Citations

8055 Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The most commonly mutated genes are N- and K-Ras, which increase in prevalence as the disease progresses. Case reports and retrospective data suggest efficacy of targeting the MAPK pathway in N/K-Ras mutated MM. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with standard therapies in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Subjects undergo molecular profiling of their MM cells and are assigned to a targeted arm if a variant allele frequency (VAF) over 25% is identified. The targeted mutated genes and respective agents (approved for non-MM indications and with a known phase 2 dose) are: KRAS/NRAS/BRAF (cobimetinib), FGFR3 (enasidenib), IDH (erdafitinib), CDKN2C (abemaciclib), t(11;14) (venetoclax). Patients receive the investigational drug for 2 cycles as a single agent followed by addition of an active MM combination (ixazomib, pomalidomide and dexamethasone, IPd). Limited dose escalation was performed with the single agent followed by dose assessment in combination with IPd. Here we present the results of the dose escalation portion of C1 arm exploring cobimetinib in patients with N/K-RAS or BRAF mutations. Cobimetinib was administered at 40 mg daily in combination with standard doses of IPd. Results: Eleven subjects with BRAF/RAS mutations were screened between August 2019 and October 2020, with 4 screen failures. Seven were enrolled, 5 males, median age 65 years, and median time from diagnosis of 30 months. N-RAS, K-RAS or BRAF mutations were seen in 4, 2, and 1 subject(s), respectively, with VAF ranging from 33-93%. Median number of prior lines of therapy was 1 (1-3), 3 patients had extramedullary disease, and 1 patient had high risk cytogenetics. Median duration of therapy was 12 months. One patient was not evaluable for dose limiting toxicity. All but 1 patient had at least one cycle delayed due to adverse events (AEs), but no dose reductions were required. No dose limiting toxicities were observed across the cycles, either during single agent therapy (Cycles 1-2) or in combination with IPd (Cycles 3 and 4). Six patients responded to therapy (4 PR, 2 VGPR). One patient was not response evaluable. Fatigue was the most common non-hematological AE followed by diarrhea. Conclusions: Here we report on the feasibility of genomically-guided, precision medicine therapy in K/N-RAS/BRAF-mutated MM. The MEK inhibitor cobimetinib in combination with IPd appears safe in functionally high-risk patients. Ongoing study will provide more information regarding the efficacy of this approach. Clinical trial information: NCT03732703.

Abstract Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on myeloma cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody (BsAb) that facilitates T cell-directed killing of myeloma cells. Initial data from the dose-escalation phase of the ongoing Phase I study (NCT03275103) of cevostamab monotherapy in patients (pts) with heavily pre-treated RRMM demonstrated promising activity and manageable safety, along with near ubiquitous FcRH5 expression on myeloma cells (Cohen et al. ASH 2020; Sumiyoshi et al. EHA 2021). We present updated safety and efficacy data from a larger cohort of pts, including results comparing Cycle (C) 1 single step-up (SS) and double step-up (DS) dosing for the mitigation of cytokine release syndrome (CRS). Methods: Participants have RRMM for which no established therapy is available or appropriate. Cevostamab (intravenous infusion) is administered in 21-day cycles. In the SS cohorts, the step dose (0.05-3.6mg) is given on C1 Day (D) 1 and the target dose (0.15-198mg) on C1D8. In the DS cohorts, the step doses are given on C1D1 (0.3-1.2mg) and C1D8 (3.6mg), and the target dose (60-160mg) on C1D15. In both regimens, the target dose is given on D1 of subsequent cycles. Cevostamab is continued for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurs. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: At data cut-off (18 May 2021), 160 pts had been enrolled (median age: 64 years, range: 33-82 years; male: 58.1%); 21.3% of pts had extramedullary disease. Median number of prior lines of therapy was 6 (range: 2-18). Most pts (85.0%) were triple-class refractory (PI, IMiD, anti-CD38 antibody). 28 pts (17.5%) had received ≥1 prior CAR-T, 13 pts (8.1%) ≥1 prior BsAb, 27 pts (16.9%) ≥1 prior antibody-drug conjugate (ADC), and 54 pts (33.8%) ≥1 prior anti-BCMA targeting agent. Median follow-up in exposed pts was 6.1 months. Almost all had ≥1 adverse event (Table). The most common was CRS (128/160 pts [80.0%]; Grade [Gr] 1: 42.5%; Gr 2: 36.3%; Gr 3: 1.3%). Immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CRS was observed in 21 pts (13.1%) and in 34/211 (16.1%) CRS events (Gr 1: 8.5%; Gr 2: 6.2%; Gr 3: 1.4%). Most CRS events occurred in C1 (87.2%), arose within 24 hours of cevostamab administration (70.5%), and resolved within 48 hours of onset (83.4%). In the pts with CRS, tocilizumab was used for CRS management in 43.8% and steroids in 25.8% (both agents: 18.0%). In SS dose-escalation (68 pts), 3.6mg was chosen as the most effective C1D1 SS dose for limiting CRS in C1, with no target dose-dependent increase in the rate or severity of CRS observed after the C1D8 administration. Likewise, in DS dose-escalation (30 pts), 0.3/3.6mg was identified as the preferred C1D1/C1D8 DS dose for limiting CRS in C1. Notably, the overall rate of CRS was lower in the pts who received the 0.3/3.6mg/target DS regimen than in those who received the 3.6mg/target SS regimen (77.3% [34/44] vs 88.2% [75/85], respectively). The rate of ICANS associated with CRS was also lower in the 0.3/3.6mg/target DS cohort than in the 3.6mg/target SS cohort (4.5% [2/44] vs 21.2% [18/85], respectively). At data cut-off, 158/160 pts were efficacy evaluable. In dose-escalation, responses were observed at the 20-198mg target dose levels, and data suggested a target dose-dependent increase in clinical efficacy. Median time to response was 29 days (range: 20-179 days). Two dose-expansion cohorts were opened: ORR was higher at the 160mg dose level (54.5%, 24/44 pts) than at the 90mg dose level (36.7%, 22/60). At target dose levels >90mg, ORRs in pts with prior exposure to CAR-Ts, BsAbs, ADCs, and anti-BCMA targeting agents were 44.4% (4/9 pts), 33.3% (3/9), 50.0% (7/14), and 36.4% (8/22) respectively. Median follow-up among all responders (n=61) was 8.1 months; estimated median duration of response was 15.6 months (95% CI: 6.4, 21.6). Conclusions: Cevostamab monotherapy continues to show clinically meaningful activity in a large cohort of pts with heavily pre-treated RRMM, with a target dose-dependent increase in ORR, but no increase in CRS rate. Responses appear durable, and are observed in pts with prior exposure to CAR-Ts, BsAbs, and ADCs. Compared with SS dosing, DS dosing at the 0.3/3.6mg level appears to be associated with a trend for an improved C1 safety profile. Figure 1 Figure 1. Disclosures Trudel: Amgen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria. Cohen: BMS/Celgene: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Oncopeptides: Consultancy; Novartis: Research Funding; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Krishnan: MAGENTA: Consultancy; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; JANSSEN: Consultancy, Research Funding; City of Hope Cancer Center: Current Employment; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Fonseca: Kite: Consultancy; Juno: Consultancy; Merck: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; GSK: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Amgen: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Spencer: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Lesokhin: Serametrix, Inc: Patents & Royalties; Behringer Ingelheim: Honoraria; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; bristol myers squibb: Research Funding; Trillium Therapeutics: Consultancy. Forsberg: University of Colorado: Current Employment; Karyopharm, Sanofi, Genentech: Research Funding. Costa: Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Kaedbey: Takeda, Sanofi: Honoraria; Celgene/BMS, Janssen: Honoraria; Royal Victoria Hospital Lakeshore Hospital: Ended employment in the past 24 months; Jewish General Hospital - McGill University: Current Employment. Richter: Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Mateos: 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; Regeneron: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. Thomas: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta Pharma: Research Funding; X4 Pharma: Research Funding; Ascentage Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Wong: Genentech: Current Employment; CTMX, UBX, BMRN: Current equity holder in publicly-traded company. Li: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Choeurng: Genentech: Current Employment, Current equity holder in publicly-traded company. Vaze: Roche/Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Samineni: Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper: Genentech: Current Employment; Roche: Current holder of individual stocks in a privately-held company. Harrison: Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria. OffLabel Disclosure: Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-directed killing of myeloma cells. Cevostamab is an investigational agent.

Background: Here we describe an online network of patients with cancer, clinicians and researchers, layered on top of a comprehensive real world database of treatments and outcomes, continuously updated in near real time, and initially focused on multiple myeloma. Methods: Patients with multiple myeloma register at www.all4cure.com and sign HIPAA release forms to provide access to all of their medical records from all of the institutions from which they have received care. From the medical records, a structured dataset of treatments and lab results is extracted by a myeloma-dedicated team for display on each patient's de-identified, personalized dashboard. A discussion panel allows more than 1200 participating patients, clinicians and researchers to post comments or questions regarding each patient's specific circumstances. For each patient, lines of therapy and responses are determined according to IMWG and published criteria (Blood [2015] 126: 921-922). Here we report initial results from the treatments and responses among patients with multiple myeloma and plasma cell leukemia. Results: A total of 493 patients includes 26 with monoclonal gammopathy of undetermined significance (MGUS), 51 with smoldering myeloma, 408 with multiple myeloma, and 8 with primary plasma cell leukemia. Among patients with multiple myeloma, 42 (10.3%) had antecedent MGUS and/or smoldering myeloma. The average age is 65.6 (+/- 9.7). 50.9% are male and 49.1% are female. 42 states in the U.S. and 8 other countries are represented. Two patients with multiple myeloma had not started treatment by the time of this report. The remaining 414 patients with multiple myeloma or plasma cell leukemia received 1 to 16 lines of therapy. Among the 414 patients that received at least one line of therapy, a remarkable 89 distinct first line therapies were administered. The most common first line therapies were lenalidomide, bortezomib, dexamethasone (n=92), cyclophosphamide, bortezomib, dexamethasone (n=50), lenalidomide, bortezomib, dexamethasone + autologous stem cell transplant + lenalidomide maintenance (n=41), lenalidomide and dexamethasone (n=29), and bortezomib and dexamethasone (n=22). 62 patients received a first line therapy that was not received by any other patient in our database. This variation was attributable to participation in clinical trials, variation in the availability of drugs over time and different geographic locations, and the very large number of distinct combinations associated with multi-agent regimens. Seventy six percent of patients with multiple myeloma or plasma cell leukemia received a second line of therapy, 52% received a third line of therapy, 34% received a fourth line of therapy, 23% received a fifth line of therapy, and 18% received a sixth line of therapy. We observed a trend toward a decline in favorable responses with successive lines of therapy (Table 1) consistent with previous reports, with a correlation coefficient between the line of therapy and overall response rate of -0.74. Among the 76 patients who received 6 or more lines of therapy (247 lines of therapy in total), only 7 achieved stringent complete responses (sCRs), of which 5 were associated with a CAR-T therapy. Table 1 also shows a trend toward more rapid changes in treatment associated with later lines of therapy. 57 of 493 patients (12%) are deceased. Conclusions: Our findings reveal remarkable variation in the treatment of myeloma and provide a potentially valuable resource of up to date and current clinical features, prognosis, treatments, side effects, and outcomes of patients with myeloma in the real world. Table 1. Summary of lines of therapy and outcomes across 414 patients with multiple myeloma and plasma cell leukemia. The percentages of patients achieving sCR, ≥ PR (overall response rate - ORR), and ≥MR (clinical benefit rate - CBR) are shown for each line of therapy. Also depicted is the interval mortality and the mean and median number of days between the beginning of a line therapy and the beginning of the next line of therapy. Table Disclosures Richter: Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy; X4 pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive biotechnologies: Consultancy; Secura bio: Consultancy; Astra Zeneca: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy. Chhun:All4Cure: Current Employment. Zheng:All4Cure: Current Employment. Piboonvaranggoon:All4Cure: Current Employment. Mallick:All4Cure: Current Employment. Wren:All4Cure: Current Employment. Nam:All4Cure: Current Employment. Lopez Barquilla:All4Cure: Current equity holder in private company. Blau:All4Cure: Current equity holder in private company. Cowan:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Research Funding. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kumar:Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Other; Sanofi: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Anderson:Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees. Blau:All4Cure: Current Employment, Current equity holder in private company.

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.

Abstract Background: Isatuximab (SAR650984) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor. In the dose escalation part of the Phase I portion of the trial (NCT01749969), isatuximab ≥10 mg/kg IV given every other week (q2w) or 10 mg/kg weekly (qw) induced responses in 6/19 recipients (ORR 32%). Responses were noted at doses as low as 1 mg/kg q2w. The maximum tolerated dose (up to 20 mg/kg IV qw) was not reached. The most common treatment-emergent adverse events (TEAEs) were fatigue and nausea; few serious grade 3/4 TEAEs were reported (pneumonia 6%). The most common category of drug-related TEAE involved infusion-associated reactions (IARs) occurring in half of the patients, with grade 3/4 IARs in <5% of the patients. Based on promising Phase I activity, a Phase II dose finding study was added to investigate single-agent isatuximab in patients with relapsed or refractory myeloma (RRMM). Methods: In Phase II, eligible patients were originally randomly assigned (1:1:1) to one of 3 treatment groups: 3 mg/kg q2w, 10 mg/kg q2w, and 10 mg/kg q2w x 4 doses then q4w. A 4th treatment group was enrolled at a higher isatuximab dose with an optimized schedule of 20 mg/kg qw x 4 doses then q2w. Patient assignment was stratified by prior anti-myeloma therapy (Stratum 1: prior treatment with pomalidomide (POM) and/or carfilzomib (CAR); Stratum 2: no prior POM or CAR). Patients continued therapy until disease progression, unacceptable AEs or physician/patient decision. Eligible patients had measurable disease (serum M-protein >1 g/dL or urine M-protein ≥200 mg/24 h, or serum free light chain ≥10 mg/dL), prior exposure to ≥3 lines of anti-myeloma therapy or were double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), prior treatment with an alkylating agent, and adequate baseline bone marrow reserve and organ function. Enrollment of 24 patients was planned for each treatment group. An interim efficacy analysis is planned when all patients have completed ≥2 disease assessments, with central review of these data currently ongoing. Enrollment has now been completed and all patients who completed at least 1 cycle of isatuximab at the cutoff date (5/29/15) are included in this preliminary analysis. Results: Patient characteristics (n=96): median age 62.5 yrs (range 38-85); median time from initial diagnosis to study treatment 5.85 yrs (1.2-24.1); 76% had IgA/G MM; 24% had light-chain only disease; and 22%, 22%, and 44% had Stage I, II, and III disease, respectively. The median number of prior lines of therapy was 5 (2-14) with 100%, 99%, and 98% having prior exposure to PIs, IMiDs, and alkylator-containing therapy, respectively. Overall, 78% of patients had previously received POM and/or CAR; 55% had been exposed to both of these agents. At data cut-off, 36.5% of patients remained on therapy and 53.1%, 6.3%, and 4.2% had discontinued therapy due to disease progression, AEs, or other reason, respectively. The median number of cycles received was 3 (1-9), with a median duration of treatment of 11.7 wks. Approximately 17% of patients required at least 1 dose delay and 7.3% of isatuximab infusions were interrupted. TEAEs occurred in 93% of patients, with 51% being grade ≥3. Drug-related TEAEs occurred in 61% of patients (grade ≥3, 10%). The most common drug-related TEAEs (>5% of patients) were nausea (14.6%), chills (14.6%), dyspnea (13.5%), chest discomfort (10.4%), flushing (7.3%), headache (7.3%), cough (6.3%), and vomiting (5.2%). The majority of the symptoms occurred within 24 h of isatuximab infusion and were attributed to an IAR. IARs occurred in 50% of patients, were predominantly grade 1/2 (grade ≥3, 3.1%), and were mostly limited to Cycle 1 (2 patients had IARs in Cycle 2). Pneumonia (6.3%) and sepsis (5.2%) were the most common serious TEAEs. Six deaths have occurred within 30 days of last dose, 4 due to disease progression, and 2 due to serious AEs unrelated to study therapy (cardiopulmonary arrest and cerebral hemorrhage). Conclusion: Isatuximab administered to heavily pre-treated patients with RRMM appears well tolerated. IARs are common in Cycle 1, but typically do not recur. Results by treatment arm, including interim analysis response data, will be presented. Disclosures Martin: Sanofi: Research Funding. Richter:Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Vij:Millennium: Honoraria, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS, Amgen, Prothena, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy; Merck: Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Millenium: Consultancy. Bensinger:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acetylon: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. San Miguel:Millennium, Celgene, Novartis, Janssen, Onyx, BMS, MSD: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Onyx: Honoraria; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Hsu:Sanofi: Employment. Charpentier:Sanofi: Employment. Strickland:Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation. Mikhael:Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; AbbVie: Research Funding.

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.

Abstract Introduction: Selinexor is a novel, oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks exportin 1 (XPO1). Selinexor treatment results in nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and translational suppression of several oncoprotein mRNAs (e.g., c-myc, cyclin D).Multiple myeloma (MM) remains incurable, and most patients (pts) eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 mAbs and others. The increased use of combinations in MM treatment, (PIs/IMiDs/mAbs), has led to a growing number of pts with penta-refractory MM (pts that have been treated with bortezomib (bort), carfilzomib (carfil), lenalidomide (len), pomalidomide (pom) and daratumumab (dara)). Active novel therapies with different mechanisms of actions are needed to address this unmet medical need. Part 1 of STORM enrolled pts with both quad- (bort, carfil, len, pom, treated MM) or penta-refractory MM and demonstrated an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Based on these findings, the Pivotal Part 2 of STORM was initiated, enrolling an additional cohort of 122 patients with penta-refractory MM. Methods: Pts with penta-refractory MM were treated with 80 mg selinexor plus 20 mg dexamethasone (Sd) twice weekly. Pts must have received an alkylator, bort, carfil, len, pom and dara, and had MM refractory to ≥1 PI, ≥1 IMiD, dara, a glucocorticoid, and their last therapy. Pts must have a total ANC ≥1000 mm3,platelets ≥50k/mm3 (or ≥75k if marrow plasma cells <50%), and creatinine clearance ≥20 mL/min. The primary endpoint was ORR. Secondary endpoints: duration of response (DOR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Efficacy was assessed by an Independent Review Committee (IRC) based on IMWG criteria. OS was also compared to a cohort of pts with PI, IMiD, dara refractory MM from the Flatiron Health Analytic Database (FHAD), (ref: ASH 2018 abs ID: 116493),who met all the inclusion criteria for STORM. Results: As of 1-Jun-2018, 122 pts (71 M/ 51 F) were enrolled in 38 sites (US and EU). Pt characteristics were [medians (range)]: age 65 yrs (40-85); 7 (3 - 18) prior treatment regimens, 6.6 yrs (<1 - 23.4) from initial MM diagnosis.65 pts (53%) had high risk cytogenetics, 86 pts (70%) had prior dara in combination, 102 pts (84%) had prior stem cell transplantation, 2 pts had prior CAR-T therapy. All pts enrolled with progressive disease (PD), 72% of pts had increases (3% - 792%) in MM markers from screening to C1D1 (median 11 days). Frequently reported Sd treatment related adverse events (AEs) included (all grades, grades 3/4): thrombocytopenia (67%, 53%), nausea (67%, 10%), fatigue (68%, 21%), anorexia (50%, 2%), anemia (46%, 28%), and weight loss (46%, 0%). Eight pts remain on study and 114 pts discontinued treatment (most commonly for PD). There were 4 deaths on treatment: sepsis, respiratory failure, pulmonary embolism, and an unrelated, unspecified cardiac event. IRC determined ORR (≥PR) was 26.2%, with 6.5% ≥ very good partial response, including 2 stringent complete responses (sCRs; MRD negative at 1:10-6 and at 1:10-4sensitivity). Both pts who relapsed after CAR-T achieved PRs. The CBR (≥minimal response, [MR]) was 39.3%, and 79% of pts achieved ≥stable disease (SD). Responses typically occurred within the first month. Medians: DOR 4.4 months (mo) (range <1 - 10 mo), PFS 3.7 mo, and OS 8.0 mo. Pts with ≥MR had significantly longer OS than pts with PD/NE (median not reached vs 1.9 mo, p=<0.0001). Compared to the FHAD cohort, STORM cohort had longer OS (Figure 1, HR 0.41, p=0.0001). Conclusions: Results of the pivotal STORM Part 2 in penta (PI, IMiD, dara)-refractory MM demonstrated that oral selinexor plus low-dose dexamethasone (Sd) was highly active with an ORR of 26.2%. Importantly, responses were rapid and deep with 2 patients achieving sCRs (both MRD negative) in these heavily pre-treated penta-refractory MM pts (median 7 prior regimens, 53% high risk). AEs are a function of dose/schedule/disease severity and can be managed with dose modifications and supportive care. No major organ toxicity was observed and AEs were typically transient and reversible. Sd is an all-oral, first in class mechanism with novel MOA and represents a potential therapeutic option to the growing number of pts with penta-refractory MM who have exhausted approved therapies. Disclosures Chari: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; 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; Bristol Myers Squibb: Consultancy. Vogl:Karyopharm Therapeutics: Consultancy. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene and Janssen: Research Funding; Amgen, Celgene, Janssen and Takeda: Consultancy. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Mohty:Amgen: Consultancy, Honoraria; Molmed: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Bristol Myers: Consultancy, Research Funding. Sylvain:Gilead: Other: scientific advisor board. Costa:Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; BMS: Research Funding. Shah:Karyopharm Therapeutics: Employment. Picklesimer:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Li:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Richardson: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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; 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:Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Novartis: Consultancy; Merck: Consultancy.