-Author name in bold denotes the presenting author
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726 Selinexor in Combination with Pomalidomide and Dexamethasone (SPd) for Treatment of Patients with Relapsed Refractory Multiple Myeloma (RRMM)

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation; Novel Approaches for Relapsed/Refractory Myeloma and Amyloidosis
Hematology Disease Topics & Pathways:
Non-Biological, Therapies
Monday, December 7, 2020: 2:00 PM

Christine I Chen, MD1, Nizar Bahlis, MD2, Cristina Gasparetto, MD3, Sascha A Tuchman, MD4, Brea Lipe, MD5, Muhamed Baljevic, MD6, Rami Kotb, MD7*, Heather J Sutherland, MD, PhD8, William I Bensinger, MD9*, Michael Sebag, MD, PhD10,11, Richard LeBlanc, MD, FRCPC12, Christopher P. Venner, MD13, Gary J. Schiller, MD14, Suzanne Lentzsch, MD, PhD15, Natalie S. Callander, MD16, Adriana C Rossi, MD, MSc17*, Noa Biran, MD18, Heidi Sheehan19*, Dane Van Domelen, PhD19*, Kai Kazuharu, MD, PhD19*, Hongwei Wang, MD, PhD19*, Jatin Shah, MD20, Sharon Shacham, PhD, MBA20*, Michael G Kauffman, MD, PhD20 and Darrell J White, MD21

1Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada
2Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
3Department of Medicine, Duke University Cancer Institute, Durham, NC
4University of North Carolina, Chapel Hill, NC
5University of Rochester Medical Center, Rochester, NY
6Division of Oncology and Hematology, University of Nebraska Medical Center- Fred & Pamela Buffett Cancer Center, Omaha, NE
7Cancer Care Manitoba, Winnipeg, MB, Canada
8Vancouver General Hospital, Vancouver, BC, Canada
9Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA
10Division of Hematology, McGill University Health Centre, Montreal, QC, Canada
11Royal Victoria Hospital, Montreal, QC, Canada
12Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, QC, Canada
13Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
14David Geffen School of Medicine at University of California, Los Angeles, CA
15Colombia University, New York
16Carbone Cancer Center, University of Wisconsin, Madison, WI
17Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY
18John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
19Karyopharm Therapeutics Inc., Newton, MA
20Karyopharm Therapeutics, Newton, MA
21Dalhousie University and QEII Health Sciences Centre, Halifax, NS, Canada

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: Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. 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: Tolero: Research Funding; Geron: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; Celgene: Research Funding, Speakers Bureau; Ariad: Research Funding; Cyclacel: Research Funding; Stemline: Speakers Bureau; Forma: Research Funding; Samus: Research Funding; Daiichi Sankyo: Research Funding; Actinium: Research Funding; Deciphera: Research Funding; Astellas Pharma: Honoraria, Research Funding; Gilead: Speakers Bureau; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Constellation: Research Funding; Abbvie: Research Funding; Sanofi: Speakers Bureau; FujiFilm: Research Funding; Celator: Research Funding; Regimmune: Research Funding; Kite Pharma: Research Funding; Sangamo: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Kaiser Permanente: Consultancy; Trovagene: 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. Biran: Karyopharma: Research Funding; Sanofi: Honoraria, Speakers Bureau; Oncopeptides: Consultancy; Janssen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: reimbursement of travel and accommodation, Research Funding, Speakers Bureau. 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.

*signifies non-member of ASH