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: 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: Background : Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing cell death in cancer cells. SEL 80 mg and dexamethasone (dex) 20 mg, both twice weekly (BIW), received accelerated approval from the FDA for patients (pts) with relapsed refractory multiple myeloma (RRMM). SEL continues to be evaluated in earlier lines of therapy with once weekly administration and in combination regimens. The SVd regimen with once weekly (QW) oral SEL (100 mg), dexamethasone (dex) and QW bortezomib (BOR) had significantly increased progression free survival (PFS) and overall response rate (ORR) with significantly reduced peripheral neuropathy as compared to standard BIW BOR/dex (Vd) in the phase III BOSTON study. The combination of lenalidomide (LEN) and dex (Rd) is an approved regimen in RRMM and newly diagnosed MM (NDMM) with an ORR of 70-76% in RRMM but a low complete response rate. SEL showed synergistic antitumor activity with LEN in a MM xenograft model. Therefore, we hypothesized that the all oral combination of weekly SEL with standard Rd (i.e., SRd) could improve the efficacy compared with Rd in pts with RRMM and NDMM with acceptable toxicity profile. Methods: STOMP is a phase 1b/2 multicenter, open-label, clinical trial with the goals of determining the maximum tolerated dose, the recommended phase 2 dose (RP2D), efficacy and safety of SRd in pts with RRMM or NDMM. For RRMM, SEL was dose escalated in two regimens QW (starting at SEL 80 mg) or BIW (starting at 60 mg), LEN 25 mg PO daily and DEX 20 mg BIW or 40 mg QW. Results: As of June 1, 2020, 24 pts (13 male, 11 female) with RRMM were enrolled. The median age was 67 years (range, 49-84) and the median number of prior lines of therapy was 1.5 (range, 1 - 8). In the 60 mg BIW dosing, 4 pts experienced dose limiting toxicities (DLTs) out of 5 pts dosed (2 thrombocytopenia, 1 anorexia, 1 & gt;25% missed dose due to unrelated QT interval prolongation). In the 80 mg QW dosing, 2 pts experienced DLTs out of 6 pts (both grade 4 thrombocytopenia). In the 60 mg QW dosing, no DLTs were observed. Based on these data, the RP2D of SRd was determined to be: SEL 60 mg QW, LEN 25 mg QD and DEX 40 mg QW. Common treatment related adverse events (TRAEs) (All Grades, ≥3) were thrombocytopenia (71%, 63%), neutropenia (63%, 63%), nausea (58%, 4%), fatigue (54%, 17%), decreased appetite (50%, 8%), and weight loss (42%, 8%). Amongst the 20 pts with RRMM where efficacy was evaluable, previously treated/documented refractory rates were: bortezomib (100%, 45%), LEN (40%, 25%), daratumumab (20%, 20%), and pomalidomide (20%, 20%). Amongst the LEN naïve pts (n=12), the ORR was 92% including 1 stringent complete response [sCR], 4 very good partial responses [VGPR] and 6 partial responses [PR, 2 unconfirmed]). PFS in LEN naïve pts has not been reached with a median follow-up period of 7.8 months. In the pts with prior LEN treatment (n=8), the ORR was 13%. Based on the high levels of activity of SRd in LEN naïve pts, 8 pts (4 males and 4 females) with NDMM were enrolled at the RP2D. The median age was 74 (range: 51-86) years. No DLTs were observed in 5 DLT evaluable pts. Common TRAEs (All Grades, ≥3) were thrombocytopenia (63%, 38%), neutropenia (75%, 75%), fatigue (63%, 50%), nausea (50%, 0%), weight loss (63%, 0%), and decreased appetite (13%, 13%). All 7 efficacy evaluable pts achieved a response, an ORR of 100%, including 1 CR, 4 VGPR, and 2 PR. With a median follow-up of 10.2 months, median PFS has not been reached. Out of these 7 pts, three pts withdrew consent to transit to successful autologous stem cell collection and transplantation. Conclusions: The all oral combination of SRd with once weekly SEL 60 mg, LEN 25 mg QD and DEX 40 mg QW was established as the RP2D for pts with RRMM or NDMM. The safety profile was similar in both settings. All TRAEs were manageable with adequate supportive care and/or dose modification. The all oral combination of SRd has demonstrated ORR of 92% in pts with LEN naïve RRMM and ORR of 100% in pts with NDMM, warranting further investigation of SRd with or without additional anti-MM agents for the treatment of pts with NDMM. Disclosures White: Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Baljevic:NCCN Hematologic Malignancies Congress: Honoraria; MediCom Myeloma CME: Honoraria; Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria. Bahlis:Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Lentzsch:Celularity: Consultancy; Sorrento: Consultancy; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Sanofi: Research Funding; Magenta: Current equity holder in private company; Karyopharm: Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Chen:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding. Lipe:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Tuchman:Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding; Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Kotb:Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in publicly-traded company; Takeda: Honoraria; Celgene: Honoraria; Sanofi: Research Funding; Amgen: Honoraria; Janssen: Honoraria. Sebag:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria; Takeda: Honoraria. Callander:Cellectar: Research Funding; University of Wisconsin: Current Employment. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rossi:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Zhou:Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Schiller:Ariad: Research Funding; Actinium: Research Funding; Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Kaiser Permanente: Consultancy; Trovagene: Research Funding; Tolero: Research Funding; Sangamo: Research Funding; Samus: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; Astellas Pharma: Honoraria, Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Abbvie: Research Funding; Constellation: Research Funding; Ono Pharma: Consultancy; Novartis: Consultancy, Research Funding; Stemline: Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Gilead: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Forma: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding.

Abstract: There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti‐B‐cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti‐BCMA‐targeted chimeric antigen receptor‐T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA‐antibody‐drug conjugate therapy. We observe that X‐containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients’ prior anti‐BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X‐based regimens following broader anti‐BCMA therapy.

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: Background: Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells. The SVd regimen with once weekly (QW) oral SEL (100 mg), dexamethasone (dex) and QW bortezomib (BOR) had significantly increased progression free survival (PFS) and overall response rate (ORR) with significantly reduced peripheral neuropathy as compared to standard twice weekly BOR/dex (Vd) in the phase III BOSTON study. Pomalidomide (POM) plus dex (Pd) achieved an ORR of 31% and PFS of 4 months in patients (pts) with disease refractory to BOR and lenalidomide (LEN). We hypothesize that the all oral Pd combination with the addition of QW SEL (SPd) would demonstrate improved activity and acceptable tolerability as compared with Pd. Methods: STOMP is a multicenter, open-label, phase 1b/2, dose escalation study with an expansion phase. Pts with RRMM who received ≥ 2 prior therapies including LEN and a proteasome inhibitor (in separate or the same regimens) were eligible for enrollment. Oral SEL was evaluated in 2 different dosing schedules in 28 days cycle: QW 60, 80 or 100 mg or twice weekly (BIW) 60 or 80 mg, with escalating doses of POM 2, 3 or 4 mg (days 1-21), and dex 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, ORR and PFS of the combination of SPd in pts with RRMM. Results: As of June 1 2020, 52 pts (28 male and 24 female) were enrolled. The median age was 64 (range: 43-85) years. Pts received a median of 3 (range: 1-10) prior therapies including 44 (84.6%) with autologous stem cell transplantation. During the escalation phase, eight dose limiting toxicities (DLTs) were observed (Table 1). Common hematologic treatment related adverse events (TRAE) included (All Grades, Grades ≥3) neutropenia (62%, 56%), anemia (60%, 37%), and thrombocytopenia (56%, 35%). Common non-hematologic TRAE included nausea (62%, 2%), fatigue (56%, 12%), decreased appetite (48%, 2%), weight loss (42%, 0%), diarrhea (35%, 0%), vomiting (23%, 2%). Rates of ≥ Grade 3 hematological TRAEs were lower in QW vs BIW schedules of SEL: thrombocytopenia (29% vs 44%) and anemia (32% vs 44%). Based on all of the safety data, the RP2D was SEL 60 mg QW, POM 4 mg (days 1-21), and DEX 40 mg QW. Out of 52 pts, 47 were evaluable for response. Previously treated / refractory rates were as follows (N=47 pts evaluable for efficacy): LEN (100% / 96%), BOR (94%, 45%), carfilzomib (38%, 34%), POM (30%, 30%), daratumumab (21%, 21%). Among POM naïve pts (N=33), all pts (100%) received prior LEN and 31 pts (94%) had MM documented LEN refractory. Among pts who were POM naive (N=33), the ORR was 58% (1 CR, 5 very good partial responses and 13 partial responses) and the median PFS and OS were 12.3 and 19.0 months, respectively. Amongst pts who received POM previously (N=14), the ORR was 36% (1 VGPR and 4 PR), and the median PFS and OS were 8.8 and 8.0 months, respectively. Conclusions: The RP2D is SEL 60 mg QW, POM 4 mg QD and dex 40 mg QW. The ORR was 58% in pts in LEN treated or refractory and POM naïve MM compared to previously published data of 31% ORR with Pd in a similar population. The median PFS on SPd of 12.3 months in POM naïve pts is longer than that historically observed with Pd (~4 months). All TRAEs were expected and manageable with appropriate supportive care (eg, G-CSF) and/or dose modifications. The all oral SPd combination appears to confer relatively high ORR with good durability and promising PFS in pts with heavily pretreated MM. Disclosures Chen: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bahlis:Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. Tuchman:Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding. Lipe:Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Baljevic:Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; MediCom Myeloma CME: Honoraria; NCCN Hematologic Malignancies Congress: Honoraria. Kotb:Celgene: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in publicly-traded company; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Amgen: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. LeBlanc:Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schiller:Kite Pharma: Research Funding; Ariad: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; DeltaFly: Research Funding; MedImmune: Research Funding; Stemline: Speakers Bureau; Actinium: Research Funding; Abbvie: Research Funding; Jazz Pharmaceuticals: Research Funding; Forma: Research Funding; Novartis: Consultancy, Research Funding; Cyclacel: Research Funding; AstraZeneca: Consultancy; Mateon: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Gamida: Research Funding; FujiFilm: Research Funding; Geron: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Constellation: Research Funding; Genentech-Roche: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Deciphera: Research Funding. Lentzsch:Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sorrento: Consultancy; Celularity: Consultancy; Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Sanofi: Research Funding; Magenta: Current equity holder in private company. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Wang:Karyopharm: Current Employment; Curis: Ended employment in the past 24 months. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. White:Sanofi: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Abstract: 8018 Background: Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins (TSPs), is associated with poor prognosis in MM, and contributes to proteasome inhibitor (PI) and immunomodulatory drug (IMiD) resistance. Selinexor (SEL) is a novel, oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, forcing the nuclear retention and activation of TSPs. SEL is approved with low-dose dexamethasone (dex) ± bortezomib (BOR) for patients (pts) with previously treated MM. In the Phase 3 BOSTON study, once weekly (QW) SEL, QW BOR, and dex (XVd) significantly increased progression-free survival (PFS) and overall response rate (ORR) with marked reduction of peripheral neuropathy as compared to standard twice weekly BOR/dex (Vd), despite XVd utilizing 40% less BOR and 25% less dex than Vd. Pomalidomide (POM) plus dex (Pd) has an ORR of 31% and median PFS (mPFS) of 4 months in MM pts refractory to BOR and lenalidomide (LEN). We hypothesized that the addition of once weekly SEL to Pd (XPd) would be an active, all-oral combination with an acceptable safety profile in pts with LEN refractory and BOR treated MM. Methods: In the SPd arm of the multi-arm Phase 1b/2 STOMP study, SEL was evaluated at 60, 80, or 100 mg QW or 60 or 80 mg twice weekly in combination with Pd. Study objectives were to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D), and assess the safety and activity of the SPd regimen including in pts receiving the RP2D. Results: As of 4 Jan 2021, 65 pts (33 male) were enrolled with median age of 64 years (range 37-85 years) and median of 3 (range 1-10) prior lines of therapy. Previously treated/refractory rates were LEN 100%/85%, BOR 92%/49%, carfilzomib 43%/37%, POM 31%/29%, and daratumumab (dara) 26%/26%. RP2D was SEL 60 mg QW, POM 4 mg (days 1-21), dex 40 mg QW. Common hematologic, treatment-related adverse events (TRAEs) included (all grades, grades ≥3) neutropenia (63%, 55%), anemia (58%, 32%), and thrombocytopenia (54%, 31%). Non-hematologic TRAEs included nausea (62%, 2%), fatigue (55%, 11%), and decreased appetite (45%, 2%). Among POM naïve or nonrefractory MM pts (N = 44), ORR was 57% (1 sCR, 1 CR, 8 VGPR, 15 PR); mPFS was 12.2 months. In pts treated with RP2D (N = 20), ORR was 65% (1 sCR, 5 VGPR, 7 PR); mPFS was not reached with a median follow-up time of 3.9 months. In POM-refractory pts and those with prior dara, ORR was 44% (7/16) and 60% (9/15), respectively. Conclusions: SEL, once weekly, can be safely combined with Pd in pts with heavily pretreated MM. No new safety signals were identified. The all-oral combination of XPd is highly active with an ORR of 65% at RP2D (compared to expected ORR ≤30% for Pd) and produces durable responses with a mPFS of 12.2 months overall. These data support a planned Phase 3 study with an all-oral combination of XPd vs Pd in pts who have been previously treated with LEN, a PI, and an anti-CD38 mAb. Clinical trial information: NCT02343042.

Abstract: Introduction: Patients with multiple myeloma (MM) have a high rate of relapse resulting in a need for multiple lines of therapy. In contrast to MM with standard risk cytogenetics (SR-Cyto), high-risk cytogenetics (HR-Cyto) in MM such as del(17p), t(4;14), t(14;16), and gain(1q) (≥3 copies), can result in shorter progression-free survival (PFS) and overall survival (OS) with less durable responses. Treatment regimens that can overcome the negative effect of HR-Cyto abnormalities are required to address this area of unmet medical need. Exportin 1 (XPO1), is overexpressed in many hematologic and solid tumor malignancies including MM, and exports tumor suppressor proteins from the nucleus to the cytoplasm, leading to their inactivation. Elevated levels of XPO1 are correlated with more aggressive MM and resistance to therapy and confers a poor prognosis. The potent oral XPO1 inhibitor, selinexor, has been approved as a triplet combination with bortezomib and dexamethasone for previously-treated MM. In the Phase 3 BOSTON study, treatment with XVd in patients with previously treated MM significantly prolonged median PFS and improved the overall response rate (ORR), with a trend towards a prolonged OS amongst all patients as well as those with HR cytogenetics. Methods: We performed post hoc analyses on patients with previously-treated MM from the XVd arm of the Phase 1b/2 study STOMP (NCT02343042) and the Phase 3 BOSTON (NCT03110562) study to determine the effects of cytogenetic abnormalities on outcomes. The HR-Cyto group included patients with at least one of the following cytogenetic abnormalities at initial diagnosis or screening: del(17p), t(4;14), t(14;16), or gain(1q) (≥3 copies). Efficacy was based on independent review committee. Results: A total of 106 patients with HR-Cyto were identified, including del(17p) (n=25), t(4;14) (n=25), t(14;16) (n=10), and gain(1q) (n=80). There were 131 patients classified as SR-Cyto including those with unknown cytogenetics. Baseline demographics were similar between groups with median age of 66 years old (range 40-87). Patients with HR-Cyto had a median PFS of 12.9 months and patients with SR-Cyto had a median PFS of 16.6 months; PFS on the BOSTON Vd control arm were 8.6 and 9.5 months with HR- and SR-Cyto, respectively. Of the individual abnormalities, a PFS of 13.2 and 13.9 months was observed in the t(4;14) and gain1q subgroups, respectively. Of the HR-Cyto subgroups with more than 10 patients, a similar median OS was observed in comparison to SR-Cyto and ranged from 20.4 months to not reached. The response of XVd treatment was maintained across HR-Cyto risk subgroups, with an ORR of 76.4% overall and the following values for subgroups: del(17p) (72.0%), t(4;14) (88.0%), and gain1q (73.8%). The ORR of the SR group was 69.5%. Of all patients that received XVd, there were 6 CRs (5.7%) and 32 VGPRs (30.2%) in the HR group and 9 CRs (6.9%) and 29 VGPRs (22.1%) in the SR group. The ORRs on the BOSTON Vd control arm were 57.7% and 64.7% for HR- and SR-Cyto, respectively. The rates of the most common treatment emergent adverse events (TEAEs) of any grade were similar across risk groups (HR- vs SR-Cyto): thrombocytopenia (65.1% vs. 54.2%), nausea (53.8% vs. 53.4%), fatigue (47.2% vs. 45.0%) decreased appetite (37.7% vs. 42.0%) and anemia (34.6% vs 40.5%). Rates of AEs of any grade peripheral neuropathy (PN) were 35.8% overall, 40.0% in del(17p), t(4;14) (40.0%), t(14;16) (30.0%), gain(1q) (38.8%), and 23.7% in the SR group. The rates of PN in the HR and SR groups of the XVd arm of the BOSTON and STOMP studies were 37.1% and 29.6% and 11.1% and 15.2%, respectively. The corresponding rates for Vd alone in the BOSTON study were 48.6% and 47.0%. Conclusions: Patients with MM with HR-Cyto treated with XVd demonstrated a comparable ORR and PFS, with a manageable safety profile compared to patients with SR-Cyto, supporting the use of XVd in patients with any cytogenetic profile. These results are consistent with the distinct and broad mechanism of action associated with XPO1 inhibition and the use of the agent in earlier lines of therapy. Further assessment of selinexor in combination with other therapies in patients with MM across the entire cytogenetic spectrum is warranted. Figure 1 Figure 1. Disclosures Bahlis: Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Richard: Karyopharm, Janssen: Honoraria. White: Amgen, Antengene, BMS/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: Consultancy, Honoraria. Chen: Gilead: Research Funding; BMS, Janssen, Abbvie, Novartis, Gilead, AstraZeneca: Consultancy. Delimpasi: Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Sutherland: Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Celgene: Consultancy; Karyopharm: Research Funding. Sebag: Janssen: Research Funding; Bristol Myers-Squibb: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Gavriatopoulou: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria. Lentzsch: Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; Janssen: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kriachok: Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau; Takeda, Roche, Abbivie, Janssen, MSD: Consultancy. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Beigene: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Garg: Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria; University Hospital Leicester: Current Employment. Quach: Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jagannath: Karyopharm Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Badros: J & J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos: Oncopeptides: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Bluebird bio: Honoraria; AbbVie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Richardson: Secura Bio: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

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.