Background: MEDALIST (NCT02631070) is a randomized, placebo (PBO)-controlled, phase 3 trial evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in pts with anemia due to lower-risk MDS (LR-MDS) with RS (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Methods: Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs; and required RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or PBO subcutaneously every 3 weeks. This analysis evaluates long-term transfusion burden reduction with luspatercept in all pts in the MEDALIST trial. Results: As of July 1, 2019, 77/153 (50.3%) and 11/76 (14.5%) pts in the luspatercept and PBO arms, respectively, achieved ≥ 50% RBC transfusion burden reduction for ≥ 24 weeks (P< 0.0001). The median longest single response episode was 131.6 weeks with luspatercept, and not estimable with PBO due to pts stopping treatment. In Weeks 9–24, mean change from baseline in RBC units transfused was −3.0 (95% CI −3.9, −2.1) vs +0.4 (95% CI −0.6, 1.4) in the luspatercept vs PBO arms. In Weeks 33–48, mean change in RBC units transfused in the luspatercept arm was −4.9 (95% CI −5.9, −3.9). In Weeks 1–24, mean number of transfusion visits was 5.9 vs 9.5 in the luspatercept vs PBO arms. Risk of recurrent transfusion visits in Weeks 1–24 for luspatercept vs PBO was 0.699 (95% CI 0.597, 0.819; P< 0.0001). Mean number (least squares [LS] mean) of RBC units transfused/48 weeks during Weeks 1–48 was 22.89 (23.28) vs 35.98 (35.20) in luspatercept vs PBO arms (LS mean difference −11.92 [95% CI −15.55, −8.28]; P< 0.0001). The mean number (LS mean) of RBC transfusion events over 48 weeks was 12.95 (13.14) vs 19.54 (19.15) in the luspatercept vs PBO arms (LS mean difference −6.00 [95% CI −8.16, −3.85]; P< 0.0001). LS mean change from baseline in serum ferritin was −2.7 µg/L vs +226.5 µg/L in luspatercept vs PBO (LS mean difference −229.1 µg/L; P = 0.0024) in Weeks 9–24; and −72.0 µg/L vs +247.4 µg/L in Weeks 33–48 (LS mean difference −319.5 µg/L; P = 0.0294). In Weeks 1–24, 38/127 (29.9%) vs 5/65 (7.7%) pts (P = 0.0005) achieved major HI-E response per IWG 2018 criteria in luspatercept vs PBO arms, respectively. Conclusions: Luspatercept demonstrated clinical efficacy in pts with LR-MDS with RS and was associated with significant reductions in RBC transfusions (≥ 50%) and serum ferritin. Clinical trial information: NCT02631070.