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2748 Once Weekly Oral Selinexor, Pomalidomide, and Dexamethasone in Relapsed Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research, Clinically Relevant
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Darrell J White, MD1, Christine I. Chen, MD2, Muhamed Baljevic, MD3, Sascha A. Tuchman, MD4, Nizar J. Bahlis, MD5, Gary J. Schiller, MD6, Brea Lipe, MD7, Rami Kotb, MD8, Heather J. Sutherland, MD, PhD, FRCPC9, William I. Bensinger, MD10*, Sumit Madan, MD11, Michael Sebag, MD, PhD12, Suzanne Lentzsch, MD, PhD13, Natalie S. Callander, MD14, Noa Biran, MD15, Christopher P. Venner, MD16*, Richard Leblanc, MD, FRCPC17, Jorge Monge, MD18*, Evgeni Chubar, MD19*, Tamar Tadmor, MD20*, Noa Lavi, MD21*, Merav Leiba, MD22*, Andrew DeCastro, PhD23*, Dane R. Van Domelen, PhD23*, Chris Zhang, MD23*, Moran Mishal, MD23*, Ohad S. Bentur, MD MHA23*, Jatin J. Shah, MD23*, Sharon Shacham, PhD, MBA23*, Michael G. Kauffman, MD, PhD23 and Cristina J. Gasparetto, MD24*

1Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
2Department of M, Princess Margaret Cancer Centre, Toronto, ON, Canada
3University of Nebraska Medical Center, Omaha, NE
4Department of Medicine, Division of Hematology, University of North Carolina, Durham, NC
5Southern Alberta Cancer Research Institute, University of Calgary, Calgary, AB, Canada
6David Geffen School of Medicine at UCLA, Los Angeles, CA
7University of Rochester Medical College, Rochester, NY
8Medical Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB, Canada
9Division of Hematology, Vancouver General Hospital, Vancouver, BC, Canada
10Myeloma and Transplant Program, Swedish Cancer Institute, Seattle, WA
11Banner MD Anderson Cancer Center at Banner University Medical Center, Phoenix, AZ
12Royal Victoria Hospital, Montreal, QC, Canada
13Colombia University, New York
14University of Wisconsin, Madison, WI
15John Theurer Cancer Center, Hackensack Meridian Health, Hackensack University Medical Center, Hackensack, NJ
16Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
17Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada
18Weill Cornell Medicine, New York, NY
19Head, Blood Bank, HaEmek Medical Center, Afula, Israel
20Hematology Unit, Bnai Zion Medical Center, Haifa, Israel
21Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
22Assuta Ashdod Medical Center, Ashdod, Israel
23Karyopharm Therapeutics Inc., Newton, MA
24Duke University Medical Center, Durham, NC

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.

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: Oncopeptides: Consultancy; Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding. Bahlis: Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genentech: Consultancy; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria. Schiller: Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Current equity holder in publicly-traded company; Millennium: Research Funding; Mateon: Research Funding; Onconova: Research Funding; Sellas: Research Funding; PrECOG: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; Kura Oncology: Research Funding; Ono: Consultancy; Incyte: Consultancy; Eli Lilly: Research Funding; National Marrow Donor Program: Research Funding; UCSD: Research Funding; Biomed Valley Discoveries: Research Funding; NCI: Consultancy; Leukemia & Lymphoma Society: Research Funding; Novartis: Speakers Bureau; Bluebird Bio: Research Funding; Evidera: Consultancy; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Samus: Research Funding; Regimmune: Research Funding; Cyclacel: Research Funding; CTI Biopharma: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; Ariad: Research Funding; Janssen: Research Funding; MedImmune: Research Funding; Pharma: Consultancy; Ambit: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; ASH foundation: Other: Chair-unpaid; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bio: Research Funding; Elevate: Research Funding; Trovagene: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Tolero: Research Funding; Takeda: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Sangamo: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Geron: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Abbvie: Research Funding. 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.

*signifies non-member of ASH