Efficacy of Elranatamab (ELRA) in Combination with Carfilzomib (CFZ) and Dexamethasone (DEX) in the Phase 1b MagnetisMM-20 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)

BACKGROUND ELRA, a bispecific antibody targeting B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, induced deep and durable responses with a manageable safety profile in the phase 2 registrational MagnetisMM-3 study (NCT04649359) in patients (pts) with RRMM and no prior BCMA-directed therapy (Lesokhin et al, Nat Med 2023). Combining ELRA with CFZ, which has been shown to inhibit myeloma cell proliferation and survival, may enhance activation of immune surveillance of MM cells through different and complementary mechanisms. Here we present results from part 1 of MagnetisMM-20 (NCT05675449), a Phase 1b, open-label, non-randomized study of ELRA + CFZ + DEX. METHODS Eligible pts (≥ 18 years) had MM relapsed or refractory to their last anti-MM therapy, 1-3 prior lines of therapy, Eastern Cooperative Oncology Group performance status ≤1, and no prior BCMA-directed therapy. Prior CFZ treatment (tx) was allowed if the pt had ≥PR to most recent CFZ-containing therapy, CFZ was not discontinued due to toxicity, and the pt did not relapse ≤60 days after CFZ discontinuation and had ≥6 month CFZ-free interval before study tx. Pts received a priming dose regimen (cycle 0) consisting of premedication and 2 step-up priming doses of subcutaneous ELRA (12 mg on day 1 and 32 mg on day 4) before the first full dose of ELRA on day 8, either 44 mg (dose level [DL] 1) or 76 mg (DL2) ELRA. ELRA was then given once weekly (QW) and in combination only after the first full dose of ELRA was administered in cycle 0. Pts who receive ≥6 months of QW dosing and achieve ≥ partial response lasting at least 2 months will be transitioned to a once every 2 weeks (Q2W) dosing schedule. Pts received 20 and 70 mg/m2 CFZ intravenously on days 1 and 8 of cycle 1, followed by 70 mg/m2 on days 1, 8 and 15 of each 4-week cycle, and 40 mg DEX either orally or intravenously QW. Tx will continue until disease progression, unacceptable toxicity, withdrawal of consent or study termination. The primary endpoint is dose limiting toxicities (DLTs) from cycle 0 day 1 through the end of cycle 1 (a total of 42 days). Secondary safety endpoints include adverse events and laboratory abnormalities graded using the NCI CTCAE (version 5.0). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) severity were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Secondary efficacy endpoints include best overall response, objective response rate (ORR), complete response rate, time to response (TTR), duration of response (DOR) and progression-free survival (PFS) (all per International Myeloma Working Group criteria), and overall survival (OS). RESULTS Of the 12 treated pts in part 1, the median age was 66.0 years (range, 45.0-80.0), 8 (66.7%) were male, none had extramedullary disease, 3 (25.0%) had high-risk cytogenic abnormalities, 4 (33.3%) had ISS stage III, and 8 (66.7%) had <30% baseline bone marrow plasma cells. Eight pts (66.7%) had Revised International Staging System disease stage I or II (unknown for 2 pts [16.7%]). Pts had a median of 2 prior lines of therapy (range, 1-3), and 41.7% had triple-class refractory disease. No pts had a stem cell transplant. At the time of data cutoff (February 22, 2024), 91.7% of pts were ongoing ELRA and CFZ tx, with DEX tx ongoing in 66.7% of pts. Median tx duration was 3.15 months (range, 0.56-13.37). Among the 10 pts evaluable for DLTs, none were reported at DL1 or DL2. In the safety analysis population (n=12), the most common adverse events (any grade [≥50%], grade 3/4 [≥10%]) were fatigue (83.3%, 8.3%), CRS (75.0%, 0%), neutropenia (58.3%, 33.3%), thrombocytopenia (58.3%, 25.0%), injection site reaction (50.0%, 0%), leukopenia (50.0%, 16.7%), anemia (41.7%, 25.0%), lymphopenia (33.3%, 25.0%), peripheral edema (33.3%, 16.7%), increased blood alkaline phosphatase (25.0%, 16.7%), and pulmonary embolism (16.7%, 16.7%). Infections were reported in 75.0% of the pts, all grade 1/2. No ICANS was reported in any pt. At a median follow-up of 3.24 months (range, 1.51-13.47), the unconfirmed ORR by investigator was 100%. Ten pts (83.3%) had confirmed ORR by investigator with a median TTR of 1.41 months (95% CI, 0.53-3.35). Median DOR was not reached. CONCLUSIONS ELRA + CFZ + DEX has demonstrated clinical efficacy and predictable safety signals. The study continues enrolling and will explore the combination of ELRA + CFZ + DEX in a larger group of pts.