An Indirect Comparison of Elranatamab's Progression-Free Survival, Duration of Response, and Overall Survival from MagnetisMM-3 Versus Real-World External Control Arms in Triple-Class Refractory Multiple Myeloma

BACKGROUND Elranatamab(ELRA) is a BCMAxCD3 bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (MM) in the United States, Europe, and several additional countries. The registrational phase 2 MagnetisMM-3 (MM-3; NCT04649359) trial was single-armed. The efficacy of ELRA in the MM-3 trial was previously contextualized with real-world (RW) data in prior publications (eg, Costa et al 2024). The aim of this study was to update these comparisons with RW data leveraging more mature MM-3 and RW data. METHODS We conducteda retrospective cohort study to indirectly compare the efficacy observed in MM-3 Cohort A (BCMA-naïve; N=123) from the 26 March 2024 data cut (representing approximately 28 months of follow-up) with COTA, a US-based oncology electronic health record database, as an external control. All MM patients with triple-class refractory disease who initiated a new line of therapy (representing RW physician's choice) between November 2015 and August 2023 in the COTA database were preliminarily included. MM-3 inclusion (eg, ≥18 years, measurable disease within 90 days of the index, ECOG ≤ 2) and exclusion (I/E) criteria (eg, plasma cell leukemia, smoldering MM) were then applied to obtain comparable patient populations across sources. After imposing MM-3 I/E criteria, we conducted comparisons between the ELRA from MM-3 and physician's choice of treatment from COTA on progression-free survival (PFS), duration of response (DOR), and overall survival (OS) using Cox proportional hazard models (“unweighted analyses”). We used additional Cox proportional hazard models implementing inverse probability of treatment weighting (IPTW) to adjust for any remaining imbalances across cohorts on confounding variables (ie, age, comorbidities, Eastern Cooperative Oncology Group (ECOG) score, International Staging System (ISS), prior lines/refractoriness, cytogenetic risk, extramedullary disease, and lab values) (“adjusted analyses”). RESULTS N=123 patients from MM-3 Cohort A were compared with the 577 patients identified from the COTA database. Age (67.1 vs 67.2 years), sex (55.3% vs 53.9% male), ECOG (36.6% vs 31.4% had a performance score of 1), high-risk cytogenetics (25.2% vs 28.6%), mean number of prior LOTs (5.2 vs 4.8) were comparable between arms, respectively (all p=ns). However, patients treated with ELRA had fewer patients with ISS stage III among those with non-missing ISS data (22.6% vs 28.5%) and higher rates of extramedullary disease (30.9% vs 16.8%) than patients treated with RW physician's choice (both p<.05). Across unweighted analyses, ELRA was associated with significantly longer PFS (hazard ratio [HR] = 0.49 [95% confidence interval [CI]: 0.37, 0.65], p<.05) than RW physicians' choice of treatment. Similarly, ELRA was associated with significantly longer DOR (HR = 0.17 [0.11, 0.26], p<.05) and OS (HR = 0.64 [0.49, 0.83], p<.05) than RW physician's choice. The results were similar after IPTW adjustment which balanced the ELRA and physician's choice arms across confounding variables. In these adjusted analyses, ELRA was associated with a significantly longer PFS (HR = 0.38 [0.22, 0.65], p<.05), DOR (HR = 0.16 [0.07, 0.34], p<.05), and OS (HR = 0.58 [0.35, 0.96], p<.05), than RW physician's choice. CONCLUSIONS Among BCMA-naïve patients who resemble those enrolled in the MM-3 trial, those treated with ELRA exhibited significantly longer PFS, DOR, and OS compared with treatments currently used in RW clinical practice.