Selinexor in Combination with Carfilzomib and Dexamethasone, All Once Weekly (SKd), for Patients with Relapsed/Refractory Multiple Myeloma
Authors: Gasparetto Cristina , Lipe Brea , Tuchman Sascha A , Callander Natalie S. , Lentzsch Suzanne , Baljevic Muhamed , Rossi Adriana C , Bahlis Nizar J. , White Darrell J , Chen Christine I , Sutherland Heather J , Kotb Rami , LeBlanc Richard , Sebag Michael , Venner Christopher P. , Bensinger William I , Sheehan Heidi , Van Domelen Dane , Kazuharu Kai , Schiller Gary J. 
Published: November 2020

Background : Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins that cause cell cycle arrest and apoptosis in cancer cells. The combination of SEL with dexamethasone (dex), each administered twice weekly (BIW), received accelerated approval from the FDA in relapsed refractory multiple myeloma (RRMM). Subsequent evaluations of combination regimens have utilized once weekly (QW) SEL. The addition of oral SEL 100 mg QW to bortezomib also QW with dex (SVd) showed superior PFS and ORR with reduced peripheral neuropathy compared with standard BIW bortezomib plus dex (Dimopoulos et al. JCO 2020).
SEL sensitized the activity of carfilzomib (CAR) in PI-resistant MM cell lines in vitro and ex vivo in PI-refractory MM cells derived from bone marrow aspirates of patients (pts) with RRMM. SEL and CAR also showed synergistic anti-tumor activity in a NOD-SCID mice xenograft model in vivo. Furthermore, a phase I trial in RRMM pts demonstrated that the combination of SEL and CAR both administered BIW with DEX showed high overall response rates (ORR) in pts with MM refractory to CAR. Carfilzomib QW was recently approved and we hypothesized that the addition of SEL QW to CAR QW plus dex (SKd) would be synergistic and convenient with an acceptable adverse event (AE) profile.
Methods: STOMP is a phase 1b/2 multicenter, open-label, clinical trial with the goals of determining the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and the ORR according to the International Myeloma Working Group (IMWG) criteria. The starting SEL dose was 100 mg QW with 20/56 mg/m2 QW CAR (20 mg/m2 only on C1D1 and 56 mg/m2 thereafter, dosed Day 1, 8, and 15, 28 days cycle) with 40 mg QW DEX (Table 1). Eligible pts had MM progressing on study entry that was not refractory to CAR, were ≥ 18 years old, with Eastern Cooperative Oncology Group (ECOG) score of 0-2, WBC ≥ 1,500/mm3,Hb ≥ 8.0 g/dL, and platelet count ≥ 75,000/mm3.
Results: The MTD was 20/56 mg/m2 CAR + 80 mg SEL + 40 mg DEX, all given QW. As of May 1, 2020, a total of 24 pts enrolled, of which 17 received the MTD. Median age was 70.5 (range, 50-76) years, 62.5% male, median number of prior therapies 3 (range, 1-8). Median years from initial diagnosis 5.0 (range, 2.7-11.3) years. Prior therapies in the 24 pts included bortezomib 24 pts (100%), lenalidomide 23 pts (95.8%), pomalidomide 15 pts (62.5%), daratumumab 14 pts (58.3%) and 19 (79.2%) stem cell transplantation. Common hematopoietic treatment-related AEs (TRAEs) were thrombocytopenia (70.8% all grades, 54.2% grades 3/4) and anemia (54.2%, 20.8%). Common non-hematological TRAEs were nausea (66.7%, 0%), fatigue (54.2%, 8.3%), anorexia (45.8%, 4.2%), weight loss (37.5%, 0%), and dysgeusia (37.5%, 0%). All TRAEs were expected and manageable with appropriate supportive care (eg, TPO receptor agonists for thrombocytopenia) and/or dose modifications; long term cumulative toxicities have not been observed. ORR was 75.0% including 4 CR (16.7%), 7 VGPR (29.2%) and 7 PR (29.2%). There was 1 MR yielding a clinical benefit rate of 79.2%. Amongst the 14 pts previously treated with daratumumab, 8 pts (57.1%) achieved ≥PR, 9 pts (64.3%) achieved ≥MR. Median time to the first response (≥PR) was 28 days (range, 27-98 days). Median progression free survival has not been reached with a median follow-up of 4.4 months.
Conclusions: Weekly SKd (20/56 mg/m2 CAR + 80 mg SEL QW + 40 mg DEX QW) is active with an ORR of 75.0% and deep responses (CR 16.7%, VGPR 29.2%) in pts who had a median of 3 prior lines of therapy including bortezomib and lenalidomide. The ORR of 57.1% in patients previously treated with daratumumab warrants further investigation of this once weekly regimen in 1st or 2nd relapse including among patients with prior daratumumab.

Disclosures
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. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Lentzsch:Sanofi: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; 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; Magenta: Current equity holder in private company; Karyopharm: Research Funding. Baljevic:NCCN Hematologic Malignancies Congress: Honoraria; 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; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Exelixis: Research Funding; MediCom Myeloma CME: Honoraria. Rossi:BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Bahlis:Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. White:Sanofi: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Chen: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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Kotb:Karyopharm: Current equity holder in publicly-traded company; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Research Funding. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. 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. 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. Schiller:MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Gilead: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Mateon: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding.