Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma.

We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.
Competing Interests: Cristina Gasparetto: No conflict of interest; Suzanne Lentzsch: research funding—Karyopharm and Sanofi; patents, royalties, other intellectual property—Caelum Bioscience; stock and other ownership interests—Caelum Bioscience, Mesoblast, Magenta, and Kadmon; consulting or advisory role—Caelum Bioscience, Sorrento, Janssen, and Celularity; Gary Schiller: research funding: AbbVie, Agios, Actinium, Ambit, AMGEN, ARIAD, Astellas, Leukemia & Lymphoma Society, BioMed Valley Discoveries, Inc., Bluebird Bio, Bristol‐Myers Squibb, Boehringer‐Ingleheim, Celator, Celgene, Cellerant, Constellation Pharmaceuticals, CTI BioPharma Corp., Forma, Cyclacel, Daiichi Sankyo, Deciphera, The California Institute for Regenerative Medicine (CIRM), Gamida Cell Ltd., GILEAD, Incyte, Janssen, Karyopharm, Kite Pharma, Inc., Mateon, MedImmune, Millennium, National Marrow Donor Program, National Institute of Health: National Cancer Institute, Novartis, Onconova, Onyx, Pfizer, PharmaMar, Sangamo, Stemline Therapeutics, Inc., National Marrow Donor Program, Tolero, Trovagene, University of California Davis, and University of California San Diego‐ UCHMC; stock and other ownership interests—Amgen, Bristol‐Myers Squibb, Pfizer, and Johnson and Johnson; consulting or advisory role—Incyte, Elevate Bio, AbbVie, ONO UK, Novartis, Evidera, Agios, AstraZeneca, National Institute of Health: National Cancer Institute, and Federal Drug Administration; speakers' bureau—Agios, Amgen, Astellas, Bristol‐Myers Squibb, Celgene, Sanofi‐Genzyme, Incyte, Janssen, Jazz, Kite (gilead)‐Yescarta, Pharmacyclics, and Stemline; Natalie Callander: research funding—Cellectar; Sascha Tuchman: research funding—Celgene, Karyopharm, Amgen, Janssen, and Sanofi; consulting or advisory role—Oncopeptides, Celgene, Karyopharm, Caelum, and Sanofi; honoraria—Celgene, Karyopharm, Caelum, and Sanofi; speakers' bureau—Celgene; Christine Chen: No conflict of interest; Darrell White: consulting or advisory role: Amgen, Antengene, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, and Takeda; honoraria—Amgen, Antengene, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, and Takeda; Rami Kotb: research funding—Merck and Sanofi; stock and other ownership interests—Karyopharm; consulting or advisory role—Celgene/BMS, Janssen, Amgen, Takeda, Sanofi, and Merck; Heather Sutherland: honoraria: Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, and GlaxoSmith Kline; Michael Sebag: consulting or advisory role—Janssen and Karyopharm; Muhamed Baljevic: consulting or advisory role—Celgene Corporation, Cardinal Health, Putnam Associates, Gerson Lehrman Group, Inc., and AlphaSights; honoraria—Karyopharm Therapeutics Inc. clinical trial internal review committee member and NCCN Hematologic Malignancies Congress panelist; William Bensinger: research funding—BMS, Acetylon, Amgen, Janssen, Regeneron, and Sanofi; consulting or advisory role—Regeneron and BMS; speakers' bureau—Amgen, Janssen, BMS, Sanofi, and GSK; travel, accommodations, and expenses: Amgen, Janssen, BMS, Sanofi, and GSK; Richard LeBlanc: consulting or advisory role—Celgene Canada, Janssen Inc., Amgen Canada, Takeda Canada, Sanofi Canada; speakers' bureau—Celgene Canada, Janssen Inc., and Amgen Canada; Chris Venner: honoraria—Celgene, Johnson & Johnson, Amgen, Sanofi, and Takeda; Nizar Bahlis: research funding—received research support from Celegen and BMS; honoraria—Janssen, Celgene/BMS. Amgen, Takeda, Karyopharm, Sanofi, and GSK; Heidi Sheehan: employee and stockholder in Karyopharm Therapeutics; Jean‐Richard Saint‐Martin: employee and stockholder in Karyopharm Therapeutics; Dane Van Domelen: employee and stockholder in Karyopharm Therapeutics; Kazuharu Kai: employee and stockholder in Karyopharm Therapeutics; Jatin Shah: Executive Vice President, CMO, and stockholder in Karyopharm Therapeutics; Sharon Shacham: President, CSO, and stockholder in Karyopharm Therapeutics; Michael Kauffman: CEO and stockholder in Karyopharm Therapeutics; Brea Lipe: research funding—Amgen and Cellectar; consulting or advisory role—BMS, Janssen, and Abbvie.
(© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)