Background: Belamaf, an antibody-drug conjugate targeting B-cell maturation antigen, induces cell death by direct cell kill and immune-mediated mechanisms. The DREAMM-2 trial (NCT03525678) showed rapid, deep and durable responses to belamaf monotherapy in pts with RRMM. The Phase 3, open-label, randomized, multicenter DREAMM-3 trial (NCT04162210) evaluated belamaf monotherapy vs Pd in adult pts with RRMM at second relapse (third line) or later. Methods: Pts were randomized (2:1) to belamaf 2.5 mg/kg Q3W or Pd (pom 4 mg PO daily on days 1–21 of 28 day cycle; dex, 40mg PO [20mg if >75 years]) Q1W. The primary endpoint was progression free survival (PFS). Results: 325 pts were enrolled (belamaf n=218, Pd n=107). Median (range) age was 68 (38–90) years; 57% were male. Median (range) duration of exposure for belamaf was 4.1 (0.4, 22.9) months (mo) and 5.3 (0.4, 24.0) for Pd. Median (range) duration of follow-up was 11.5 (0.6, 24.2) mo for belamaf and 10.8 (0.0, 26.4) mo for Pd. Median PFS was longer for belamaf (11.2 [6.4, 14.5] mo) vs. Pd (7.0 [4.6, 10.6] mo). There was no statistically significant difference in PFS between the 2 treatment groups, (HR 1.03 [95% CI: 0.72, 1.47]), based on the stratified Cox model (p=0.558). Belamaf induced deeper responses vs Pd (Table). Median duration of response (DoR) was more durable for belamaf than for Pd (Table). At 12 mo, the probability (95% CI) of maintaining response was 0.768 (0.641, 0.854) for belamaf and 0.484 (0.258, 0.679) for Pd. Median PFS2 was 18.7 mo (95% CI 14.5, NR) for belamaf and 12.7 mo (9.3, 21.1) for Pd. PFS2 rate at 6 mo was 73% for belamaf and 76% for Pd. Overall survival (OS) data were immature (37.5% overall maturity) at this analysis; median OS was 21.2 mo (95% CI 18.7, NR) for belamaf and 21.1 mo (15.1, NR) for Pd (HR 1.14 [95% CI 0.77, 1.68]; p=0.746). Adverse events (AEs) were reported in 97% and 93% of patients (Table). The safety profile was consistent with previous reports for belamaf and Pd. Conclusions: Belamaf monotherapy did not demonstrate PFS superiority when compared to a doublet (Pd). However, median PFS was longer for belamaf monotherapy and belamaf induced deeper, more durable responses than Pd. No new safety signals were observed. Subgroup analyses and PRO outcomes will be reported. Belamaf continues to be investigated in combination with established and novel agents.