Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
Authors: Chari Ajai , Vogl Dan T. , Jagannath Sundar , Jasielec Jagoda K. , DeCastro Andrew , Unger TJ , Shah Jatin , Jakubowiak Andrzej 
Published: November 2019

Introduction: There are limited data on treatment options for patients with multiple myeloma whose disease has progressed after chimeric antigen receptor T-cell (CAR-T) therapy. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) that forces nuclear retention and activation of tumor suppressor proteins. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study wherein, Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. The activity of Sel-dex was preserved regardless of specific prior therapies, as expected given its unique and novel mechanism of action. The efficacy of selinexor after CAR-T therapy remains unknown. Here, we report on observations of the efficacy of Sel-dex alone or administered as a triplet in combination with bortezomib or carfilzomib in patients with multiple myeloma whose disease has progressed after CAR-T therapy.
Methods: We identified 7 patients across all selinexor myeloma trials who had received lymphodepleting conditioning (fludarabine/cyclophosphamide n=6; Cyclophosphamide n=1) followed by an effective dose of CAR-T cell therapy (>108 CAR-positive cells targeting B-cell maturation antigen) for their multiple myeloma prior to being enrolled in a trial using a selinexor-containing regimen. Four were female and 3 were male. Median age was 64 years (range: 35-70 years). One patient was treated in the STORM study, with selinexor (starting at 80 mg twice-weekly) and dexamethasone (20 mg twice-weekly), 1 patient was treated with selinexor (100 mg once-weekly) plus bortezomib (1.3 mg/m2 once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly) and 5 patients were treated with selinexor (100 mg once-weekly) plus carfilzomib (20/56 mg/m2 or 20/70 mg/m2) and dexamethasone (40 mg once-weekly or 20 mg twice-weekly). Response was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria.
Results: Patients had a median of 10 prior therapeutic regimens (range:5-15), all had high-risk cytogenetics, and 6 of the 7 had rapidly progressing disease as indicated by the percent increase in paraprotein (17-91%) between screening and Cycle 1 Day 1 (range: 7-22 days). All patients responded to treatment, including 1 unconfirmed complete response (uCR), 2 very good partial responses (VGPR), 3 partial responses (PR), and 1 minimal response (MR). Responses were rapid and typically occurred within the first cycle of treatment (median 28 days; range 14-83 days). At the time of data cutoff, the median time on a selinexor-based regimen was 4.1 monthsange: 2.5-8.0 months); 2 patients' disease had progressed, 1 patient had withdrawn consent, and 4 patients were still responding on therapy. Adverse events were consistent with what has previously been reported with selinexor-containing regimens in heavily-pretreated patients with multiple myeloma and included nausea, fatigue, thrombocytopenia, neutropenia, and anemia.
Conclusions: These results suggest that Sel-dex alone or in combination with bortezomib or carfilzomib may offer therapeutic benefit for patients who have exhausted available treatment options, have rapidly progressing disease, and who have progressed after CAR-T therapy. Importantly patients are able to tolerate and remain on therapy with weekly Sel-dex in combination with bortezomib or carfilzomib, with time on therapy of >4 months and 4/7 patients remaining on therapy. Although based on a small sample size, the findings of this analysis are intriguing and warrant further investigation in a larger study.

Disclosures
Chari: Sanofi: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Jagannath:Merck: Consultancy; Celgene: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Novartis: Consultancy. DeCastro:Karyopharm Therapeutics: Employment, Equity Ownership. Unger:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Jakubowiak:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Amgen: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.