Background: Elranatamab (ELRA), a bispecific antibody targeting BCMA and CD3, has demonstrated clinical efficacy in relapsed/refractory multiple myeloma (RRMM) with an overall response rate of 61% in the MagnerisMM-3 trial. However, real-world evidence on safety and outcomes remains limited. Given the differences between clinical trial populations and real-world patients, this analysis addresses a critical knowledge gap in understanding ELRA's effectiveness and toxicity profile in routine clinical practice. This study evaluated real-world survival and adverse events associated with ELRA therapy using a large, multi-institutional electronic health record database.

Methods: We conducted a multicenter retrospective cohort study using the TriNetX Global Health Research Network to identify patients with relapsed/refractory multiple myeloma (RRMM) who received Elranatamab therapy from database inception through June 2025. The analysis included data from 172 million patients across 151 healthcare organizations worldwide, predominantly academic centers in the U.S. Eligible patients had a confirmed RRMM diagnosis, documented Elranatamab exposure, and at least 30 days of follow-up. Patients were selected based on diagnosis and drug exposure codes. Key outcomes included all-cause mortality, grade ≥3 cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicities. Kaplan-Meier analysis was used to estimate 6-month overall survival (OS), and toxicities were graded according to CTCAE v5.0.

Results: A total of 124 RRMM patients treated with ELRA were identified. The mean age was 68 years (±9); 53.2% were male, and 61.3% identified as White. Treatment exposure patterns indicated a heavily pretreated, triple-class refractory population: proteasome inhibitors (bortezomib 61%, carfilzomib 47%), IMiDs (lenalidomide 67%, pomalidomide 69%), and anti-CD38 monoclonal antibodies (daratumumab 67%). Additional therapies included CAR T-cell therapy (8%), autologous stem cell transplant (23%), Belantamab mafodotin (8%), Talquetamab (10%), and Teclistamab (8%). High-risk disease features were observed, with extramedullary disease in 9% and plasma cell leukemia in 11% of patients. At six months, the all-cause mortality rate was 22.6%, and the Kaplan-Meier estimated OS probability was 74.2% (95% CI: 65.8% – 81.1%). Median overall survival was not reached at 6-month follow-up. Grade ≥3 CRS and ICANS occurred in <10 patients each (8%), consistent with low rates reported in MagnetisMM-3. Tocilizumab was used in 21% of patients. Hematologic toxicities were common: grade ≥3 neutropenia (49.2%), anemia (46.0%), and thrombocytopenia (32.3%). Any grade Infections included Upper respiratory Tract infection (11%), Urinary Tract Infection (8%), Skin and soft tissue infection (8%), influenza/pneumonia (16%), severe sepsis (10%), and CMV reactivation (8.1%).

Conclusion: In comparison to the MagnetisMM-3 trial, this real-world analysis confirms the manageable immune toxicity profile of ELRA, with similarly low rates of grade ≥3 CRS and ICANS. However, the higher 6-month mortality (22.6%) observed in this cohort may reflect broader patient inclusion, including those with significant comorbidities and prior BCMA-directed therapies. Hematologic and infectious toxicities were substantial, reinforcing the need for enhanced monitoring and supportive care strategies in routine clinical use.

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2025
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