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

Overview

Journal Target Oncol

Specialty Oncology

Date 2025 Feb 25

PMID 40000533

Authors

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

Diane Wang

Affiliations

Soon will be listed here.

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.

References

Costa L, Hungria V, Mohty M, Mateos M . How I treat triple-class refractory multiple myeloma. Br J Haematol. 2022; 198(2):244-256. DOI: 10.1111/bjh.18185. View

Kumar S, Dimopoulos M, Kastritis E, Terpos E, Nahi H, Goldschmidt H . Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017; 31(11):2443-2448. DOI: 10.1038/leu.2017.138. View

Gandhi U, Cornell R, Lakshman A, Gahvari Z, McGehee E, Jagosky M . Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019; 33(9):2266-2275. PMC: 6820050. DOI: 10.1038/s41375-019-0435-7. View

Xiao X, Huang S, Chen S, Wang Y, Sun Q, Xu X . Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. J Exp Clin Cancer Res. 2021; 40(1):367. PMC: 8600921. DOI: 10.1186/s13046-021-02148-6. View

Holstein S, Grant S, Wildes T . Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future. J Clin Oncol. 2023; 41(27):4416-4429. PMC: 10522112. DOI: 10.1200/JCO.23.00512. View

Ball K, Dovedi S, Vajjah P, Phipps A . Strategies for clinical dose optimization of T cell-engaging therapies in oncology. MAbs. 2023; 15(1):2181016. PMC: 9980545. DOI: 10.1080/19420862.2023.2181016. View

Soltantabar P, Sharma S, Wang D, Lon H, Czibere A, Hickmann A . Impact of Treatment Modality and Route of Administration on Cytokine Release Syndrome in Relapsed or Refractory Multiple Myeloma: A Meta-Analysis. Clin Pharmacol Ther. 2024; 115(6):1258-1268. DOI: 10.1002/cpt.3223. View

Elmeliegy M, Chen J, Dontabhaktuni A, Gaudy A, Kapitanov G, Li J . Dosing Strategies and Quantitative Clinical Pharmacology for Bispecific T-Cell Engagers Development in Oncology. Clin Pharmacol Ther. 2024; 116(3):637-646. DOI: 10.1002/cpt.3361. View

Chen H, Li M, Xu N, Ng N, Sanchez E, Soof C . Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells. Leuk Res. 2019; 81:62-66. DOI: 10.1016/j.leukres.2019.04.008. View

10.

Su M, Chen L, Xie L, Fleurie A, Jonquieres R, Cao Q . Identification of early predictive biomarkers for severe cytokine release syndrome in pediatric patients with chimeric antigen receptor T-cell therapy. Front Immunol. 2024; 15:1450173. PMC: 11424402. DOI: 10.3389/fimmu.2024.1450173. View

11.

Gu T, Hu K, Si X, Hu Y, Huang H . Mechanisms of immune effector cell-associated neurotoxicity syndrome after CAR-T treatment. WIREs Mech Dis. 2022; 14(6):e1576. PMC: 9787013. DOI: 10.1002/wsbm.1576. View

12.

Lee D, Santomasso B, Locke F, Ghobadi A, Turtle C, Brudno J . ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2018; 25(4):625-638. DOI: 10.1016/j.bbmt.2018.12.758. View

13.

Neelapu S, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke F . Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2017; 15(1):47-62. PMC: 6733403. DOI: 10.1038/nrclinonc.2017.148. View

14.

Neelapu S . Managing the toxicities of CAR T-cell therapy. Hematol Oncol. 2019; 37 Suppl 1:48-52. DOI: 10.1002/hon.2595. View

15.

Martin T, Usmani S, Berdeja J, Agha M, Cohen A, Hari P . Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up. J Clin Oncol. 2022; 41(6):1265-1274. PMC: 9937098. DOI: 10.1200/JCO.22.00842. View

16.

Munshi N, Anderson Jr L, Shah N, Madduri D, Berdeja J, Lonial S . Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021; 384(8):705-716. DOI: 10.1056/NEJMoa2024850. View

17.

Martin T, Mateos M, Nooka A, Banerjee A, Kobos R, Pei L . Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma. Cancer. 2023; 129(13):2035-2046. DOI: 10.1002/cncr.34756. View

18.

Berdeja J, Madduri D, Usmani S, Jakubowiak A, Agha M, Cohen A . Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021; 398(10297):314-324. DOI: 10.1016/S0140-6736(21)00933-8. View

19.

Lim K, Zhu X, Zhou D, Ren S, Phipps A . Clinical Pharmacology Strategies for Bispecific Antibody Development: Learnings from FDA-Approved Bispecific Antibodies in Oncology. Clin Pharmacol Ther. 2024; 116(2):315-327. DOI: 10.1002/cpt.3308. View

20.

Wang D, Zhang S, Zhao H, Men A, Parivar K . Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009; 49(9):1012-24. DOI: 10.1177/0091270009337512. View