Cole, Craig E.

Objective To identify the association between aneuploidy and clinical outcome in patients with relapsed and/or refractory multiple myeloma (RRMM) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. Background: Aneuploidy, defined by abnormal copy number changes of chromosomes, is one of the hallmarks in cancer, reflecting and also contributing to genome instability (Ye, Regan et al. 2018). Approximately 90% of cancers have gained or lost one or both arms of at least one chromosome (Taylor, Shih et al. 2018). In recent years, large scale sequencing efforts have extended aneuploidy study, identifying DNA somatic copy number alterations (SCNAs). Published data suggest aneuploidy has a stronger impact on prognosis than gene mutations in multiple myeloma (Walker, Boyle et al. 2015; Bolli, Biancon et al. 2018; Jamal-Haniani, Wilson et al. 2017). Methods: Fifty one RRMM patients from our institute participated in Clinical-Grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies (MMRF-002) from Multiple Myeloma Research Foundation (MMRF) between March 2016 and November 2018. Genomic DNA was obtained from CD138+ sorted myeloma cells and a peripheral blood sample from each patient. Capture exome sequencing on a targeted panel of 1500 genes was performed by the Illumina HiSeq 2500 (2x115bp paired-end reads, average 520X coverage). Copy number changes, loss of heterozygosity (LOH) and tumor purity were jointly estimated using an in-house pipeline for matched tumor/normal libraries. We assessed aneuploidy using chromosomal and arm level SCNAs which are determined by the median of SCNAs and summation of gain and loss of SCNAs for a given chromosomal arm, which are then used for a time-to-event analysis of overall survival (OS) of the patients. The differences between Kaplan-Meier overall survival curves were tested using the log-rank test. Hazard ratios (HR) were estimated from Cox proportional hazard regression. A threshold of significance was taken as p<0.05. Results Patient demographic data is summarized in Table 1. All the patients in this study harbor DNA somatic copy-number abnormalities (SCNAs) on the arm level for at least one chromosome (Figure 1). Gain of a chromosome or a whole arm mostly occurs on 1q, 3, 5, 7, 9, 11, 15, 19, 21 while loss was noted in 1p, 8p, 13, 16q, and 17p. At a global-level, we find that whole genomic aneuploidies (genomic-level across all chromosomes) have a significant association with inferior OS. Specifically, patients with a high frequency of genomic aneuploidies (defined as number of SCNA >8, the first quartile) had a significantly worse prognosis than those with low number of SCNA events (<=8) (p=0.037, Figure 2). Arm-level aneuploidies with high incidences include 11q (54.9%), 13q (52.9%), 15q (51.0%), 1q (51.0%), 9q (51.0%), a finding consistent with previous studies (Walker, Leone et al. 2010). Aneuploidies in 10p (11.8%) and 10q (7.8%) are uncommon in agreement with previous studies (Tricot G, Sawyer et al. 2017) as myeloma structural or numerical abnormalities rarely occur on chromosome 10. Using univariate analysis, we identified five arm-level aneuploidies which are significantly associated with worse OS: 10p, 10q, 11p, 18q and 20q. It is noteworthy that aneuploidies in either arm of chromosome 10 (10p and 10q) had significant negative OS prognostic effect: 10p (median survival for diploid 28.9 vs. aneuploid 4.1 mo; p<0.001) and 10q (28.9 vs 3.8 mo; p=0.015). Similar results with a negative impact on OS were found from 11p (not reached vs 13.8 mo; p=0.036); 18q (28.9 vs 8.5 mo; p=0.025); and 20q (28.9 vs 3.1 mo; p=0.009). Given the small sample size we did not conduct a multivariable analyses and multiplicity adjustment in this preliminary analyses. Conclusion Aneuploidy measured by SCNAs is correlated with unfavorable survival in relapsed/refractory myeloma. The higher the occurrence of aneuploidies, the worse the overall survival, illustrating of the impact of cancer genome instability. Disclosures Ye: Janssen: Research Funding; Karyopharm: Research Funding; Portola: Research Funding; MingSight: Research Funding; Sanofi: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: 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.

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.

Abstract BACKGROUND:In recent years,we saw four patients with iron deficiency anemia (IDA) in our clinical practices who developed a compulsive craving for certain odors including rubber tires, gasoline, Pine-Sol® (a popular household alcohol ethoxylate-based cleaning agent), and "musty odor of the basement." Such behavior resolved after treatment of IDA, and recurred in a patient whose IDA relapsed. This resembled pica, a craving to eat non-nutritive items, which is commonly associated with IDA. Because we had never heard of or read about this phenomenon, we reviewed the English medical literature and World Wide Web to determine if such experience had been previously reported. METHODS: We searched the PubMed, Google, and Google Scholar to find publications, reports, presentations, or testimonies of individual in online blogs using a combination of search terms including "nasal, olfactory, smell, craving, iron deficiency, and anemia." RESULTS: We found no scientific publication, report, or presentation similar to our experience in PubMed and Google Scholar. However, using Google search engine, we found several testimonies of individuals in online blog posts (mostly at babycenter.com and medhelp.org), several of which were pregnancy blogs that reported these peculiar symptoms. Individuals were reporting powerful cravings of olfaction, frequently being overtaken by a desire to smell certain odors. The types of substances for which they craved and their associated medical conditions (when reported) are summarized in the Table. CONCLUSIONS:These preliminary findings and testimonies give suggestive evidence that a condition, entirely separate from pica, exists in certain patients suffering from IDA or during pregnancy. For this, we propose the name, desiderosmia, derived from the Latin word "desiderare" for desire and the Greek word "osme" for smell. In naming this condition, we hope to inspire further investigation, and hopefully shed some light for patients who suffer from this newly described olfactory symptom. Table Reports of smell cravings and associated medical conditions found in online blogs Table. Reports of smell cravings and associated medical conditions found in online blogs Disclosures No relevant conflicts of interest to declare.

Abstract Introduction - With over 12,000 deaths from MM anticipated in 2016, nearly all patients (pts) with multiple myeloma (MM) will become "quad refractory" to IMIDs (lenalidomide and pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib), and eventually "penta refractory" to anti-CD38 Abs (daratumumab and isatuximab), defining high unmet need populations. Selinexor, an oral selective XPO1 inhibitor, induces nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and inhibition of translation of several oncoprotein mRNAs such as c-myc and cyclin D. Selinexor showed potent induction of apoptosis of MM cells independent of p53 signaling. In phase 1 clinical studies, selinexor with low dose dexamethasone (Sd) demonstrated potent anti MM activity in pts with MM. Methods - This phase II clinical trial evaluated Sd in pts with MM refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide ("quad"), with a subset also refractory to an anti-CD38 Ab ("penta"). Inclusion required CrCL≥20 mL/min, ANC≥1000/µL, platelets ≥50K/µL (≥30K if plasma cells were ≥50% of marrow cellularity). Pts were treated twice weekly (BIW) with oral selinexor 80 mg for 6 or 8 doses per 28 day cycle and dexamethasone (dex) 20 mg BIW. All pts received 5-HT3 antagonists. The primary objective was to determine the overall response rate (ORR) per IMWG criteria and duration of response (DOR), both adjudicated by an independent review committee (IRC). Secondary endpoints include progression free survival (PFS) and overall survival (OS). FISH analyses and gene expression profiling were performed on bone marrow aspirates. Results - 79 pts were enrolled: 48 quad (24 M/24 F, median age 62 yrs) and 31 penta (13 M / 18 F, median age 68 yrs). Both groups had a median of 7 prior treatment regimens including multiple dex-containing regimens. Baseline laboratory abnormalities included grade (Gr)≥3 anemia in 13% and Gr≥3 thrombocytopenia in 8%. Most penta pts received 8 doses / cycle (65%); most quad pts received 6 doses / cycle (83%). Common treatment-related adverse events (TRAEs) hematological: thrombocytopenia (72%, Gr 3/4 58%), anemia (48%, Gr 3 25%) and neutropenia (29%, Gr≥3 21%). TRAEs non-hematological: nausea (72%, Gr 3 6%), fatigue (62%, Gr 3 14%) anorexia (49%, Gr 3 3%), vomiting (43%, Gr3 4%), asymptomatic hyponatremia (42%. Gr 3 20%), diarrhea (42%, Gr 3 5%) and weight loss (33%, Gr 3 1%). There was one case of febrile neutropenia (1%) and one case of clinically significant bleeding related to thrombocytopenia (1%). Seventy pts have discontinued therapy: PD (73%), AEs (17%), physician/pt preference (1%) and 6 deaths (one case related to selinexor, intracranial bleed in pt with Gr4 thrombocytopenia). Nine pts remain on study. Efficacy was evaluated in 78 pts (1 pt did not have measurable disease). The IRC-determined ORR (≥PR) for all pts was 21%, including 5% VGPR. ORR was 21% for quad pts and 20% for penta pts. Clinical benefit rates (≥MR) were 32% (all), 29% (quad), and 37% (penta). Median OS was 9.3 months (mo) for all pts, >11 mo (median not reached) for responders (≥PR), and 5.7 mo for non-responders. Median DOR in responding pts was 5 mo, and median PFS in all pts was 2.1 mo. Baseline cytogenetics were assessed in 41 pts. The ORR in 18 pts with high-risk FISH abnormalities was 33% (Table 1). Notably, 3 of the 13 pts with a 17p abnormality responded (ORR 23%). Transcriptomic profiling revealed differentially expressed genes (DEGs) between responders and non-responders in both whole blood RNA and CD138+ bone marrow cells. Pathways enriched in responders included IL-6, IL-8 and IGF-1 pathways. Conclusions - Oral Sd is active in heavily pretreated pts with refractory MM, including those with MM refractory to anti-CD38 Ab and those with high-risk cytogenetic abnormalities. Response was associated with longer survival. The main toxicities of Sd are thrombocytopenia, nausea, anorexia, and fatigue. AEs were manageable with supportive care and dose interruptions/reductions. To our knowledge, this is the first report of anti-tumor activity in the penta-refractory MM population. This population of MM pts has exhausted all currently available treatment options and has an extremely poor prognosis and therefore requires new therapies. Expansion of this trial in this high unmet medical need, penta refractory population is planned. Table 1 Activity of Sd in Patients with High Risk MM Cytogenetics Table 1. Activity of Sd in Patients with High Risk MM Cytogenetics Disclosures Vogl: Constellation: Research Funding; Karyopharm: Consultancy; Acetylon: Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Research Funding. Jagannath:Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Merck: Consultancy; Celgene: Consultancy. Baz:Bristol-Myers Squibb: Research Funding; Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Signal Genetics: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Merck: Research Funding. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Richter:Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Vij:Karyopharm: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Schiller:Incyte Corporation: Research Funding. Costa:Sanofi: Honoraria, Research Funding. Chari:Array Biopharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding. Siegel:Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Merck: Honoraria. Fonseca:Janssen: Consultancy; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Sanofi: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Novartis: Consultancy; Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Bayer: Consultancy; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy. Kauffman:Karyopharm Therapeutics Inc: 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. Saint-Martin:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment.

SummarySelinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non‐clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose‐escalation trial of twice‐weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib‐refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP2D of twice‐weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment‐emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual‐class refractory (PI and immunomodulatory drug)/quad‐exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression‐free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re‐established disease control in RRMM patients, including carfilzomib‐refractory patients.Registered at ClinicalTrials.gov (NCT02199665)

TPS8053 Background: The advent of proteasome inhibitors and immunomodulatory drugs (IMiDs) have significantly improved outcomes in MM, and the first monoclonal antibodies for MM have been recently approved (daratumumab, elotuzumab). Despite novel therapies and improved disease management, MM is still considered incurable and most pts relapse, confirming the need for additional treatment options. MM cells express PD-L1, with higher levels observed after relapse and with advanced disease. Additionally, PD-L1–expressing immune cells in the microenvironment promote MM cell survival and potential immune escape. However, anti–PD-1 monotherapy did not result in objective responses in the MM cohort of a Ph I study, suggesting that MM pts need combination therapy. Daratumumab has activity as a single agent, as well as in combination with IMiDs plus dexamethasone and bortezomib plus dexamethasone in R/R MM. Immunomodulatory activity for daratumumab has also been reported. Thus, disruption of the PD-L1/PD-1 pathway may be additive or synergistic. The safety and efficacy of atezo (anti–PD-L1) alone or with lenalidomide or pomalidomide and/or daratumumab will be evaluated in a Ph Ib study of MM pts. NCT02431208. Methods: R/R MM pts with ≤ 3 prior therapies will be enrolled in Cohorts A (atezo), B (atezo + lenalidomide), D (atezo + daratumumab) and E (atezo + daratumumab + lenalidomide); MM pts with measurable disease after ASCT (Cohort C: atezo) or ≥ 3 prior therapies (Cohort F: atezo + daratumumab + pomalidomide) will also be enrolled. Cohorts B, D, E and F include a safety run-in (D) or dose escalation phase (B, E, F) and an expansion. Lenalidomide and pomalidomide will be dose escalated and the MTD evaluated in expansion phases. Atezo will be given at 1200 mg IV (A, B, C) or 840 mg IV (D, E, F); pts will get daratumumab at 16 mg/kg IV (D, E, F). All pts will be ECOG PS ≤ 2. Primary endpoints are ORR and the RP2D of lenalidomide and pomalidomide with atezo and daratumumab and the RP2D of lenalidomide with atezo. DOR and PFS are secondary endpoints; safety, PK and the relationship between biomarkers and other endpoints, including efficacy, will be assessed. Pts will be enrolled at 19 US sites. Clinical trial information: NCT02431208.

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.