Shacham, Sharon

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461 ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

Abstract Introduction: Patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) who cannot tolerate or who are not eligible for autologous or chimeric antigen receptor T cell (CAR-T) therapy have limited therapeutic options and suboptimal long-term outcomes. In patients who were not eligible for HSCT, the rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) regimen (and variations using methylprednisolone or carboplatin/oxaliplatin) have shown an overall response rates (ORR) of ~50%, a complete response (CR) rate of ~25% (Gopal, Leuk Lymphoma, 2010), and a median progression-free survival (PFS) and an overall survival (OS) of 3 and 9 months, respectively (Crump, Hematol Oncol Clin N Am. 2016; Gopal Leuk Lymphoma, 2010; Ng, Br J Cancer, 2005; Sirohi, Hematology, 2007; Barton, Eur J Haematol. 2015; Moccia Leuk Lymphoma, 2017). Selinexor is an oral small molecule selective inhibitor of exportin-1 (XPO1) mediated nuclear export (SINE) compound leading to activation of tumor suppressor proteins and reduction in oncoprotein levels. It also reduces the expression of deoxyribonucleic acid (DNA) damage repair proteins and therefore potentiates DNA damage-based therapies leading to an increased death of cancer cells. Selinexor has synergistic effects with gemcitabine and cisplatin, and enhanced anti-lymphoma effects with dexamethasone. In the SADAL study (n=134), single-agent oral selinexor 60 mg twice weekly induced an ORR of 29% and a CR rate of 13% in patients with RR DLBCL. The response rates were consistent across various subgroups including patients &lt;70 vs ≥70 years old, those with de novo and transformed DLBCL, and GCB and non-GCB subtypes of DLBCL. The median duration of response (DOR) was 9.3 months, and 23 months for patients who achieved CR. OS was 9.0 months. In June 2020, selinexor monotherapy was approved in the US for the treatment of adult patients with RR DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor in combination with R-GDP was evaluated in a Phase 1 clinical trial (SELINDA), in which patients with DLBCL received either 40 or 60 mg selinexor once or twice weekly in combination with standard dose R-GDP. The recommended phase 2 dose for further exploration was 40 or 60 mg once weekly with an ORR of 60-80%. Therefore, combining selinexor with R-GDP is expected to improve response rates, and continuation of treatment with single-agent selinexor is expected to prolong the duration of responses, improve PFS (and potentially OS) in patients with RR DLBCL. Materials and methods: XPORT-DLBCL-030 is a Phase 2/3, multicenter study. The Phase 2 portion of the study is an open-label randomized study to identify the optimal dose of selinexor (40 or 60 mg) in combination with R-GDP in patients (n=120) with RR DLBCL. Patients ≥18 years with 1-3 prior lines of therapy and ECOG performance status ≤2 who are not intended for HSCT or CAR-T therapy are randomized 1:1:1 to one of 3 treatment arms: Arm 1: selinexor 40 mg+R-GDP (S40+R-GDP); Arm 2: selinexor 60 mg+R-GDP (S60 + R-GDP); Arm 3: R-GDP. Combination treatment will be given for up to 6 cycles (21 days/cycle). After completing the SR-GDP combination therapy (EoC), patients in Arms 1 and 2 who reach at least partial response (PR), will receive weekly single-agent selinexor 60 mg (28 days/cycle) as "continuous therapy" until disease progression (PD) or unacceptable toxicity. After PD, patients will be followed up for survival. Patients in the R-GDP arm will be followed up for PD and survival. Patients who are ineligible for HSCT due to an active disease, or those who have primary refractory DLBCL, defined as no response or relapse within 6 months after ending first-line treatment, will be allowed to enroll in the study (up to 15% and 25%, respectively of all patients enrolled). The primary endpoint of the study is ORR according to the Lugano 2014 criteria. Secondary endpoints include PFS, OS, ORR-EoC, DOR and incidence and severity of adverse events. Figure 1 Figure 1. Disclosures Pinto: Takeda: Consultancy; MSD: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau; Bristol Myers Squibb-CELGENE: Honoraria. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Canales: Sanofi: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; iQone: Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; Jagiellonian University: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees. Sureda: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Ma: Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Li: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arriola: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arazy: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

2016 Background: Among the primary aims of new therapies for glioblastoma (GBM) are the reduction of morbidity and restoration or preservation of quality of life (QoL). Selinexor (SEL) is a first-in class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cell death in cancer cells. SEL is approved for the treatment of previously treated multiple myeloma and DLBCL. XPORT-GBM-029 (NCT04421378) is a phase 1 dose finding study followed by an open-label randomized phase 2, 3-arm trial to evaluate SEL in combination with standard therapies for newly diagnosed and recurrent GBM: Arm A (ndGBM, uMGMT) – radiation +/- SEL; Arm B (ndGBM, mMGMT) – radiation and temozolomide +/- SEL; Arm C (rGBM) – lomustine +/- SEL at first relapse. We look to identify sensitive, reliable, and clinically meaningful digital assessments of the functional status of ndGBM and rGBM patients via a patient-centric approach. Methods: XPORT-GBM-029 incorporates standard clinical and imaging evaluations of GBM progression with novel digital tools that objectively measure motor and cognitive function. The study is conducted at 50 sites globally with the aim of enrolling 350 patients with newly diagnosed and recurrent GBM. Following discussions with KOLs and patient advocacy partners at EndbrainCancer, we surveyed GBM patients and their caregivers to identify disease manifestations critical to patients’ QoL. The survey revealed four key areas impacting patients’ QoL that can be affected by GBM therapies and can be objectively monitored: cognitive function, lateralization, fatigue, and sleep. In this trial we use objective measurements to evaluate SEL’s effects on GBM patients’ QoL. Patients wear inertial sensors to measure their activity and sleep and complete a cognitive battery at baseline and before each MRI. Results: Associations between objective digital measures of activity, gait, fatigue, sleep, and cognition will be examined with respect to clinical assessments including physical examinations, modified Response Assessment in Neuro-Oncology (mRANO), Neurologic Assessment in Neuro-Oncology (NANO), Karnofsky Performance Score (KPS) and Patient Reported Outcome (PRO) QoL questionnaires. Descriptive summary statistics and plots are employed in exploratory data analysis, and other advanced data mining methods may also be considered. Conclusions: XPORT-GBM-029 trial is probably the first large, prospective, longitudinal study in GBM patients employing digital markers and may provide useful information regarding the utility of wearable and mobile devices for measuring functional outcomes in clinical trials. Clinical trial information: NCT04421378.

AbstractTriple‐class‐refractory multiple myeloma (MM) describes MM refractory to proteasome inhibitors, immunomodulatory agents, and anti‐CD38 monoclonal antibodies. In the Phase IIb STORM study (NCT02336815), oral selinexor plus low‐dose dexamethasone (Sel‐dex) demonstrated a 26.2% overall response rate in triple‐class‐refractory MM. Here, we compare overall survival (OS) of 122 patients with triple‐class‐refractory MM who received Sel‐dex in STORM Part 2 with that of 64 similar patients treated with other available therapies in a Flatiron Health Analytic Database (FHAD) cohort. OS from the date that the patients’ MM became triple‐class‐refractory was longer in STORM versus FHAD, with an unadjusted hazard ratio (HR) of 0.43 (P = .0002; adjusted HR 0.35 [P = .011]). In a subset analysis of highly resistant patients receiving further therapies after their MM first became at least triple‐class‐refractory (i.e., who received Sel‐dex in STORM,n = 64, and non‐Sel‐dex in FHAD,n = 36), the OS was significantly longer in STORM with an unadjusted HR of 0.52 (P = .0331; adjusted HR 0.33 [P = .041]). Within the limits of this analysis, the OS of patients with at least triple‐class‐refractory MM was significantly better with Sel‐dex versus available therapies, suggesting that Sel‐dex may be associated with a meaningful OS benefit in these patients.

8014 Background: TCR-MM is defined as being refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 mAbs, representing an urgent unmet medical need with a median OS of 3-5 months( Pick M et al, Eur J Haem 2018; Gandhi U et al, ASH 2018). Sd has shown a 26.2% overall response rate (ORR) in 122 patients (pts) with TCR-MM in the Phase 2b STORM study ( Chari A et al, ASH 2018). Here, we evaluate the OS of pts in the STORM study with Sd and in pts with bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (“penta”)-exposed, TCR-MM from an observational cohort not receiving Sd. Methods: Data were drawn from STORM and a retrospective cohort from the nationally representative Flatiron Health Analytic Database (FHAD). All pts from both sources had penta-exposed TCR-MM. In order to align study populations, OS was evaluated in pts in STORM whose first therapy after their MM reached TCR status was Sd and in pts in the FHAD who received ≥1 therapy after their MM reached TCR status. The index date for this evaluation was the start date of treatment after their MM reached TCR status. A Cox proportional hazards regression model was performed to assess the survival impact of Sd. In STORM, ORR was assessed by an Independent Review Committee based on IMWG criteria. Results: In the FHAD, 69 pts with TCR-MM were identified. Characteristics of the two groups of pts were similar, except that pts in STORM were more heavily pretreated, had a higher frequency of high-risk MM, a longer time since initial diagnosis of MM, and higher baseline hemoglobin and platelet values. Among the 122 pts in STORM, 64 received Sd as their first therapy after their MM became TCR, and ORR was 32.8%. Among the 69 pts from FHAD, 37 received ≥1 therapy after their MM became TCR. Median OS (N = 64) was 10.4 months for pts receiving Sd in STORM and 5.2 months (N = 37) for pts not receiving Sd in FHAD (HR = 0.49, p = 0.0241). Conclusions: The prognosis of TCR-MM in the real-world population appears very poor. Within the limits of this analysis, median OS of pts receiving Sd as their first therapy after their MM becomes TCR is significantly better than those not receiving Sd, suggesting that Sd may be associated with an OS benefit in pts with TCR-MM. Clinical trial information: NCT02336815.

Introduction: Proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and the CD38 monoclonal antibody daratumumab (dara) have transformed the management of MM, yet eventual refractoriness to these agents seems inevitable. Relapsed and refractory MM (RRMM) which becomes triple class refractory (TCR, i.e. refractory to a PI, an IMiD and Dara) uncommonly responds to further lines of therapy and survival is dismal. Selinexor is a selective inhibitor of nuclear export compound targeting exportin 1 (XPO1) which is overexpressed in MM cells and essential for their survival. In the STORM study, selinexor in combination with low-dose dexamethasone (Sd) demonstrated promising efficacy in TCR, penta-exposed (TCR-PE, i.e. exposed to lenalidomide, pomalidomide, bortezomib, carfilzomib and dara) MM. Establishing the natural history for outcomes in the TCR-PE population can help provide context to understand the outcomes observed with Sd in STORM. In the retrospective MAMMOTH study, we reported the outcomes of patients with RRMM after they became refractory to dara, including a subset of patients who were TCR. We further analyzed the MAMMOTH dataset to generate a cohort of patients similar to patients in STORM in order to compare conventional care vs. Sd. Methods: We included all patients in STORM who received Sd as the first line therapy after they achieved TCR-PE status (n=64). We extracted from the MAMMOTH dataset all patients who were not exposed to Sd in a subsequent line of therapy, became TCR-PE and who received subsequent MM-directed therapy (n=128). Overall response rate (ORR) was evaluated according to IMWG criteria. Overall survival (OS) was calculated from the time of initiation of next line of therapy after TCR-PE status until death or last follow-up. We compared OS in STORM vs. MAMMOTH utilizing cox-regression analysis with adjustment for covariables potentially influencing the outcome. Results: Baseline patient characteristics and prior therapies are per table. The two cohorts were similar in terms of age, number of prior lines of therapy and presence of high-risk cytogenetic abnormalities. STORM patients had longer time between MM diagnosis and post TCR-PE therapy with a higher proportion of refractoriness to carfilzomib. Patients in STORM had ORR to Sd of 32.8% vs 25.0% for patients receiving conventional care in MAMMOTH (P=0.078). In direct comparison, patients in STORM had better OS than patients in MAMMOTH (median 10.4 vs. 6.9 months) (P=0.043, figure). In multivariate analysis, STORM patients had lower risk of death in comparison with MAMMOTH patients (aHR=0.55, 95%C.I. 0.35-0.86, P=0.009). Refractoriness to carfilzomib (aHR=2.20, 95%C.I. 1.16-4.15, P=0.015) and high-risk cytogenetics (aHR-1.66, 95% C.I. 1.13-2.42, P=0.009) were also associated with inferior OS. Conclusion: Despite inherent limitations in comparison of trial enrollees vs. real world patients, this analysis suggests improved OS with Sd vs conventional care in patients with TCR-PE RRMM. Prognosis for these patients remains poor and underscores the need for therapeutic advancements. Disclosures Costa: Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hari:Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Tang:Karyopharm: Employment. Shah:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Jagannath:BMS: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau. Chari:Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Ma:Karyopharm: Employment, Equity Ownership. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding. Lonial:BMS: Consultancy; Genentech: Consultancy; GSK: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Celgene Corporation: Consultancy, Research Funding; Karyopharm: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Malek:Adaptive: Consultancy; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding. Fiala:Incyte: Research Funding. Usmani:Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Kang:Takeda Oncology: Consultancy; InCyte Corportation: Research Funding. Cornell:Takeda: Consultancy; KaryoPharm: Consultancy.

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

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