Safety and efficacy of elranatamab + nirogacestat in patients with relapsed or refractory multiple myeloma: Results from the Phase 1b MagnetisMM-4 study

Abstract Background Elranatamab (ELRA) is a bispecific antibody (BsAb) targeting B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells. In the phase 2 MagnetisMM-3 study (NCT04649359), ELRA demonstrated deep, durable responses (objective response rate [ORR] 61.0%) with manageable safety in patients (pts) with relapsed or refractory multiple myeloma (RRMM) and no prior BCMA-directed therapy (Lesokhin et al, Nat Med 2023). MagnetisMM-4 (NCT05090566) is a phase 1b/2 umbrella trial evaluating ELRA in combination with other anti-cancer treatments for pts with MM. Gamma-secretase inhibitors (GSIs) block BCMA cleavage, potentially enhancing efficacy of BCMA-directed therapy (Pont et al, Blood 2019). Here, we present phase 1b safety, tolerability, and dose optimization results from MM-4 sub-study A evaluating ELRA plus the GSI nirogacestat (NIRO) in pts with RRMM. Methods Eligible pts (age ≥18 years) for sub-study A had ≥3 prior lines of therapy, RRMM refractory to ≥1 immunomodulatory drug, ≥1 proteasome inhibitor, and ≥1 anti-CD38 antibody, ECOG performance status ≤1, adequate liver, renal and bone marrow function, and no prior BCMA-BsAb treatment. Dose escalation followed a Bayesian logistic regression model. Dose level (DL) 1 pts received a 4-mg ELRA priming dose subcutaneously on day (D) 1, cycle (C) 0, then 4 mg weekly (QW) from C1D1, in 28-day cycles. DL2 pts received 2 step-up priming doses of ELRA 4/8 mg on C0D1/D4, then 12 mg QW from C1D1. DL3 pts received ELRA 12/32 mg on C0D1/D4, then 32 mg QW from C1D1. All DL1-DL3 pts received NIRO 100 mg orally twice daily from C1D1. In DL3A, ELRA dosing matched DL3 but NIRO was reduced to 100 mg once daily (QD). DL4A pts received ELRA 12/32 mg on C0D1/D4, then 76 mg QW from C1D1, with NIRO 100 mg QD. The primary endpoint was dose-limiting toxicities (DLTs) in C0 and C1, approximately 35 days after the initial dose. Secondary endpoints included safety and efficacy measures including ORR and complete response rate (CRR) per IMWG criteria by investigator. Results Pts in DL1 (n=2), DL2 (n=6), DL3 (n=10), DL3A (n=10) and DL4A (n=6) had a median (range) age of 61.0 (59-63), 55.0 (42-67), 68.0 (44-78), 69.5 (59-80), and 67.5 (57-79) years, respectively. Zero, 1 (16.7%), 2 (20.0%), 2 (20.0%), and 0 pts in DL1-DL4A had R-ISS stage III disease; high-risk cytogenetics [any of the following chromosomal abnormalities t(4;14), t(14;16), del(17p)] were present in 0, 2 (33.3%), 5 (50.0%), 3 (30.0%), and 3 (50.0%) pts. Median (range) prior lines of therapy (LOTs) were 5.5 (5-6), 3.5 (3-5), 5.0 (4-12), 5.0 (3-11), and 5.0 (4-8). DLTs were evaluable in 2 (100%), 4 (66.7%), 8 (80.0%), 7 (70.0%) and 5 (83.3%) pts in DL1 to DL4A and 6 DLTs were reported in 2 dose levels. In DL3, DLTs were reported in 4 (50.0%) pts, including 1 pt with grade (G) 3 pneumonia, 2 pts with G3 diarrhea, and 1 pt with G3 fatigue and G4 neutropenia. In DL4A, DLTs were reported in 2 (40.0%) pts (1 pt with G3 diarrhea, 1 pt with G3 decreased appetite and G3 dehydration). The optimal dose level for the combination with no DLT was identified as DL3A (32 mg QW ELRA + 100 mg QD NIRO). At data cutoff (March 14, 2025), the median (range) duration of treatment was 11.1 (11.1-11.1), 19.1 (1.9-161.3), 34.4 (3.7-115.4), 20.4 (5.0-39.3) and 12.8 (5.0-19.0) weeks; ELRA/NIRO treatment was ongoing in 0, 2 (33.3%), 2 (20.0%), 4 (40.0%), and 4 (66.7%) pts from DL1 to DL4A. TEAEs were reported in 100% of pts (G3/4 73.5%). The most frequent TEAEs (any grade ≥40%) were diarrhea (64.7%, G3/4 23.5%), neutropenia (58.8%, G3/4 52.9%), infections (55.9%, G3/4 14.7%), anemia (47.1%, G3/4 29.4%), cytokine release syndrome (47.1%, G3/4 0%), thrombocytopenia (41.2%, G3/4 29.4%), hypokalemia (41.2%, G3/4 23.5%), and nausea (41.2%, G3/4 11.8%). Immune effector cell-associated neurotoxicity syndrome occurred in 5.9% (G1 only) of pts. With a median follow-up of 8.5 (95% CI, 3.8-20.4) months, estimated by reverse Kaplan-Meier, ORR (95% CI) was 61.8% (43.6-77.8) overall; 50.0% (1.3-98.7) for DL1, 50.0% (11.8-88.2) for DL2, 70.0% (34.8-93.3) for DL3, 60.0% (26.2-87.8) for DL3A, and 66.7% (22.3-95.7) for DL4A. CRRs (95% CI) were 0.0% (0.0-84.2), 33.3% (4.3-77.7), 40.0% (12.2-73.8), 30.0% (6.7-65.2), and 16.7% (0.4-64.1), respectively. Conclusions Across 5 evaluated dose levels, the combination of ELRA plus NIRO yielded response rates of 50.0% to 70.0%. These initial results suggest careful evaluation is warranted when combining BCMA-targeted BsAbs with a GSI.