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Abstract Background Elranatamab (ELRA) is a B-cell maturation antigen (BCMA)xCD3 bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM) in the United States, European Union, Japan, and several additional countries. The registrational phase 2 MagnetisMM-3 (MM-3; NCT04649359) trial was single armed. Prior publications have investigated the comparative efficacy of ELRA from the MM-3 trial with real-world (RW) data external control arms (eg, Costa et al. Future Oncol2024). This study aimed to generate comparative data between ELRA from the MM-3 trial versus the predominant treatment regimens available in China, leveraging RW data. Methods This retrospective cohort study compared the efficacy observed in MM-3 Cohort A (BCMA-naive; N=123) from the March 26, 2024, data cut (median 28.4 months of follow-up) with patients in 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 (with their initiation of this new line of therapy set as the index date). MM-3 inclusion (eg, age ≥18 years, measurable disease within 90 days of the index, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤ 2) and exclusion criteria (eg, plasma cell leukemia, smoldering MM) were then applied to obtain comparable patient populations across sources. Two China-specific physician's choice of therapy (CSPCT) subgroups were created by identifying patients receiving the predominant treatment regimens in China from the identified COTA cohort (CSPCT1: DVd, D-VMP, DKd, IxaDd, DRd, DPd, DRVd, DVTd; CSPCT2: daratumumab + [either carfilzomib or bortezomib or ixazomib] + any non-IMiD). Progression-free survival (PFS), duration of response (DOR), and overall survival (OS) using Cox proportional hazard models (“unweighted analyses”) were compared between ELRA from MM-3 and CSPCT1 and CSPCT2 from COTA. Inverse probability treatment weighting (IPTW) Cox models were also used to adjust for any remaining imbalances on confounding variables (ie, age, sex, race/ethnicity, comorbidities, ECOG PS, International Staging System [ISS], prior lines/refractoriness, time since diagnosis, cytogenetic risk, extramedullary disease [EMD], and laboratory values) (“adjusted analyses”). Accelerated failure time models were conducted when proportional hazards assumptions were not met. Results Patients from MM-3 Cohort A (N=123) were compared with the 100 and 49 patients identified from the COTA database for CSPCT1 and CSPCT2, respectively. For the comparison of ELRA vs CSPCT1, the overall weighted standardized mean difference (SMD) across baseline demographics, clinical characteristics, and treatment history was 0.15, below the threshold of 0.20 indicating adequate balance across cohorts after weighting. Differences that remained generally favored the RWD subgroup (eg, EMD remained more common among ELRA patients [30.9% vs 10.0%]). In the IPTW-adjusted analyses, ELRA was associated with longer PFS (median [m] PFS, 17.25 vs 3.78 months; hazard ratio [HR], 0.50; 95% CI, 0.30-0.83; P<.05) and longer DOR (mDOR, not reached [NR] vs 4.63 months; HR, 0.16; 95% CI, 0.08-0.33; P<.05). ELRA was associated with numerically better OS (mOS, 17.58 vs 15.38 months; acceleration factor [AF], 0.78; 95% CI, 0.47-1.30; P=.34). For the ELRA vs CSPCT2 comparison, IPTW analyses were not possible due to small sample size. Baseline characteristics were largely similar across cohorts, although exceptions generally favored the RWD subgroup (eg, compared with CSPCT2, ELRA patients were more likely to have EMD [30.9% vs 12.2%], higher penta-refractoriness [41.5% vs. 18.4%], and a greater number of prior treatment lines [mean, 5.2 vs 4.6]). In unweighted analyses vs CSPCT2, ELRA was associated with longer PFS (mPFS, 17.25 vs 4.93 months; HR, 0.55; 95% CI, 0.34-0.89; P<.05), numerically longer OS (mOS, 24.61 vs 14.95 months; HR, 0.70; 95% CI, 0.46-1.08; P=.11), and longer DOR (mDOR, NR vs 4.70 months; HR, 0.17; 95% CI, 0.07-0.41; P<.05). Conclusions Among BCMA-naive patients with RRMM who resemble those from the MM-3 trial, patients treated with ELRA have better outcomes than patients using the predominant treatment regimens available in China.