Nivolumab As an Adjunctive Therapy in Relapsed Refractory Multiple Myeloma Patients with Sub-Optimal Response to Idecabtagene Vicleucel

Background: Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor T-cell (CAR-T) targeting B-cell maturation antigen (BCMA) approved in the US for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) after two or more prior lines of therapy, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody. Prior studies of ide-cel have shown that depth of response (DOR) correlates with progression free survival (PFS). Specifically, median PFS was 20.2 months in patients who achieved a CR/sCR compared to only 11.3 and 5.4 months in patients who achieved a VGPR or PR as best response respectively. Nivolumab is a fully human anti-programmed death 1 (PD-1) antibody which has been shown to restore the function of existing antitumor T cells and enhance antitumor immunity through direct or indirect immune-system activation in multiple malignancies. Our study evaluates fixed duration nivolumab starting within 60 days post-ide-cel in RRMM patients who achieved a sub-optimal response to ide-cel (defined as a VGPR, PR, MR, or SD) on initial restaging-approximately 30-days post-CAR-T infusion-a timepoint when CAR-T cells should still be present in most patients.

Study Objective: Our study aims to determine if adjuvant nivolumab administered within 8 weeks of CAR-T infusion in patients with RRMM who achieve a sub-optimal response to ide-cel (as defined as VGPR, PR, MR, or SD) at 30-day response assessment will improve DOR, PFS, and CAR-T cell expansion, and persistence, while maintaining manageable toxicity compared to historical controls.

Study Design and Methods: This is a single arm, two-stage, phase II study designed to assess for deepening of response with nivolumab as an adjunctive therapy in patients with RRMM who achieved a sub-optimal response after treatment with ide-cel. The estimated enrollment is 50. The study will enroll adult patients with RRMM who have been treated with >= 2 prior lines of therapy and are refractory to or intolerant of at least one IMiD, PI, and anti‐CD38 antibody who achieved a sub-optimal response (defined as a VGPR, PR, MR, or SD by IMWG 2016 criteria) to ide-cel. Key exclusion criteria include any evidence of residual cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) at time of screening and active autoimmune disease (except well-controlled type 1 diabetes mellitus or hypothyroidism). Enrolled subjects will receive 2 cycles of nivolumab at a dose of 480 mg on day 1 of each 28-day cycle.

The primary endpoint is the CR/sCR rate with adjuvant nivolumab. Key secondary endpoints are PFS, DOR, MRD negativity rate, and OS. Safety and tolerability will be evaluated from the first dose of nivolumab administration through the end of the 100-day safety follow up period. Key translational endpoints include sequential assessments of CAR-T expansion, persistence, and fitness. We also plan to characterize the mechanism(s) of immune exhaustion and T cell dysfunction in RRMM patients. These translational endpoints are aimed to determine patients who would be at highest likelihood to derive benefit from adjuvant nivolumab in future studies.

Statistical Considerations: Historically, 12% of patients with a suboptimal response to ide-cel at 30-days subsequently achieve a CR/sCR without additional therapy. Stage 1 of our study will enroll 21 patients; if at least 3 response evaluable patients achieve a CR/sCR in stage 1 the trial will enroll an additional 29 patients in stage 2 for a total of 50 patients. Based on a 1-sided alpha=0.10 significance level, 50 patients will provide 90% power to detect a post-adjuvant nivolumab treatment CR/sCR rate of 25%.

Conclusion: This Phase II study will evaluate the safety, tolerability, and efficacy of a short course of adjuvant nivolumab given soon after ide-cel infusion. The study will be open soon and will be enrolling at 5 centers in the United States

This study is registered with ClinicalTrials (NCT06523621)

Paul:Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie Inc: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Foureau:Astrazeneca: Research Funding. Bhutani:Takeda: Research Funding; Caribou Biosciences: Research Funding; BMS: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Abvvie: Research Funding. Ferreri:Janssen: Consultancy; Affimed Therapeutics.: Current equity holder in private company; Sanofi: Consultancy. Varga:LavaTherapeutics: Research Funding; Janssen: Consultancy, Research Funding. Duda:Bristol-Myers Squibb: Ended employment in the past 24 months. Cooper:Bristol-Myers Squibb: Ended employment in the past 24 months. Kitali:Bristol-Myers Squibb: Current Employment. Voorhees:Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy; Karyopharm: 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; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Lava Therapeutics: Consultancy; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding.