first part of the study compared KCd with VCd as fixed duration therapy for patients at first relapse, or primary refractory to one line of treatment. Inclusion criteria included Hb>80g/L, neutrophils>1.0x109/L, platelets≥50x109/L and GFR>30ml/min. Participants with ≥SD after KCd were randomised (R2) 1:1 to receive maintenance K (36mg/m2 days 1, 2, 15, 16 for 6m, then days 1, 2 for 12m) or no further treatment, minimization factors: disease response (≥VGPR vs Results 300 participants were randomised, 201 KCd and 99 VCd. Superior response to KCd has previously been reported (ORR 84.1% vs 68.1%, p=0.0014, ≥VGPR 40.2% vs 31.9%, non-inferior). For R2, 141 patients were randomised, 69 K, 72 observation (obs); 60 patients did not enter R2, 1/3 due to disease progression. Arms were balanced for patient and disease features: ≥VGPR (K 58.0%, obs 54.2%), ECOG, ISS, MRD status (MRD neg (MRD-): K 11.6%, obs 13.9%) and adverse risk genetics (K 16/39 41.0%, obs 24/48, 50%) at end of KCd. Safety population was 141 (67 K; 74 obs). Safety and adverse reactions in the K arm were consistent with data from previous studies (previously presented). 44.3% of patients completed 6 cycles K, 18% completed 18 cycles. 82.1% of patients had a dose modification, but 88.7% of all cycles were received on time. Reasons for stopping K were completed treatment (18%), disease progression (65.6%), toxicity (4.9%), withdrew consent (6.6%). At a median follow-up from R2 of 10.5m (0.9-31.3), 49 patients have progressed/died in the K arm, 58 in obs. Median PFS from R2 for K was 11.9m vs 5.6m obs (HR 0.59, p=0.009). In multivariate Cox's model for PFS including minimisation factors, only treatment arm and response to KCd were significant (p At time of R2, 8/69 (11.6%) and 10/72 (13.9%) of patients were MRD- in the K and obs arms respectively. MRD- rate increased after 6m of K to 11/45 (24.4%), while in the obs group, only 1/30 (3.3%) remained MRD-. At 12m, 12.5% in the K arm were MRD- compared to only 4.5% in obs group. Of 8 patients who were MRD- at start of K, 5 remained MRD- at 6m (3 inadequate sample) and 2 at 12m, of 40 MRD+ patients, 4 became MRD- at 6m, 1 remaining so at 12m. In contrast, only 1 patient who was MRD- at start of observation remained so at 6m, remaining negative at 12m. Patients who were MRD- at R2 had longer PFS (median PFS adjusted for treatment from R2 10.5m vs 7.2m for MRD+, HR=0.59, p=0.0795). Conclusion Single agent carfilzomib is well tolerated and improves quality of response (increase in MRD negative disease at 6 months). Deepening of response is reflected in the longer PFS associated with K maintenance, in patients completing fixed duration treatment with KCd. The impact of genetic risk on MRD status and conversion, and the impact of conversion on outcomes will be presented at the meeting. Disclosures Yong: Takeda: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria. Williams:Celgene: Honoraria, Other: travel support, Speakers Bureau; Janssen: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Other: travel support, Speakers Bureau; Novartis: Honoraria. Cavenagh:Novartis: Honoraria, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Kaiser:Chugai: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Other: travel support; Takeda: Consultancy, Other: travel support; Amgen: Consultancy, Honoraria. Rabin:Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Janssen: Consultancy, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Other: Travel support , Speakers Bureau. Ramasamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garg:Amgen: Honoraria, Other: Travel Support; Novartis: Other: travel support, Research Funding; Janssen: Honoraria; Takeda: Other: Travel Grant. Auner:PharMar: Consultancy; Novartis: Consultancy; Amgen: Honoraria, Research Funding; Takeda: Consultancy. Morgan:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Davies:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; ASH: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Abbvie: Consultancy; TRM Oncology: Honoraria. Owen:Janssen: Consultancy, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel Support.

Background Proteasome inhibitors (PIs) are central to anti-MM therapy and 3 are currently licensed: bortezomib, carfilzomib and ixazomib, increasing treatment options. Bortezomib (BZ) and carfilzomib (CFZ) have been studied in head-to-head comparison using a CFZ dose of 56mg/m2 in doublet with dexamethasone in relapse (ENDEAVOR), and also at 36mg/m2 in triplet with melphalan and prednisolone in newly diagnosed non-transplant eligible patients. Differing results may relate to dosing and scheduling, as well as to different study populations. There is growing evidence for triplet regimens especially at relapse. Aims The MUK five phase 2 study compared the activity and safety of CFZ and BZ in triplet combination using a CFZ dose of 36mg/m2, with cyclophosphamide and dexamethasone (KCD vs VCD), for patients at first relapse, or refractory to no more than 1 prior line of therapy. Methods The study compares 8 cycles of VCD with 6 cycles of KCD (24 weeks treatment), and also assesses the benefit of maintenance carfilzomib in the KCD arm. Participants were randomised (R1) in a 2:1 ratio in favour of KCD, minimisation factors were β2M, prior bortezomib, prior ASCT and timing of first relapse (< or ≥12 months). Participants in the KCD arm with at least stable disease (SD) after 6 cycles of KCD were randomised (R2) 1:1 to receive maintenance carfilzomib or no further treatment. Participants in the VCD arm did not receive maintenance. Inclusion criteria included Hb>80g/L, neutrophils>1.0x109/L, platelets 50x109/L and GFR>30ml/min. KCD therapy was 28 day cycles of biweekly carfilzomib 20/36mg/m2 IV (weeks 1-3) while VCD was 21 day cycles of biweekly bortezomib 1.3mg/m2 SC (weeks 1 and 2), both with cyclophosphamide 500mg orally weekly (weeks 1-3 only for KCD) and dexamethasone 40mg orally weekly. Co-primary endpoints were ≥VGPR rates at 24 weeks post R1 (powered for non-inferiority comparison, deemed non-inferior (NI) if 90% confidence interval (CI) for odds ratio (OR) >0.8), and PFS from R2 (superiority). Disease response was assessed according to the Modified IWG Uniform Response Criteria, and minimal residual disease (MRD) by multiparameter flow cytometry (10-4). Results From Feb 2013 to Sept 2016, 300 participants were randomised, 201 to KCD and 99 to VCD. Patient and disease features were balanced between arms, median ages 67 and 69 years, 57.5% and 64.6% male, 93.5% and 94.9% ECOG 0-1 for KCD and VCD respectively. Median time from diagnosis was 32.5 and 36.1 months, 50.0% and 45.5% were ISS 2/3, and 66.2 and 67.7% had had an ASCT. While 81.6% of patients in the KCD arm received all 6 treatment cycles, only 53.5% in the VCD arm received all 8 cycles; reasons for stopping treatment were toxicity (KCD, 7%; VCD, 19.2%), disease progression (6.5%, 6.1%) and withdrawal of consent (2.5%, 11.1%). Dose modifications occurred in 78.6%, and 85.4% of patients in the KCD and VCD arms respectively. A total of 196 and 96 patients were evaluable for efficacy analysis in the KCD and VCD arms. Major response (≥VGPR) at 24 weeks for KCD and VCD was 40.2% and 31.9% respectively (OR 1.48; 90% CI (0.95, 2.31), deemed NI). Overall response (≥PR) was 84.0% and 68.1% (OR 2.72; 90% CI (1.62, 4.55); p=0.0014, deemed superior). MRD negativity (all evaluable patients; n=134 KCD, n=48 VCD) at 24 weeks was 16.4% for KCD and 12.5% for VCD. The safety population was 292 patients (KCD, 196; VCD 96). Treatment emergent neuropathy occurred in 21.4% and 56.3% of patients in the KCD and VCD arm, respectively. The proportion of patients with grade ≥3 neuropathy or grade ≥2 neuropathy with pain (key secondary endpoint) was lower with KCD (1.5%, vs 19.8% with VCD; p Conclusion Major response (≥VGPR) to KCD therapy is non-inferior to VCD and overall response rate is superior to VCD over a fixed treatment duration. This may be related to better tolerability and reduced incidence of neurotoxicity with KCD, with superiority of KCD in terms of grade ≥3 neuropathy or grade ≥2 neuropathy with pain. Further details on safety and activity will be presented at the meeting. Disclosures Yong: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Auner: Amgen: Honoraria, Research Funding. Williams: Janssen: Honoraria, Other: travel support, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau; Takeda: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Cavenagh: Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Kaiser: Chugai: Consultancy; BMS: Consultancy, Other: Travel expenses; Takeda: Consultancy; Janssen: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Rabin: Novartis: Consultancy, Speakers Bureau; Takeda: Consultancy, Other: Travel support for meetings, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Other: Travel support for meetings, Speakers Bureau. Ramasamy: Janssen: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Honoraria. Garg: Janssen: Other: travel support, Research Funding, Speakers Bureau; Takeda: Other: travel support; Novartis: Other: travel support, Research Funding. Hawkins: janssen: Honoraria. Morgan: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers: Consultancy, Honoraria. Davies: Amgen: Consultancy, Honoraria; Bristol-Myers: Consultancy, Honoraria; Takeda: 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; Seattle Genetics: Consultancy, Honoraria. Owen: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: travel support; Janssen: Consultancy, Other: travel support.

Apoptosis of short-lived plasma cells after a few days of intense immunoglobulin secretion is critical for maintaining a controlled humoral immune response. The mechanisms that regulate this process are poorly understood. Here we report that the key apoptotic caspases, caspase-3 and caspase-9, become resistant to activation by apoptotic stimuli when B cells differentiate into short-lived plasma cells. As a consequence, apoptosis of most short-lived plasma cells in vitro and in vivo is effector caspase-independent. We also show that a triaspartic acid repeat that normally prevents activation of caspase-3 becomes stabilized in short-lived plasma cells and myeloma cell lines. The block on caspase activation occurs before the accumulation of intracellular immunoglobulins and a progressive rise in secretory stress in the endoplasmic reticulum (ER). Plasma cells show increased susceptibility to ER stress–induced apoptosis and activate the ER-associated caspase-12, which is required specifically for nuclear apoptotic events. In nonlymphoid cells that cannot activate effector caspases, programmed cell death is delayed in response to ER stress. These observations suggest that the block on activation of key apoptotic caspases has evolved in short-lived plasma cells to prolong survival under conditions of ER stress resulting from high-level immunoglobulin secretion.

Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second- and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib.

Abstract 4548 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma (MM). In the face of almost inevitable disease relapse, there is growing evidence for second ASCT as salvage therapy in certain patient groups. However, few published data exist regarding efficacy and safety of third ASCT in relapsed disease. We retrospectively analysed the results of eight patients treated at a single UK institution who each received three separate autologous stem cell transplants for relapsed MM between May 1997 and April 2012. There were four men and four women. Median age at diagnosis was 48 years (range, 25–64 years). Paraprotein isotype was IgA in two patients and IgG in the remaining six patients. At the time of 1st transplant, seven patients were in partial response (PR) and one in complete response (CR). Conditioning melphalan dose was 200mg/m2 in all but two patients who received 140mg/m2. Three patients entered CR following 1st transplant and four patients showed PR. Median time to disease progression was 31 months (range, 11.8–52.9 months). Prior to 2nd transplant, five patients achieved very good partial response (VGPR) and three PR with induction chemotherapy. Melphalan dose was 200mg/m2 in five patients and 140mg/m2 in the remaining three. Median time to disease progression was 22.3 months (range, 10.1– 39.6 months). At the time of 3rd transplant, two patients had achieved VGPR following induction chemotherapy, one showed PR, two stable disease (SD) and three evidence of disease progression. For the 3rd transplant, melphalan dose was reduced in most cases. Median follow up post 3rd transplant was 8.3 months (range 1.1–29.3 months). One patient died of overwhelming sepsis within one month of transplantation (treatment related mortality). At the time of analysis, five patients had relapsed following 3rd ASCT, with median time to disease progression of 10.4 months (range, 2.7–23.7 months). Three of these patients died at 3.5, 17.6 and 27.1 months post 3rd transplant. The remaining two patients are alive with no evidence of disease relapse (progression free survival (PFS) time of 3.3 and 1.3 months). Overall survival (OS) for the group from diagnosis is 62% at 10 years with a median OS from diagnosis of 149 months (range 68.5 – 189.2 months) (Figure 1). Median OS for the group from 3rd transplant is 17.6 months (range, 1.1–29.3 months) (Figure 2). Median PFS is 10.4 months (range 1.1–23.7 months). These results demonstrate that third ASCT is a possible treatment strategy for patients with relapsed MM and may prolong patient survival. Figure 1: Overall survival from diagnosis for patients receiving 3rd autologous stem cell transplantation for relapsed multiple myeloma Figure 1:. Overall survival from diagnosis for patients receiving 3rd autologous stem cell transplantation for relapsed multiple myeloma Figure 2: Overall survival from time of 3rd autologous stem cell transplant Figure 2:. Overall survival from time of 3rd autologous stem cell transplant Disclosures: No relevant conflicts of interest to declare.

Abstract 4554 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response. We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation. At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2. Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2). Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease. Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant Disclosures: No relevant conflicts of interest to declare.

Abstract 3488 It is important to determine prognostic indicators which may predict outcome of hematopoietic stem cell transplantation (HCT). The European Group for Blood and Marrow Transplantation (EBMT) proposed a scoring system for CML which, after modification, also predicted outcomes for patients transplanted for other hematologic malignancies. The HCT comorbidity index (HCT-CI) developed by Sorror et al. enabled further selection of patients for HCT based on their comorbidities. We have recently shown that the level of C-reactive protein (CRP) measured shortly before transplantation is another important prognostic factor in patients transplanted for CML in first chronic phase. In this study we tested the value of CRP together with other known prognostic factors in an independent cohort of 263 patients transplanted in a single institution from 1992 through 2009 for ALL (N=38, 14%) AML (N=72, 27%), MDS (N=19, 7%), and advanced phase CML (N=134, 51%). For the 130 (49%) recipients of stem cells from matched siblings conditioning consisted of cyclophosphamide and TBI. For the 133 (51%) unrelated donor transplant recipients in vivo T-cell depletion with anti CD52 antibody (Campath) was used in addition. Serum CRP levels were measured at a median of 16 days before stem cell infusion using a standard latex immunoassay (normal range 0–9 mg/L) while the patients were well without infection and off antibiotics. Patients' comorbidities were defined and assigned different weights (1-3) by the HCT-CI and disease stage was assessed in accordance with EBMT criteria. Thus, patients transplanted for AML (N=32) or ALL (N=27) in first complete remission were classified as early stage (N=59). Those with CML in accelerated phase (N=70), CML in second (N=42) or third (N=5) chronic phase, AML (N=19) or ALL (N=6) in second complete remission and MDS (N=19) were classified as intermediate stage (N=161). Patients with CML in blast phase (N=17) and acute leukemia in >2nd complete remission (N=26) or in relapse were defined as late stage (N=43). In univariate analysis, factors associated with day 100 nonrelapse mortality (NRM) were recipient's age at HCT, disease stage and preconditioning CRP level whereas disease stage, CRP level, and EBMT score were associated with overall survival (OS). In multivariate analysis only two factors showed independent prognostic value: late disease stage and elevated CRP level (>9 mg/L). Both predicted for inferior NRM (RR: 3.83, CI 1.65–8.92, P=.002 and RR: 1.51, CI 1.51–4.26, P9 mg/L, 17% for those with CRP 0–9 mg/L (figure) and 25% for the whole cohort. The 5-year OS was 31.5% for patients with CRP 0–9 mg/L, 22.2% for those with CRP >9 mg/L and 28% for the whole cohort. There was no association between elevated preconditioning CRP levels and infection, either as a comorbidity or as a cause of death. The HCT-CI did not have a prognostic role in this cohort. These results confirm the high prognostic value of disease stage. Importantly, they extend our findings in early phase CML to other hematologic malignancies and establish pretransplantation levels of CRP as an independent predictor of allogeneic HCT outcomes. Disclosures: No relevant conflicts of interest to declare.

Abstract 3392 Poster Board III-280 Although imatinib has replaced allogeneic stem cell transplantation (SCT) as the first treatment option for CML in first chronic phase (CP1), approximately 35% of patients do not obtain long-term benefit. As only 40-50% of these patients can be salvaged with second-generation tyrosine kinase inhibitors there is considerable debate about use of SCT as second line therapy. It is therefore important to identify groups of patients who would have a good outcome after SCT so that it may be offered after imatinib failure. In a previous analysis we identified the pre-conditioning level of C-reactive protein (CRP) as a prognostic factor for the outcome of SCT in CML. In this study, we investigated the prognostic value of comorbidities together with CRP at the time of myeloablative SCT, for patients with CML in CP1. Clinical data on 312 consecutive patients who underwent SCT between January 1991 and July 2008 was reviewed; 41 patients with incomplete data were omitted from the analysis. The median age of 271 analyzed patients was 34.3 years (range 9.7 – 59.6). 256 (94.5%) patients received bone marrow (BM) and 15 (5.5%) patients received peripheral blood stem cells (PBSC). Conditioning consisted of cyclophosphamide and TBI for 130 (48%) recipients of sibling stem cells. In addition in vivo T cell depletion with anti CD52 antibody (Campath 1H) was used for 141 (52%) unrelated donor transplants. Comorbidities were defined and assigned different weights (1-3) by the hematopoietic cell transplantation comorbidity index (HCT-CI; Sorror, ML et al, Blood 2005). HCT-CI scores were calculated for each patient stratifying them into low risk (LR, no comorbidities, HCT-CI =0), intermediate risk (IR, HCT-CI 1 or 2) and high risk (HR, HCT-CI ≥3) groups and were evaluated for their effects on transplant related mortality (TRM) and overall survival (OS). In multivariate analysis the HCT-CI score failed to predict OS or TRM at 1 year. The only significant difference was in TRM at 100 days between the patients with HCT-CI =0 (LR group) and patients with HCT-CI ≥1 (IR and HR groups; relative risk (RR) 4.0; 95% CI: 1.4 – 11.6). The absolute number of comorbidities (CMn) was a better prognostic indicator for day 100 TRM then the weighted HCT-CI (CMn=1, RR: 3.1, CI 1.3-7.3; CMn ≥1, RR: 4.9, CI: 1.7-14.1). Pre-conditioning CRP was predictive for both TRM and survival and was independent of CMn. We thus combined these two parameters into a new risk assessment tool (CRP/CMn), with 3 prognostic groups: LR (no comorbidities and CRP 10 mg/L or >1 comorbidity) and IR (remaining patients). These groups yielded probabilities of OS at 10 years of 81% (N=61, LR), 63% (N=159, IR) and 38% (N=25, HR; p=0.0001, Figure 1). When adjusted for patient age, duration of disease pre-SCT, donor type and patient/donor gender mismatch in a multivariate analysis, the relative risk of treatment failure (death) was 5.3 (95% CI: 2.5 – 11.5) for the HR group, and 2.3 (95% CI: 1.2 – 4.4) for the IR group when compared to the LR group. Fig 1 Probability of survival by CRP/CMn group Fig 1. Probability of survival by CRP/CMn group In our single center cohort of patients with CML in CP1 the HCT-CI was a poor indicator of prognosis post SCT. However, by removing the weighted scores and combining absolute number of co-morbidities with pre-conditioning CRP levels, we identified a new risk assessment tool that helps to select patients with CML in CP1 who could benefit from SCT as second line therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 1229 Poster Board I-251 Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is standard treatment for the non-elderly multiple myeloma (MM) patients. Relapses invariably occur and therefore reinduction therapy followed by ASCT is often considered. We retrospectively analysed the results of second ASCT after relapse and re-induction and assessed the effect of bortezomib therapy prior to second ASCT. We included 177 MM patients who relapsed after the initial melphalan 140-200mg/m2 ASCT and treated in a single institution from July 1994 to April 2009. Patients who received melphalan/TBI conditioning, planned upfront tandem transplants, allogeneic SCT, palliation only or who suffered early death or death in remission were excluded from our analysis. The patients were divided into 4 groups based on the type of salvage treatment. Group 1 included 96 patients with median age 59.6 years (range 31.16 – 73.5) at the time of progression who were salvaged with treatment modalities other than a second ASCT or bortezomib. Group 2 received bortezomib based salvage but not a second ASCT and included 31 patients aged 61.7 years (49.3 – 72.9), group 3 included 28 patients aged 58.6 years (31.1 – 70.6) who were treated with a second ASCT and no bortezomib, and finally group 4 included 22 patients aged 59.1 years (32.6 – 70.6) who were treated with bortezomib and second ASCT. For the transplanted patients, the conditioning consisted of melphalan 140-200mg/m2. Bortezomib was given at standard doses (1.3mg/m2 at days 1,4,8, and 11) plus dexamethasone 20mg same and next day of bortezomib injection for 3 to 4 21-day cycles. Survival was estimated from the time of progression after the initial transplant. Univariate analysis showed longer survival for the transplanted patients (median 41.2 and 60.9 months for groups 3 and 4, 15.2 and 29.8 months for groups 1 and 2 respectively, Log Rank p=0.003). In multivariate Cox analysis the type of salvage treatment retained significance (p=0.013, OR 2.75, 95%CI 1.23 – 6.16). When patients treated with a second ASCT (groups 3 and 4) were analysed separately, the difference in survival between groups did not reach significance (p=0.32). Multivariate analysis showed longer survival if complete remission (CR) or near CR (nCR) had been achieved with the first ASCT (p=0.05, OR 6.4 95%CI 1.7 – 23.19) and if disease progression had occurred at least 12 months after the initial ASCT (p65 years, reduced melphalan dose (12 months following the initial ASCT is the most significant prognostic factor of PFS and survival after the second ASCT. Bortezomib based induction is suggested to improve CR and nCR rates after the first ASCT, however its use prior to second ASCT does not appear to produce longer PFS or survival. Disclosures No relevant conflicts of interest to declare.

Abstract 1781 Poster Board I-807 Previous studies have shown that ethnic differences exist in the treatment of a number of malignant diseases, with non-white ethnic minorities frequently receiving suboptimal care. High-dose chemotherapy and autologous stem cell transplantation (ASCT) became the standard of care for most patients with multiple myeloma (MM) under the age of 65 and some older patients in the early 1990s. In this study, we investigated whether patients from ethnic minorities have had appropriate access to ASCT for the treatment of MM in a large, multiethnic, equal access healthcare provision area in the UK. Hammersmith Hospital (HH) is a tertiary referral centre for SCT for the Northwest London catchment area with a population of 1.732.020 in 2001 according to the last UK Census (65.5% Whites, 19.9% Asians, 8.8% Blacks, and 5.8% others). All patients diagnosed with haematological malignancies within the catchment area who are considered eligible for SCT are referred to HH from primary or secondary healthcare providers. A Cancer Research UK/National Cancer Intelligence Network report 2002-2006 has shown ethnicity-specific MM incidence rate ratios of 1.89-2.86 (upper and lower 95%CI) for Blacks and 0.82-1.02 for Asians relative to Whites (1.0) in the UK. Considering the 2001 ethnic distribution in the catchment area, this means that the ratio of MM patients expected to undergo ASCT at HH would be 0.25-0.38 for Blacks and 0.22-0.31 for Asians relative to Whites. Between 1994 and 2008, 311 MM patients received a planned single ASCT at HH as standard post-induction therapy. Of those, 235 were White, 47 were Black, and 29 were Asian. There were no differences between the ethnic groups in terms of age, time from diagnosis to ASCT, or remission status at the time of the transplant. IgA myeloma was significantly (p=0.007) more frequent in Whites (24%) than in Asians (10%) and Blacks (6%). Thus, the ethnic ratio of MM patients who actually received ASCT at HH was 0.2 for Blacks and 0.12 for Asians relative to Whites, indicating an under-representation of ethnic minorities. We next analysed the ethnicity-specific treatment ratios observed over three 5-year periods (94-98, 99-03, and 04-08) and found that the ratio of Blacks undergoing ASCT had been gradually increasing, and was reaching the lower end of the expected rate in the most recent 5-year period (0.13, 0.18, and 0.25). Asians had been dramatically under-represented in the first 5-year period and were still slightly outside the expected ratio in the last (0.03, 0.12, and 0.19). When we analysed the outcome of treatment, there was no significant difference between the ethnic groups in terms of overall survival from diagnosis or from the time of ASCT. Although these data have been gathered in one healthcare provision area only, they indicate that MM patients from ethnic minorities may not have had appropriate access to ASCT in the UK particularly in the early years of this treatment becoming a standard of care. Further studies are needed to determine whether ethnic minorities are generally at risk not to receive new standards of care for haematological diseases and whether patient- or healthcare provider-based factors are responsible for ethnic disparities. Disclosures No relevant conflicts of interest to declare.

Abstract 2147 Poster Board II-124 In the era of novel therapeutic agents, high-dose chemotherapy and autologous stem cell transplantation (ASCT) remains an integral component of treatment for multiple myeloma (MM), with a proportion of patients undergoing more than one ASCT during the course of their disease. Therefore, the choice of new drug combinations for induction therapies must take into consideration the requirement to collect a sufficient number of stem cells, which is also reflected in a recently published consensus perspective of the International Myeloma Working Group. The immunomodulatory drug Lenalidomide and the alkylating agent Melphalan have a substantial impact on stem cell mobilization, but the effect of induction therapies containing either Thalidomide or Cyclophosphamide on the stem cell collection yield is negligible. We considered the possibility that the combination of Cyclophosphamide and Thalidomide, which is widely used as an induction regime particularly in the UK as part of the CTD regime (with Dexamethasone), could have an additive impact on the stem cell pool and cause mobilization failures. We carried out a retrospective analysis of the outcome of peripheral blood stem cell mobilizations in MM patients performed at our institution over a four-year period in patients who had received CTD (n=55), and compared them with a control group of patients (n=56) who had received VAD (Vincristine, Doxorubicin, Dexamethasone; n=30) or Z-Dex (Idarubicin, Dexamethasone; n=26) during the same period. There were no differences between the CTD and control group in terms of age, MM subtype, disease stage, or remission status at the time of stem cell mobilization. All mobilizations were performed with Cyclophosphamide (4g/m2) and G-CSF (5-10μg/kg). Apheresis was attempted when the peripheral blood CD34 count was >10 × 103/ml, and the standard harvest target was 4 × 106 CD34+ cells/kg, with a minimal target of 2 × 106 CD34+ cells/kg. The total number of CD34+ cells harvested was substantially lower in the CTD group (5.2 vs. 9.7 × 106/kg, p=0.002), and a higher number of patients in the CTD group underwent more than one apheresis procedure (52.8% vs. 32.1%, p=0.012). The number of CD34+ cells harvested on the first day of apheresis and per apheresis procedure were also lower in the CTD group (2.8 vs. 7.3 × 106/kg, p=0.002; 2.6 vs. 6.7 × 106/kg, p=0.002). More patients in the CTD group failed to achieve both the standard (36.4% vs. 16.1%, p=0.021) and minimal (19.2% vs. 5.4%, p=0.036) stem cell harvest target. The failure rate on the first day of apheresis was also higher in the CTD group both for the standard (56.3% vs. 28.6%, p=0.003) and the minimal target (36.7% vs. 16.1%, p=0.041). There was no difference in stem cell yield between the VAD and Z-Dex groups. Age and number of induction chemotherapy cycles did not have an impact on mobilization failure in the entire cohort or the CTD group alone. In the CTD group, 18% of patients underwent re-mobilization with Etoposide (1.6g/ m2) and G-CSF (n=8), or with Plerixafor (240μg/kg) and G-CSF (n=2), which was successful in all patients. These results demonstrate that the CTD induction regime results in a high rate of stem cell mobilization failures, which is associated with the requirement for an increased number of apheresis and re-mobilization procedures. The observations provide novel evidence that drugs with no previously demonstrated significant effect on stem cell mobilization can have a considerable negative impact on the stem cell yield when used in combination. The possible benefit of new drug combinations has to be balanced against the increase in cost, the potentially higher rate of complications, and delays or failures to progress to ASCT resulting from impaired stem cell mobilization. Disclosures: No relevant conflicts of interest to declare.

Plasma cells (PCs) are the terminally differentiated effector cells of the humoral immune system. The majority of PCs are short-lived and undergo programmed cell death in the form of apoptosis after a few days of intensive immunoglobulin secretion. Despite potentially wide-ranging implications for infection control, auto-immunity, and PC dyscrasias, the mechanisms that govern the initiation and execution of PC apoptosis are poorly understood. We used two well-established murine systems of PC differentiation and immunohistochemistry of human lymphoid tissue sections to study the regulation of PC apoptosis. IgM-secreting post-mitotic CD138+B220− PCs were differentiated in vitro from primary mouse splenic B cells using cytokines and LPS and purified by magnetic selection. Murine I.29mu+ B lymphoma cells were induced to undergo plasmacytic differentiation by stimulation with LPS. In both systems, terminal PC differentiation is followed by spontaneous apoptosis of half of the PCs within 48h, similar to PC apoptosis in vivo. We found that a sharp increase in endoplasmatic reticulum (ER) stress, which is caused by an imbalance between secretory load and capacity in the ER, occurs in PCs that have completed differentiation and begin to undergo apoptosis. In parallel, susceptibility specifically to ER stress-induced apoptosis but not to other apoptotic stimuli increases substantially in differentiated PCs, despite an ongoing ER stress response and expansion of the secretory machinery. Caspase-12, which has been linked specifically to ER stress-induced apoptosis, is activated and processed during programmed PC death. Using the specific inhibitor of caspase-12, zATADfmk, we found that caspase-12 mediates apoptotic DNA fragmentation and chromatin condensation in PCs undergoing apoptosis but not in B cells undergoing tunicamycin-induced apoptosis. In contrast, the major apoptotic effector caspases (caspase-9, caspase-3, caspase-7) downstream of the mitochondria become resistant to activation by apoptotic ER stress during terminal PC differentiation and are not activated during PC apoptosis. We observed that he pan-caspase inhibitor, zVADfmk, completely blocks tunicamycin-induced apoptosis in B cells but does not inhibit PC apoptosis or tunicamycin-induced cell death in PCs. Using the small molecule PAC-1, which specifically activates caspase-3 by targeting a “safety-catch” amino acid sequence that keeps caspase-3 inactive, we found that caspase-3 is stabilized in its inactive form in PCs and human myeloma cell lines, but not in B cells. Immunohistochemistry of human lymphoid tissue sections demonstrated that most primary reactive PCs and extramedullary myeloma cells undergo spontaneous apoptosis in vivo without activation of caspase-3. Thus, ER stress plays a major role in limiting the life span of short-lived PCs and activates caspase-12, which mediates nuclear apoptosis specifically in PCs. The major apoptotic effector caspases, however, become resistant to activation during terminal PC differentiation, and PC apoptosis is largely independent of caspases downstream of the mitochondria. These observations lead us to propose that developmentally regulated inhibition of key apoptotic caspases, which rapidly execute apoptosis in most cells, has evolved in PCs as a means to delay apoptosis under conditions of increasing ER stress linked to immunoglobulin secretion. Overwhelming ER stress ultimately limits the life span of short-lived PCs by inducing apoptosis using alternative mechanism involving caspase-12, which is redundant for the execution of ER stress-induced apoptosis in cells that can activate the classical effector caspases.

Constitutive activation of the RAS-RAF-MEK-ERK signaling cascade plays an important role in the pathogenesis of AML. We were interested whether abnormalities of the serine-threonine kinases A -, B, - and C -RAF occur in AML and whether they might be causative for activation of this pathway. Expression of these genes was assessed by real-time quantitative (rtq) PCR in 102 patient samples of AML, three AML cell lines and normal CD34+ cells of seven individuals. Results were correlated with the phosphorylation status of ERK 1/2, as measured by immunoblot analysis. 45/82 (54,9%) of AML cases showed ERK phosphorylation indicating constitutive activation of the pathway. However, there was no correlation with expression levels of either A-, B- or C-RAF. Deletions of the B-RAF gene as revealed by rtq PCR were observed in 20/99 (20%) of AML cases and were consistent with cytogenetic results but did not correlate with ERK activity, either. In addition, we screened for mutations of B- and C-RAF in all samples showing ERK phosphorylation using PCR and sequence analysis. Two novel C-RAF missense mutations, both of them located in the kinase domain, were detected in the subgroup of therapy related AML (t-AML): S427G in one and I448V in another patient. Expression of the mutated proteins in mammalian cells resulted in the constitutive activation of MEK and ERK, thus strongly suggesting that the mutations activated C-RAF. Sequence analysis of the primary tumors (colon cancer and teratoma, respectively) as well as buccal epithelial cells revealed these mutations of germline origin and denaturing high pressure liquid chromatography revealed a frequency of