A clinical overview of infection in patients receiving elranatamab (ELRA) in combination with daratumumab (DARA) and lenalidomide (R) for newly diagnosed multiple myeloma in the MagnetisMM-6 trial

Abstract Background MagnetisMM-6 (NCT05623020) is an open-label, 2-arm, randomized, phase 3 study evaluating ELRA in combination with DARA and R (EDR) versus DARA, R, and dexamethasone (DRd) in patients (pts) with transplant-ineligible (TI) or -deferred (TD) newly diagnosed multiple myeloma (NDMM). Initial results from the dose-finding phase showed early and promising efficacy with a predictable safety profile in TI pts with NDMM (Quach et al. J Clin Oncol 2025). Pts with active MM are particularly vulnerable to infections early in treatment before effective disease control is achieved. Understanding the infection profile during this period – especially with the EDR combination, which has overlapping infectious and hematological adverse events (AEs) – is critical to guide prophylaxis and early intervention. Here, we describe the characteristics of infections observed in pts who received EDR at the recommended phase 3 dose (RP3D) in the dose-finding Part 1 of MagnetisMM-6. Methods In dose level G (DLG), eligible pts had TI (age ≥65 or <65 y with comorbidities impacting the possibility of transplant) NDMM per IMWG criteria, an ECOG performance status ≤2, and adequate liver, renal, and bone marrow function. Pts received subcutaneous (SC) ELRA monotherapy (Cycle [C]0) as a priming regimen (12 mg D1 and 32 mg D4), followed by ELRA 76 mg on D8, then ELRA 76 mg SC every 4 weeks (Q4W) starting on C1D1; DARA 1800 mg SC weekly (D1, D8, D15, D22 in C1-C2), every 2 weeks (D1, D15 in C3-C6), and Q4W (D1 in C7+); and oral R 25 mg daily on D1-D21 in 28-day cycles. This schedule is the RP3D for MagnetisMM-6 with the exception that in the phase 3 DARA will be stopped after 12 cycles if the pt is in CR. Anti-infective prophylaxis and immunoglobulin (Ig) replacement when functional (ie, excluding the M-spike in pts with IgG myeloma) IgG levels are <400 mg/dL should be administered. Results In DLG, 37 pts with TI NDMM received ≥1 dose of ELRA; 34 pts received the EDR combination. As of April 1, 2025 (data cutoff) and with a median (range) follow-up of 7.85 (1.22-9.49) months, infections were reported in 70.3% of pts (grade [G] 3, 18.9%; no G4). One pt (2.7%) had a G5 AE of Candida pneumonia in C1. The most frequent (any G ≥10%) infections (any G; G3) were upper respiratory tract infection (21.6%; 0%), pneumonias (clustered) (16.2%; 8.1%), and Escherichia urinary tract infection (10.8%; 2.7%). The overall exposure-adjusted event rate (95% CI) of G ≥3 infections was 0.06 (0.03, 0.10) events per month, 0.10 (0.05, 0.18) and 0.02 (0.004, 0.06) with and without hypogammaglobulinemia (ie, IgG <400 mg/dL), respectively. The median (range) time to onset of any G and G ≥3 infections was 37.5 (1-141) and 42.5 (4-137) days, respectively, with the majority (56.8%) of first infections occurring within 8 weeks of starting treatment. Overall, infections occurred early after treatment initiation and tended to decrease over time for those still being followed for AEs in each cycle. The proportion of pts with any G/G3 infections in each cycle was 35.1%/5.4% in C1; 33.3%/8.3% in C2; 16.7%/5.6% in C3; 9.1%/6.1% in C4; 12.5%/3.1% in C5; 9.7%/0% in C6. Infections by pathogen type were 27.0% viral, 29.7% bacterial, 8.1% fungal, and 43.2% where the pathogen was unspecified. Anti-infectious prophylaxis (PJP, viral, fungal, and bacterial) was given to 83.8%, 81.1%, 16.2%, and 10.8% of pts, respectively. Overall, 83.8% of pts had ≥1 postbaseline IgG level <400 mg/dL and 91.9% received Ig replacement. At baseline, 29.7% of pts already had functional IgG levels <400 mg/dL. Among pts with functional IgG >400 mg/dL at baseline, the median (range) time to IgG <400 mg/dL prior to Ig replacement was 44.0 (14-73) days. The median (range) time to the first Ig replacement administration was 56.0 (9-219) days. G 3/4 neutropenia was reported in 73.0% of pts and 8.1% had febrile neutropenia; 73.0% received G-CSF. The median (range) time to the onset of the first G ≥3 neutropenia event and first G-CSF administration was 42.0 (3-179) and 36.0 (3-169) days, respectively. ConclusionsPatients with NDMM are prone to infections due to both disease- and treatment-related immunosuppression. Pts receiving EDR are at risk of developing infections, especially early in the treatment course, highlighting the need for appropriate screening, anti-infective prophylaxis including Ig replacement, close monitoring and prompt intervention.

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