research summary

Optimized Step-Up Dosing Reduces Cytokine Release Syndrome with Elranatamab in Relapsed or Refractory Multiple Myeloma

Edited by:
Anthony Calabro, MA

Key Highlights:

  • Subcutaneous elranatamab demonstrated slower absorption and lower cytokine release syndrome risk than intravenous dosing across 4 MagnetisMM studies totaling 364 patients.
  • The 12/32-mg step-up priming regimen with premedication was identified as the optimal dosing strategy.
  • Fixed subcutaneous dosing was effective across body weights and baseline soluble BCMA levels.

In an analysis of 364 patients across 4 MagnetisMM trials, subcutaneous elranatamab administered with a 2-step-up priming regimen of 12 mg and 32 mg followed by a full 76-mg dose reduced the incidence of cytokine release syndrome to 57.9% for any-grade events and 14.2% for grade ≥2 events. Elmeliegy and colleagues determined this dosing approach as the optimal regimen for mitigating cytokine release syndrome (CRS) risk in patients with relapsed or refractory multiple myeloma.

Elranatamab, a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, is approved for the treatment of relapsed or refractory multiple myeloma. Cytokine release syndrome remains a common adverse event associated with T-cell–redirecting therapies. In a study published in Targeted Oncology, researchers analyzed data from multiple clinical trials to determine an elranatamab dosing regimen that minimizes CRS while maintaining therapeutic efficacy.

Researchers pooled safety, pharmacokinetic, and exposure–response data from four trials (MagnetisMM-1, MagnetisMM-2, MagnetisMM-3, and MagnetisMM-9) encompassing 364 patients with relapsed or refractory multiple myeloma. The analysis compared intravenous and subcutaneous elranatamab administration and evaluated three priming regimens before the first full dose of 76 mg on day 8: a 1-step-up regimen (44 mg), a 2-step-up regimen (12 mg on day 1 and 32 mg on day 4), and a 2-step-up regimen (4 mg on day 1 and 20 mg on day 4). All priming regimens included premedication in select cohorts. CRS and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per established guidelines. Logistic regression modeling assessed the relationship between elranatamab exposure and CRS incidence, with baseline body weight and soluble BCMA (sBCMA) evaluated as covariates.

Study Findings

The maximum serum concentration (Cmax) of elranatamab on day 1 was positively correlated with the likelihood of any-grade and grade ≥2 CRS. Subcutaneous dosing resulted in slower absorption, lower dose-normalized Cmax, and delayed time to peak concentration compared with intravenous dosing, supporting its use to mitigate CRS.

Among the priming regimens studied, the 12/32-mg 2-step-up regimen with premedication produced any-grade and grade ≥2 CRS rates of 57.9% and 14.2%, respectively, aligning with exposure–response model predictions. In contrast, the one-step-up regimen without premedication led to CRS in all patients. Recurrent CRS was more frequent with the lower 4/20-mg regimen, indicating inadequate early immune priming. ICANS occurred in 3.3% of patients treated with the 12/32-mg regimen and in 4.7% of those treated with the 4/20-mg regimen, with all events grade 3 or lower. Neither baseline body weight nor sBCMA level significantly affected CRS incidence or severity.

Clinical Implications

According to the study authors, subcutaneous administration of elranatamab, combined with a 2-step-up priming regimen and premedication, reduces the incidence and severity of CRS while maintaining a predictable and manageable safety profile. The 12/32-mg regimen with premedication before the first full 76-mg dose was identified as the optimal dosing approach for patients with relapsed or refractory multiple myeloma and was selected for subsequent studies.

The authors noted that some cohorts included a limited number of patients and that the incidence of certain adverse events, particularly ICANS, was low. Additionally, the different priming regimens were not compared through randomization. However, baseline characteristics were generally balanced between groups.

Expert Commentary

“Based on the incidence, severity, and predictable profile of cytokine release syndrome, the 12/32-mg priming-dose regimen with premedication was determined to be the optimal regimen before the first full dose of 76 mg on day 8,” the researchers concluded.

Reference:
Elmeliegy M, Viqueira A, Vandendries E, et al. Dose optimization of elranatamab to mitigate the risk of cytokine release syndrome in patients with multiple myeloma. Targeted Oncol. 2025;20:349-359. doi:10.1007/s11523-025-01064-5