Elranatamab, a BCMA Targeted T-Cell Engaging Bispecific Antibody, Induces Durable Clinical and Molecular Responses for Patients with Relapsed or Refractory Multiple Myeloma

Introduction: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by expression of B-cell maturation antigen (BCMA). Elranatamab (PF-06863135), a bispecific antibody that targets BCMA and CD3 on T-cells, activates and redirects the T-cell mediated immune response against MM. This clinical trial, MagnetisMM-1 (NCT03269136), is the ongoing Phase 1 first-in-human study evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of elranatamab for patients (pts) with relapsed or refractory MM. Methods: Elranatamab was administered subcutaneously (SC) at doses from 80 to 1000µg/kg either weekly or every 2 weeks. Treatment-emergent adverse events (TEAEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (v4.03), whereas cytokine release syndrome (CRS) was assessed by criteria of the American Society for Transplantation and Cellular Therapy. PK, cytokines, lymphocyte subsets, and soluble BCMA were analyzed over time. Clinical response was assessed by criteria of the International Myeloma Working Group (IMWG). Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10-5 in accordance with IMWG criteria. Results: A total of 55 pts received single-agent elranatamab SC at a dose ≥215μg/kg as of 22-Jun-2022. Median age was 64 (range 42-80) years, and 27% of pts were Black/African American or Asian. Median number of prior regimens was 5 (range 2-14), 91% were triple-class refractory, 69% had prior stem cell transplantation, 29% had high cytogenetic risk, and 24% received prior BCMA-targeted therapy. The most common TEAEs regardless of causality included CRS, neutropenia, anemia, injection site reaction, and lymphopenia. With pre-medication and a single priming dose (600µg/kg or 44mg), the overall incidence of CRS at the recommended dose (1000µg/kg or 76mg) was 67% and limited to Grade 1 (33%) or Grade 2 (33%), with no events Grade 3 or higher. Elranatamab exposure was dose dependent. Cytokine increases occurred with the first dose and were reduced by pre-medication. Soluble BCMA decreased with disease response, elranatamab therapy was associated with increased peripheral T-cell proliferation, and median time to response was 36 days (range 7-262). With a median follow-up of 12.0 months (range 0.3-29.0) and including only IMWG confirmed responses, the objective response rate (ORR) was 64% (95% CI 50-75%) with 56% of pts (31/55) achieving very good partial response (VGPR) or better and 38% of pts (21/55) achieving complete response (CR) or better. Among 13 pts with prior BCMA-directed therapy (antibody drug conjugate, chimeric antigen receptor T-cell therapy, or both), 54% (7/13) achieved response including 46% (6/13) with VGPR or better. For responders (n=35), the probability of being event-free at 12 months was 59% (95% CI 39-74%) and the Kaplan-Meier estimate for median duration of response was 17.1 months (95% CI 10.6-NE). Single-agent elranatamab induced durable clinical and molecular responses, and 100% (12/12) of evaluable pts with confirmed CR or better achieved MRD negativity at a sensitivity of 1×10-5 including 2 pts with MRD negativity and ongoing stringent CR beyond 2 years. Conclusions: Elranatamab induced durable clinical and molecular responses for pts with relapsed or refractory MM. The ORR was 64% with more than half of these pts (38%) achieving CR or better, and 100% of evaluable pts achieved MRD negativity. Together with emerging data from pivotal studies MagnetisMM-3 (NCT0469359) and MagnetisMM-5 (NCT05020236), these results support further development of elranatamab for patients with MM.