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 in patients (pts) with transplant-ineligible (TI) or -deferred (TD) newly diagnosed multiple myeloma (NDMM). Part 1 of the study was designed to evaluate various dose levels of the EDR combination in pts with TI NDMM or relapsed/refractory MM (RRMM) to select the phase 3 dose. Tumor burden has been associated with an increased incidence and severity of CRS and other neurological toxicities with certain T-cell redirecting therapies. The influence of tumor burden on ELRA CRS rate and severity has not been described. In MagnetisMM-3, CRS was reported in 57.7% of pts (n=123) treated with ELRA monotherapy (Lesokhin et al. Nat Med 2023). No CRS event was grade (G) ≥3. Most CRS events occurred with step-up doses 1 and 2 (44.5% and 20.2%, respectively); 15.1% of pts had a recurrent CRS event. Here, we present data on the risk of CRS, stratified by disease status (NDMM vs RRMM) and tumor burden (high vs intermediate vs low) in pts who were enrolled in the EDR cohorts in Part 1 of the MagnetisMM-6 trial.

Methods In Part 1 of the study, eligible pts had TI (age ≥65 or <65 years with comorbidities impacting the possibility of transplant) NDMM or RRMM (with 1-2 prior lines of MM therapy including ≥1 IMiD and ≥1 proteasome inhibitor) per IMWG criteria; ECOG performance status ≤2; and adequate liver, renal, and bone marrow function. Part 1 of the study evaluated the EDR combination across multiple dose-level cohorts. All pts across all dose levels received the same initial dose of subcutaneous (SC) ELRA (Cycle [C] 0) as a priming regimen (12 mg day [D] 1 and 32 mg D4), followed by ELRA 76 mg SC on D8 with the combination starting on C1D1. Starting with C1, SC ELRA 76 mg was given weekly (QW), every 2 weeks (Q2W), or every 4 weeks (Q4W), DARA 1800 mg SC given QW (D1, D8, D15, D22 in C1-C2), Q2W (D1, D15 in C3-C6), and Q4W (D1 in C7+), and oral R 15 or 25 mg was given daily on D1-D21 of each 28-day cycle. The CRS and ICANS severity was assessed according to the American Society for Transplantation and Cellular Therapy criteria. High tumor burden was defined as having any of the following: bone marrow plasma cells (BMPCs) ≥80%, serum M-spike ≥5 g/dL, or involved free light chain (FLC) ≥5000 mg/L. Low tumor burden was defined as having all of the following: BMPC <50%, serum M-spike <3 g/dL, and involved FLC <3000 mg/L. Pts not meeting the criteria for high or low tumor burden were categorized as intermediate. Data cutoff was Dec 23, 2024 with last pt first dose Oct 7, 2024.

Results A total of 117 pts were enrolled in the EDR cohorts. Overall, 57.3% of pts developed CRS; 41.0% were G1, 14.5% were G2, and 1.7% were G3. There were no G4 or G5 CRS events. Most CRS events occurred after the first or second priming dose (48.7% and 14.5%, respectively). Few CRS events occurred after the first full dose of ELRA (5.1%); 6.8% of pts developed CRS after the first dose of EDR and 15.4% had >1 CRS event. Tocilizumab was used to treat CRS in 33 (28.2%) pts and 2 (1.7%) pts received tocilizumab during the priming period, but not for treatment of a CRS event.

In pts with NDMM (n=77) and RRMM (n=40), CRS was reported in 57.1% (1.3% G3; 16.9% recurring) and 57.5% (2.5% G3; 12.5% recurring) of pts, respectively. In pts with high (n=21), intermediate (n=26), and low (n=68) tumor burden, CRS was reported in 47.6% (0% G3; 14.3% recurring), 57.7% (7.7% G3; 26.9% recurring), and 58.8% (0% G3; 11.8% recurring) of pts, respectively. Across cohorts, the CRS profile was consistent with that of the overall population; most events occurred with the first and second doses of ELRA; few events occurred with the first full ELRA dose or the first EDR dose.

Among the 117 pts, 2 developed ICANS, both events occurred in pts with NDMM and low tumor burden.

Conclusions Disease status and tumor burden did not have an impact on the rate or the severity of CRS. The CRS profile observed overall and across the different subgroups was consistent with the profile observed with ELRA monotherapy in MagnetisMM-3. These data demonstrate that debulking prior to ELRA administration is not needed, which may be especially important in pts with NDMM. In the absence of prophylactic tocilizumab, ELRA continues to demonstrate a predictable CRS profile with most events being low grade and occurring during step-up dosing.

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2025
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