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Clinical Trial
. 2025 Mar;20(2):349-359.
doi: 10.1007/s11523-025-01134-8. Epub 2025 Feb 25.

Dose Optimization of Elranatamab to Mitigate the Risk of Cytokine Release Syndrome in Patients with Multiple Myeloma

Mohamed Elmeliegy  1 , Andrea Viqueira  2 , Erik Vandendries  3 , Anne Hickman  4 , Umberto Conte  5 , Donald Irby  6 , Jennifer Hibma  6 , Hoi-Kei Lon  7 , Joseph Piscitelli  7 , Pooneh Soltantabar  7 , Athanasia Skoura  5 , Sibo Jiang  7 , Diane Wang  7
Affiliations
Clinical Trial

Dose Optimization of Elranatamab to Mitigate the Risk of Cytokine Release Syndrome in Patients with Multiple Myeloma

Mohamed Elmeliegy et al. Target Oncol. 2025 Mar.

Abstract

Background: Elranatamab is a BCMA-CD3 bispecific antibody approved for the treatment of relapsed or refractory multiple myeloma. Cytokine release syndrome is one of the most common adverse events associated with bispecific antibodies.

Objective: We aimed to determine the optimal elranatamab dosing regimen for mitigating cytokine release syndrome.

Patients and methods: Safety, pharmacokinetics, and exposure-response were analyzed across four clinical studies (MagnetisMM-1, MagnetisMM-2, MagnetisMM-3, and MagnetisMM-9). Different priming regimens evaluated across these studies included a one-step-up dose priming regimen of 44 mg with or without premedication, a two-step-up dose priming regimen of 12 mg on day 1 and 32 mg on day 4 with premedication, and a two-step-up dose priming regimen of 4 mg on day 1 and 20 mg on day 4 with premedication.

Results: The maximum elranatamab serum concentration on day 1 was positively associated with any-grade and grade ≥ 2 cytokine release syndrome. A slower time to maximum serum concentration and a lower dose-normalized maximum serum concentration were observed with subcutaneous versus intravenous administration, supporting subcutaneous dosing to help mitigate cytokine release syndrome.

Conclusions: 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.

Clinical trial registration: ClinicalTrials.gov identifiers: NCT03269136, NCT04798586, NCT04649359, and NCT05014412.

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Conflict of interest statement

Declarations. Funding: This study was funded by Pfizer. Conflicts of interest/competing interests: Mohamed Elmeliegy, Andrea Viqueira, Erik Vandendries, Anne Hickman, Umberto Conte, Donald Irby, Jennifer Hibma, Hoi-Kei Lon, Joseph Piscitelli, Pooneh Soltantabar, Athanasia Skoura, Sibo Jiang, and Diane Wang report employment and stock ownership at Pfizer. Ethics approval: All studies reported here were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization guidelines for Good Clinical Practice. The study protocols and relevant documents were approved by independent institutional review boards or ethics committees at each investigative center. Consent to participate: All patients provided written informed consent. Consent for publication: Not applicable. Availability of data and material: Upon reasonable request and subject to review, Pfizer will provide the data that support the findings of this article. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizeroncologydevelopment.com/trials for more information. Code availability: Not applicable. Authors’ contributions: All authors were involved in the trial conception/design, or the acquisition, analysis, or interpretation of data. All authors contributed to the drafting of the manuscript and approved the final version.

Figures

Fig. 1
Fig. 1
Relationship between elranatamab exposure and cytokine release syndrome (CRS) based on data from patients treated with elranatamab in MagnetisMM-1. Two binomial logistic regression analyses, one for any-grade CRS and another for grade ≥ 2 CRS, were performed. The gray solid line and the gray shaded area represent the median and 95% confidence interval predicted probability of any-grade CRS. The orange solid line and the orange shaded area represent the median and 95% confidence interval predicted probability of grade ≥ 2 CRS. Vertical (dashed) lines represent the geometric mean maximum elranatamab serum concentration on day 1 (Cmax-24h) at the corresponding doses of 4 mg (blue), 12 mg (green), and 44 mg (red), respectively. Rug lines on the top and bottom of the plot indicate Cmax-24h values for participants who did (top) and did not (bottom) experience CRS. American Society for Transplantation and Cellular Therapy grading was used for CRS and immune effector cell-associated neurotoxicity syndrome grading for all cohorts except the intravenous cohort where the Common Terminology Criteria for Adverse Events criteria (Lee et al., 2014) grading system [37] was used because American Society for Transplantation and Cellular Therapy grading was not available
Fig. 2
Fig. 2
Cytokine release syndrome (CRS) profile in patients who received a 1-step-up dose priming regimen of 44 mg without (A) or with (B) premedication or the 2-step-up dose priming regimen of 12/32 mg with premedication (C) or 4/20 mg with premedication (D). Sankey plot demonstrating the CRS profile in patients who received a 1-step-up dose priming regimen of 44 mg of elranatamab either with or without premedication or a 2-step-up dose priming regimen of either 12 and 32 mg or 4 and 20 mg with premedication. G grade
Fig. 3
Fig. 3
Cytokine release syndrome (CRS) profile per body weight quartiles (A) and per baseline soluble B-cell maturation antigen (sBCMA) levels (B) in patients who received the 12/32-mg priming regimen. Sankey plots demonstrating the CRS profile in patients with varying baseline body weights using quartiles (quartile 1, < 62 kg; quartile 2, 62 to < 72 kg; quartile 3, 72 to < 84.5 kg, quartile 4, ≥ 84.5 kg) and varying baseline sBCMA levels (quartile 1, free baseline sBCMA < 13.9 ng/mL; quartile 2, 13.9 to < 48.3 ng/mL; quartile 3, 48.3 to < 149 ng/mL; quartile 4, ≥ 149 ng/mL) who received a 2-step-up dose priming regimen of either 12 and 32 mg or 4 and 20 mg with premedication. G grade
Fig. 3
Fig. 3
Cytokine release syndrome (CRS) profile per body weight quartiles (A) and per baseline soluble B-cell maturation antigen (sBCMA) levels (B) in patients who received the 12/32-mg priming regimen. Sankey plots demonstrating the CRS profile in patients with varying baseline body weights using quartiles (quartile 1, < 62 kg; quartile 2, 62 to < 72 kg; quartile 3, 72 to < 84.5 kg, quartile 4, ≥ 84.5 kg) and varying baseline sBCMA levels (quartile 1, free baseline sBCMA < 13.9 ng/mL; quartile 2, 13.9 to < 48.3 ng/mL; quartile 3, 48.3 to < 149 ng/mL; quartile 4, ≥ 149 ng/mL) who received a 2-step-up dose priming regimen of either 12 and 32 mg or 4 and 20 mg with premedication. G grade
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