Abstract: Background: Once multiple myeloma (MM) becomes refractory to αCD38 mAb, pts have limited effective treatment options and poor prognoses. With standard therapies, overall response rate (ORR) to the first regimen after refractoriness to an αCD38 mAb is 31%, median progression-free survival (PFS) - 3.4 months and median overall survival (OS) - 9.3 months (Gandhi et al, Leukemia, 2019). Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins. XPO1 is required for MM cell growth, is associated with poor prognosis and mediates resistance to standard MM and other anticancer therapies. Selinexor (SEL) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound approved for patients (pts) with previously treated MM as well as DLBCL. The doublet SEL-dexamethasone (Xd) achieved ORR ~26% in triple-class (Immunomodulatory drug [IMiD] , proteosome inhibitor [PI], αCD38 mAb) refractory MM and improved OS over matched cohorts in community (Richardson et al, eJHaem, 2021) and academic (Cornell et al, AJH, 2020) settings. Hence, SEL-based triplets could be more effective in this triple class-treated population. We analyzed the efficacy and safety of SEL-containing triplets in pts in the STOMP study who were previously treated with regimens containing αCD38 mAb. Methods: STOMP is a multi-arm, open-label, Phase 1b/2 study evaluating SEL in various combinations (NCT02343042). Here, we analyzed ORR, clinical benefit rate (CBR), duration of response (DOR), PFS, OS, and treatment-emergent adverse events (TEAEs) of pts who received Xd plus pomalidomide (XPd, n=23) or carfilzomib (XKd, n=23) after prior therapy with αCD38 mAb. Results: Among 46 pts treated, median age was 64 yrs (XPd), 70 yrs (XKd), females 57% (XPd) and 39% (XKd), median time from diagnosis was 5 yrs, and median number of prior regimens 4 (range, 2-10). All pts were previously treated with a PI and IMiD and αCD38 mAb; 78% (XPd) and 52% (XKd) had triple refractory MM. Prior treatment with αCD38 mAb included daratumumab (XPd: 91%, XKd: 100%) and isatuximab (XPd: 9%); 52% (XPd) and 74% (XKd) had αCD38 mAb in their most recent prior regimen. Refractoriness to daratumumab was documented in 87% (XPd) and 96% (XKd); isatuximab in 9% (XPd). Median durations from end of most recent αCD38 mAb therapy to first dose of study treatment were 8 weeks (XPd), 4 weeks (XKd). Among evaluable pts, ORR and CBR were 52% and 76%, respectively in the XPd arm (n=21; 2 pts were not efficacy evaluable) and 65% and 74%, respectively in the XKd arm. In the XPd arm median PFS was 8.7 months (95% CI: 7.6, NE), median DOR was 7.9 months (95% CI: 3.9, NE), and median OS was 21.8 months (95% CI: 8, NE). In the XKd arm median PFS was 15 months (95% CI: 12.0, NE), median DOR was 13.1 months (95% CI: 10.2, NE), and median OS was 33.0 months (95% CI: 20.4, NE). Among the evaluable pts, response to SEL-containing triplets compared favorably to the prior αCD38 mAb-containing regimen used at least 1 line earlier: XPd arm (n=21), ORR 52% vs 58% for prior regimen, CBR 76% vs 58%, median PFS 8.7 months (95% CI: 7.6, NE) vs 10.2 months (95% CI: 5.2, 20.5); XKd arm (n=23), ORR 65% vs 52%, CBR 74% vs 57%, median PFS 15.0 months (95% CI: 12.0, NE) vs 8.5 months (95% CI: 5.9, 17.3). The most common hematological TEAEs (total; grade≥3) were thrombocytopenia (XPd: 35%; 30%; XKd: 78%; 39%), anemia (XPd: 57%; 39%; XKd: 57%; 22%), and neutropenia (XPd: 57%; 48%; XKd: 35%; 4%). Other common TEAEs (total; grade≥3) were nausea (XPd: 74%; 0; XKd: 74%; 4%), fatigue (XPd: 61%; 4%; XKd: 52%; 4%) and decreased appetite (XPd: 48%; 4%; XKd: 48%; 4%). No cases of severe bleeding with thrombocytopenia occurred. Three pts (13%, all XPd) had febrile neutropenia (the outcome of which was fatal in 1 pt, deemed related to SEL and pomalidomide). TEAEs were managed with standard supportive care and dose modifications. Summary/Conclusion: XPd and XKd administered to pts with heavily pretreated MM, including prior αCD38 mAb therapy, exhibit tolerability and comparable effectiveness to that of the prior αCD38 mAb-containing regimen. These results suggest that the use of SEL-containing triplets, implementing the novel XPO1 inhibition mechanism, can provide prolonged disease control with good tolerability rather than recycling previously utilized drugs/mechanisms. The all oral XPd regimen will be evaluated in Study EMN29 against elotuzumab-Pd in patients who have received lenalidomide, a PI and an αCD38 mAb. Disclosures Lentzsch: Janssen: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Oncopeptides: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Bahlis: Takeda: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Sebag: Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Janssen: Research Funding. Sutherland: Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Amgen: Consultancy. Monge: Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Research Funding. Gasparetto: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Connect Registry: Membership on an entity's Board of Directors or advisory committees. Baljevic: Exelixis: Research Funding; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Janssen Research: Other: Advisory Board; Oncopeptides: Other: Advisory Board; BMS/Celgene: Consultancy; Amgen: Research Funding. Venner: Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; BMS: Honoraria; GSK: Honoraria; Takeda: Honoraria. White: Amgen, Antengene, BMS/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: Consultancy, Honoraria. Kotb: Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Akcea: Honoraria; Pfizer: Honoraria. Chen: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Schiller: Celator: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Tolero: Research Funding; Constellation Pharmaceuticals: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Sangamo: Research Funding; Trovagene: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Cyclacel: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Forma: Research Funding; Daiichi-Sankyo: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Delta-Fly: Research Funding; FujiFilm: Research Funding; Deciphera: Research Funding; Arog: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Regimmune: Research Funding; Ono: Consultancy; Samus: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Madan: Karyopharm: Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Leblanc: Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) .

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

Abstract: Background: Overexpression of the nuclear export protein exportin 1 (XPO1) mediates the functional inactivation of tumor suppressor proteins (TSPs), facilitates the export of oncogene mRNA thus facilitating oncoprotein expression, is associated with poor prognosis in multiple myeloma (MM), and contributes to immunomodulatory drug (IMiD) resistance. Selinexor is an oral, first-in-class, selective inhibitor of nuclear export (SINE) compound that by blocking XPO1 forces the nuclear retention and activation of TSPs and nuclear retention and inactivation of oncoproteins. 1 Selinexor is approved with low-dose dexamethasone ± bortezomib for patients with previously treated MM. Pomalidomide plus dexamethasone (Pd) has an overall response rate (ORR) of ~30% and median PFS (mPFS) of ~4 months in patients with MM refractory to bortezomib and lenalidomide. We hypothesized that selinexor could be safely combined with Pd (XPd) and would improve the combination's efficacy. Methods: In the XPd arm of the multi-arm Phase 1b/2 STOMP study, selinexor was evaluated at 60, 80, or 100 mg in combination with Pd. Study objectives were to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) and to assess the safety and activity of the XPd regimen. The dose of selinexor 60 mg once weekly (QW), pomalidomide 4 mg once daily (days 1-21), dexamethasone 40 mg QW (XPd-60) was the lowest evaluated dose of selinexor in combination with the approved dose of Pd, and in light of the marked efficacy of that dose (ORR 65%), Phase 2 cohorts at a lower (40 mg weekly) dose of selinexor (XPd-40), were evaluated. Of the 19 patients enrolled at XPd-40 and evaluable for efficacy, 12 patients were enrolled into STOMP and 7 patients were enrolled at the same dose level and similar inclusion criteria into a parallel study XPORT-MM-028. Results: As of 14 July 2021, 39 patients were enrolled into the 60 (N=20) and 40 (N=19) mg selinexor dose levels in combination with Pd: 19 males, median age 66.0 years (range 37-85 years), median number of prior lines of therapy 2 (range 1-9). 85% of patients had MM refractory to a proteasome inhibitor (PI; bortezomib or carfilzomib or ixazomib), 79% to an IMiD (thalidomide or lenalidomide or pomalidomide), 33% to an anti-CD38 mAb (daratumumab or isatuximab); 26% had triple class refractory disease. Common hematologic, treatment-emergent adverse events (TEAEs) consisted of (all grades, grade ≥3) neutropenia (72%, 59%; and two cases of grade 3 [G3] febrile neutropenia one in each of the dose levels), and anemia (51%, 15% all G3). Non-hematologic TEAEs were reversible and included fatigue (56%, 10% all G3) and nausea (49%, 0%). On XPd-60, the RP2D (N=20), ORR was 65% (1 stringent complete response [sCR] , 5 very good partial responses [VGPR], 7 PR); mPFS was 8.9 months (95% CI, 7.6 - NE, median follow-up 8.3 months). In patients treated at XPd-40 (N=19), ORR was 42% (3 VGPR, 5 PR); mPFS was not reached (95% CI, 5.7 - NE, median follow-up 2.8 months). Among patients who had received anti-CD38 mAb, the ORR was 64% overall and 100% at the RP2D (1 sCR, 2 VGPR, 3 PR). All patients who had MM refractory to pomalidomide (N=3; all at the 60 mg dose level) responded with 1 VGPR and 2 PR. For the 21 responders across both dose levels, median time to response was 1.0 months (95% CI 1.0 - 2.0) and median duration of response was not reached (95% CI: 8.0, NE). Conclusions: Selinexor, once weekly, can be safely combined with Pd in patients with relapsed MM. The all-oral combination of XPd is highly active with an ORR of 65% at XPd-60, the RP2D, and an ORR of 42% at XPd-40 dose level (compared to expected ORR ~30% for Pd). The high ORR that was achieved at the RP2D, including in patients previously treated with anti-CD38 mAb, supports XPd-60 as a promising therapy with no significant cross-resistance to anti-CD38, PIs or lenalidomide. No new safety signals were identified. The most common TEAE, neutropenia, is a common AE of Pd and was managed effectively with standard G-CSF. The regimen leverages the concept of mechanism switching from an anti-CD38 mAb-based regimen to a selinexor-based regimen. These data support the new Phase 3 study (XPORT-MM-031) with an all-oral combination of XPd vs elotuzumab-Pd in patients who have been previously treated with lenalidomide, a PI, and an anti-CD38 mAb. Figure 1 Figure 1. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Forus: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria. Chen: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Baljevic: BMS/Celgene: Consultancy; Exelixis: Research Funding; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Amgen: Research Funding; Janssen Research: Other: Advisory Board; Oncopeptides: Other: Advisory Board. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy. Bahlis: Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria. Schiller: Eli Lilly: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ambit: Research Funding; MedImmune: Research Funding; Cyclacel: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Trovagene: Research Funding; Gamida Cell Ltd.: Research Funding; Bio: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; Deciphera: Research Funding; Regimmune: Research Funding; Delta-Fly: Research Funding; FujiFilm: Research Funding; Tolero: Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Daiichi-Sankyo: Research Funding; Celator: Research Funding; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Elevate: Research Funding; Samus: Research Funding; PrECOG: Research Funding; Constellation Pharmaceuticals: Research Funding; Onconova: Research Funding; Novartis: Consultancy, Research Funding; Ono-UK: Consultancy, Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Sangamo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Pharma: Consultancy; Sanofi: Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Kotb: Akcea: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Amgen: Honoraria; Pfizer: Honoraria; Merck: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; BMS: Honoraria. Sutherland: Celgene: Consultancy; Karyopharm: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy. Bensinger: Amgen, BMS, Janssen, Sanofi: Speakers Bureau; BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding. Madan: Amgen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Sebag: Janssen: Research Funding; Takeda: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Venner: GSK: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria. Leblanc: BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding. Monge: Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Zhang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Gasparetto: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Connect Registry: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM) and associated with poor prognosis. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, therefore forces the nuclear retention and re-activation of cell cycle regulators such as p53, FOXO, IkB, and Rb. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Pomalidomide/dexamethasone achieved an ORR of 31% and progression-free survival (PFS) rate of & lt; 4 months in patients refractory to prior bortezomib and lenalidomide. We conducted the STOMP study to assess the efficacy and safety of the combination of selinexor, pomalidomide and dexamethasone (SPd) in patients with relapsed/refractory multiple myeloma. Methods: STOMP is a multicenter, open-label, phase 1/2b, dose escalation study with an expansion phase. Patients with relapsed/refractory multiple myeloma who received prior therapies including lenalidomide and a proteasome inhibitor were eligible for enrollment. Oral selinexor was evaluated in 2 different dosing schedules: once-weekly (QW, 60 or 80 mg) or twice-weekly (BIW, 60 or 80 mg), with escalating doses of pomalidomide 2, 3 or 4 mg PO (days 1-21), and low dose dexamethasone 20 mg BIW or 40 mg QW. The primary objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, and preliminary efficacy of the combination of SPd in patients with relapsed/refractory multiple myeloma. Results: As of July 01 2019, 48 patients (26 male and 22 female) were enrolled. The median age was 64 years (range:43-83 years). Patients received a median of 4 (range: 2-13) prior treatment regimens. Forty patients (83%) received prior autologous stem cell transplantation (one patient received prior autologous and allogenic stem cell transplantation). The phase 1 dose escalation enrollment is now complete. Across all cohorts, eight dose limiting toxicities (DLTs) were observed (Table 1). Common hematologic treatment related adverse events (TRAE) included (Grades 1/2, Grades ≥3): neutropenia (8%, 54%), thrombocytopenia (21%, 33%), anemia (17%, 29%) and leukopenia (13%, 15%). Common non-hematologic TRAE included: nausea (56%, 0%), fatigue (40%, 10%), decreased appetite (46%, 0%), weight decreased (33%, 0%), diarrhea (27%, 0%), vomiting (21%, 2%). Lower rates of ≥ Grade 3 thrombocytopenia (27% vs 44%) and anemia (20% vs 44%) were observed in QW dosing vs BIW dosing. Out of 48 patients, 44 were evaluable for response (27 patients lenalidomide refractory/pom naive, 4 patients lenalidomide treated/pom naïve, 13 patients refractory to pomalidomide and lenalidomide, and 19 patients refractory to lenalidomide and bortezomib). Among patients who were pomalidomide naive (N=31), the ORR was 58% (7 very good partial responses and 11 partial responses) and the median PFS was 12.2 months. Among patients refractory to lenalidomide/pomalidomide (N=13) the ORR was 31% (4 partial responses) and the median PFS was 4.2 months. Conclusions: The all oral SPd combination is durable and active with an ORR of 58% in patients with disease that is lenalidomide refractory and pomalidomide naïve compared to previously published data of 31% ORR for pomalidomide/dexamethasone in a similar patient population. The median PFS on SPd of 12.2 months in pomalidomide naïve patients is longer than that observed with pomalidomide/dexamethasone ( & lt;4 months). No unexpected adverse events were noted. Selinexor QW demonstrated a manageable side effects with ≤2% Grade 3/4 nausea, vomiting, diarrhea, weight decreased and decreased appetite suggesting that the side effects of selinexor are a function of the dose and schedule. This observed activity and manageable side effect profile with QW selinexor in combination with pom/dex supports further studies. Disclosures Chen: Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Bahlis:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Honoraria; Alnylam: Honoraria, Research Funding; Sanofi: Research Funding; Prothena: Research Funding; Roche: Research Funding; Amgen: Research Funding; Merck: Research Funding. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Karyopharm: Other: Internal Review Committee participant; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kotb:Celgene: Honoraria; Karyopharm: Equity Ownership; Merck: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Bensinger:Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant; Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Leblanc:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Takeda: Honoraria; J & J: Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria. Schiller:Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J & J: Research Funding; Astellas: Research Funding; Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. White:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

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

Abstract: Background Multiple myeloma (MM) is considered an incurable hematologic malignancy despite a plethora of standard and novel agents. There is no consensus on the optimal sequencing of available therapies in relapsed/refractory MM (RRMM), even in the second line setting. Novel agents such as selinexor (XPOVIO [X]), an oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, or those that target B-cell maturation antigen (BCMA), have shown significant activity in RRMM. X is approved with bortezomib (V) and dexamethasone (XVd) in patients (pts) with at least 1 prior therapy and is not associated with known long-term clinically significant toxicities such as visual loss, cardiac dysfunction, renal failure, neuropathy, irreversible bone marrow suppression, second malignancies, venous thromboembolism, or rash. Currently, BCMA-targeting agents include 1 form each of chimeric antigen receptor T cell (CAR-T cell) and antibody drug conjugate (ADC) therapy approved in RRMM: idecabtagene vicleucel and belantamab mafodotin, respectively. BCMA-refractory MM represents an area of unmet need in MM without known standards for best treatment. Various novel combinations with X have demonstrated strong benefit in RRMM after 1 or more lines of therapy and activity even in CAR-T cell BCMA-refractory MM (N=7): 1 pt stringent complete (sCR), 3 very good partial (VGPR), 2 partial (PR), and 1 minimal (MR) response (Chari BJH 2020). Here we report on the outcomes of heavily pretreated RRMM pts, a majority of whom had received ADC-BCMA, and who were treated with X-containing regimens on the STOMP trial. Methods STOMP (NCT02343042) is a phase 1b/2, multi-arm, open-label trial of various combinations of X with backbone agents for pts with RRMM or newly diagnosed MM. Here we report on all pts in STOMP with prior anti-BCMA treatment who were treated on STOMP with X+pomalidomide +dexamethasone (XPd); XVd; X+carfilzomib+d (XKd); XPVd; and XPd+elotuzumab (E) (XPEd). Results In total, 11 pts with prior anti-BCMA therapy (6 pts with belantamab mafodotin; 1 each with MEDI2228, SEA-BCMA, BCMA BITE; 2 with idecabtagene vicleucel) were treated with 5 X-containing regimens (Table 1): 9 pts were treated with triplets XPd (4), XVd (3), or XKd (2) and 2 pts with quadruplets XPVd (1) or XPEd (1). Median age was 71 years (range 46-85), 7 pts (63.6%) were women, 11 pts were white. Median duration from MM diagnosis to treatment with a STOMP regimen was 6.9 years (range 2.3-12.8). Five pts (45.5%) had high-risk cytogenetics; pts received median of 6 prior therapies (range 4-10). Eight pts (72.7%) received anti-BCMA in their immediate prior line of therapy. Ten pts (90.9%) were previously treated with all backbone drugs of the STOMP treatments (i.e., X was the only new drug). The overall response rate (ORR) and clinical benefit rate (CBR) for the prior anti-BCMA-containing regimens were 40.0% (2 pts VGPR, 2 PR, 5 stable disease [SD], 1 progressive disease, 1 unknown). Median progression free survival (PFS) was 1.8 months (95% CI: 1.5, NE), and the 6-month PFS probability was 12.5% (95% CI: 2.1, 76.2). ORR for the X-based treatments was 54.5% and CBR was 81.8%: 1 pt VGPR, 5 PR, 3 MR, 2 SD. Median PFS was not reached (95% CI: 5.9, NE) and the 6-month PFS probability was 68.6% (95% CI: 40.3, 100.0). Median overall survival was 10.5 months (95% CI: 9.6, NE) and median time to discontinuation was 8.1 months (95% CI: 6.1, NE). The most common treatment-emergent adverse events were nausea and thrombocytopenia. Nausea was Grade (G) 1/2 (n=8, 72.7%); thrombocytopenia G1-4 in 8 pts (72.7%), 4 with ≥G3; there were no concurrent bleeding events. One pt on XPEd died of pulmonary nocardiosis considered to be associated with the 4-drug regimen. No new safety signals or long-term toxicities due to X were reported. Conclusions In this follow-up cohort of heavily pretreated pts, a majority of whom with MM refractory to ADC-BCMA, we demonstrate impressive potency and durability of the X-based treatments, particularly as compared to that of their prior anti-BCMA therapies. These data support the rationale for the development of novel regimens containing X plus immunomodulatory drugs or proteasome inhibitors in earlier lines of therapy, including first relapse, and further suggest their strong value in the emerging BCMA RRMM space. Figure 1 Figure 1. Disclosures Baljevic: Exelixis: Research Funding; Amgen: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen Research: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gasparetto: Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptide: Consultancy, Honoraria, Speakers Bureau. Schiller: Sangamo: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Geron: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; PrECOG: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Genentech-Roche: Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; FujiFilm: Research Funding; Gamida Cell Ltd.: Research Funding; Constellation Pharmaceuticals: Research Funding; Mateon: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Tolero: Research Funding; Samus: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Trovagene: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy. Lentzsch: Sanofi: Consultancy, Research Funding; Celularity: Consultancy; AbbVie: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Monge: Karyopharm: Research Funding; BMS: Consultancy. Kotb: Celgene: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Pfizer: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BMS: Honoraria; Sanofi: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Akcea: Honoraria. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy. White: Forus: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Chen: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sutherland: GSK: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Amgen: Consultancy. Madan: Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Leblanc: Celgene/BMS: Research Funding; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag: Janssen: Research Funding; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding.

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