Tumor Burden Does Not Impact CRS Risk with Elranatamab Combo in Myeloma

Disease status and tumor burden did not significantly impact the risk of cytokine release syndrome (CRS) among patients treated with elranatamab-bcmm (Elrexfio) plus daratumumab (Darzalex) and lenalidomide (Revlimid; EDR) for newly diagnosed or relapsed/refractory multiple myeloma, according to an analysis of part 1 of the phase 3 MagnetisMM-6 trial (NCT05623020) presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

Between patients with newly diagnosed (n = 77) vs relapsed/refractory (n = 40) disease, the rate of CRS was 57.1% vs 57.5%, with respective grade 3 rates of 1.3% and 2.5%. Additionally, among these patients, most events occurred following the first or second priming dose, which investigators noted was consistent with the overall population. The median time to CRS onset and resolution in the respective groups was 2.0 days (range, 1.0-6.0) vs 2.0 days (1.0-4.0) and 2.0 days (range, 1.0-9.0) vs 2.0 days (range, 1.0-9.0).

Furthermore, among patients classified as high (n = 21), intermediate (n = 26), or low tumor burden (n = 68), CRS events were reported in 47.6%, 57.7%, and 58.8% of patients, respectively. Additionally, 7.7% of the intermediate group experienced a grade 3 event, with no instances reported in the low or high tumor burden groups. Furthermore, relatively few CRS events occurred after the first full elranatamab dose (6.0%) or after the first dose of the EDR combination (6.8%).

The median time to CRS onset in the high, intermediate, and low tumor burden groups was 2.0 days (range, 2.0-3.0), 3.0 days (range, 1.0-6.0), and 2.0 days (range, 1.0-4.0), respectively. Moreover, the median time to resolution was 2.0 days (range, 1.0-6.0), 2.0 days (range, 1.0-9.0), and 2.0 days (range, 1.0-6.0), respectively.

“Disease status and tumor burden did not have an impact on the rate or severity of CRS with [elranatamab] alone or when used in the EDR combination,” Cyrille Touzeau, MD, PhD, professor of Hematology at the University Hospital Hôtel-Dieu in Nantes, France, and board member of Intergroupe Francophone du Myélome, wrote in the publication with study coinvestigators. “The CRS profiles observed overall and across the different subgroups were consistent with the profile observed for [elranatamab] monotherapy in [the phase 2] MagnetisMM-3 [trial (NCT04649359)].”

In part 1 of the MagnetisMM-6 trial, patients had newly diagnosed or relapsed/refractory multiple myeloma and were 65 years or older or younger than 65 with comorbidities impacting transplant feasibility. They also had received 1 or 2 prior lines of therapy for their disease, including 1 or more immunomodulatory drugs and proteasome inhibitors, an ECOG performance status of 0 to 2, and adequate liver, renal, and bone marrow function.

Treatment with elranatamab consisted of a subcutaneous formulation given as a priming agent during cycle 0 at 12 and 32 mg on days 1 and 4, respectively, followed by 76 mg on day 8. Combination therapy began on day 1 cycle 1 and included: subcutaneous elranatamab given at 76 mg weekly, biweekly, or every 4 weeks; subcutaneous daratumumab at 1800 mg weekly for cycles 1 and 2, biweekly for cycles 3 to 6, and every 4 weeks for cycles 7 and beyond; and oral lenalidomide given at 15 or 25 mg on days 1 to 21 of each 28-day cycle.

The severity of CRS was assessed via the American Society for Transplantation and Cellular Therapy criteria. Additionally, high tumor burden was identified as a bone marrow plasma cell (BMPC) concentration of 80% or greater, a serum M-spike of 5 g/dL or greater, and an involved free light chain (FLC) of at least 5000 mg/L. Low tumor burden was identified as: BMPC of less than 50%, a serum M-spike of less than 3 g/DL, and an involved FLC of less than 3000 mg/L. Those who did not meet the criteria for low or high tumor burden were categorized as intermediate.

In the MagnetisMM-3 trial, CRS occurred among 57.9% of patients with relapsed/refractory multiple myeloma, with 43.7%, 13.7%, and 0.5% experiencing grade 1, 2, and 3 events, respectively.² Most events occurred during step-up dosing, 43.2% and 19.1% of which occurred during doses 1 and 2, respectively, with fewer instances observed after the third (7.1%) and fourth (1.6%) full doses.

Reference

1. Touzeau C, Sia H, Grosicki S, et al. Impact of tumor burden on the risk of cytokine release syndrome (CRS) in patients with multiple myeloma treated with elranatamab (ELRA) in combination with daratumumab (DARA) and lenalidomide (R) in the MagnetisMM-6 trial. Blood. 2025;146(suppl 1):2283. doi:10.1182/blood-2025-2283
2. Niesvizky R, Arnulf B, Mohty M, et al. Clinical factors associated with cytokine release syndrome and dosing recommendations for restarting elranatamab following an interruption. Presented at: 2023 American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Poster 3384.