Background : Pts with TCE RRMM who have been exposed to ≥3 lines of therapy (LOT) have a poor prognosis and limited tx options. Tec is a B-cell maturation antigen × CD3 bispecific antibody being evaluated in MajesTEC-1 (NCT04557098), a single-arm, phase 1/2 study in pts with RRMM who were TCE to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody and received ≥3 LOT. Since MajesTEC-1 lacks a control arm, we assessed the comparative efficacy of tec vs tx currently used in real-world clinical practice (RWCP) by creating an external real-world control arm from LocoMMotion (NCT04035226), a prospective study of RWCP efficacy and safety outcomes in pts with TCE RRMM who received ≥3 LOT. Methods: An external control arm for MajesTEC-1 was created from pts in LocoMMotion (248 pts, clinical cutoff May 21, 2021) who met MajesTEC-1 eligibility criteria. Individual pt-level data from MajesTEC-1 were included from 150 pts treated with tec (1.5 mg/kg weekly) at a clinical cutoff of Sep 7, 2021. Inverse probability of tx weighting with average tx effect on the treated was used to adjust for imbalances in baseline covariates of prognostic significance (refractory status, International Staging System stage, time to progression on prior LOT, extramedullary disease, number of prior LOT, time since diagnosis, average duration of prior LOT, age, hemoglobin, lactate dehydrogenase, creatinine clearance, Eastern Cooperative Oncology Group performance status, gender, type of MM, and prior transplant). Comparative efficacy of tec vs RWCP was estimated for overall response rate (ORR), very good partial response (VGPR) rate, complete response or better (≥CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). For binary endpoints (ORR, VGPR rate, and ≥CR rate), relative effect of tec vs RWCP was estimated with an odds ratio, transformed into a response-rate ratio (RR) and 95% confidence interval (CI), derived from weighted logistic regression. A weighted Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% CIs for time-to-event endpoints (DOR, PFS, and OS). Results: Baseline characteristics were well balanced between the 2 cohorts after reweighting the external RWCP cohort. Pts treated with tec had improved outcomes vs tx used in RWCP: ORR (RR 2.31; 95% CI 1.75–2.87; P< 0.0001), VGPR rate (RR 5.54; 95% CI 3.38–7.70; P< 0.0001), ≥CR rate (RR 91.50; 95% CI 12.66–661.43; P< 0.0001), DOR (HR 0.17; 95% CI 0.08–0.36; P< 0.0001), PFS (HR 0.47; 95% CI 0.34–0.67; P< 0.0001), and OS (HR 0.69; 95% CI 0.46–1.05; P= 0.08). Conclusions: Tec showed significantly improved efficacy over RWCP for almost all outcomes, highlighting its potential as a highly effective tx option for pts with TCE RRMM who have been exposed to ≥3 LOT.