The CD3/BCMA bispecific antibody elranatamab demonstrated significant clinical activity in heavily pretreated multiple myeloma patients, achieving a 61.0% objective response rate in the phase 2 MagnetisMM-3 study. Results from cohort A, presented at the 2022 American Society of Hematology Annual Meeting, showed promising efficacy in patients with penta- or triple-class refractory disease who had not received prior B-cell maturation antigen (BCMA)-targeted therapy.
Clinical Efficacy and Response Characteristics
The study enrolled 123 patients with multiple myeloma refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody. Patients had received a median of 5.0 prior therapies, with 96.7% being triple-class refractory and 42.3% being penta-class refractory.
"Elranatamab is very efficacious and well tolerated in patients with relapsed/refractory multiple myeloma. Overall response rate is high at 61%, and it was early, deep, and durable," said lead investigator Nizar Jacques Bahlis, MD, from the Arnie Charbonneau Cancer Institute at the University of Calgary.
The treatment achieved deep responses, with 55.3% of patients reaching very good partial response or better and 27.6% achieving complete remission or better. Among the 22 patients who achieved complete remission, 90.9% demonstrated minimal residual disease negativity at a threshold of 10⁻⁵. The median time to response was rapid at 1.2 months.
Survival Outcomes and Duration of Response
Although median progression-free survival was not reached at the time of analysis, the 6-month and 12-month progression-free survival rates were 65.2% and 58.8%, respectively. Overall survival rates were 76.1% at 6 months and 63.6% at 12 months.
At the October 14, 2022 data cutoff, with a median follow-up of 10.4 months, the median duration of response had not been reached. Notably, 77.3% of responses remained ongoing, with a 9-month duration of response rate of 84.4%.
Dosing Strategy and Safety Profile
Patients received a step-up subcutaneous dosing regimen designed to mitigate adverse events. The protocol consisted of 12 mg on day 1 followed by 32 mg on day 4, then weekly 76 mg doses thereafter. This approach was implemented for 119 of the 123 patients, with premedication including acetaminophen, diphenhydramine, and dexamethasone administered prior to the first three doses.
The most commonly reported grade 3/4 treatment-emergent adverse events were hematologic, including neutropenia (48.0%), anemia (36.6%), lymphopenia (24.4%), and thrombocytopenia (22.0%). Non-hematologic grade 3/4 events included COVID-19 (11.4%) and hypokalemia (9.8%).
Cytokine Release Syndrome Management
The step-up dosing strategy proved effective in managing cytokine release syndrome (CRS), with 56.3% of patients experiencing CRS events that were all grade 1 or 2 in severity. Immune effector cell-associated neurotoxicity syndrome occurred in only 3.4% of patients. CRS events were predictable and occurred early, with 90.6% of cases during the step-up phase and 98.8% within the first three doses. The median time to CRS resolution was 2.0 days, with no treatment discontinuations due to these events.
"The step-up priming regimen successfully mitigated the rate and severity of CRS, and the CRS profile was predictable," Bahlis noted. "CRS events occurred early, with the majority limited to the step-up doses."
Regulatory Recognition and Future Development
The FDA granted elranatamab breakthrough therapy designation in November 2022, recognizing its potential to address significant unmet medical need in this patient population. Multiple phase 3 studies are now underway, including MagnetisMM-5 (NCT05020236), which is evaluating elranatamab as monotherapy and in combination with daratumumab for relapsed/refractory multiple myeloma, and MagnetisMM-7 (NCT05317416), examining the agent as maintenance therapy compared with lenalidomide in newly diagnosed patients.
