Background: Anemic pts with LR-MDS and high baseline RBC transfusion burden (HTB) have very few treatment options and constitute a pt population with significant clinical unmet need. In this secondary analysis of the MEDALIST trial (NCT02631070), we sought to evaluate the clinical benefit of luspatercept in this pt population. Methods: MEDALIST is a randomized, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of luspatercept in pts with anemia due to LR-MDS with ring sideroblasts (RS) (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). 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 erythropoiesis-stimulating agents (serum erythropoietin > 200 U/L); and had anemia requiring regular RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or PBO subcutaneously every 3 weeks. HTB was defined as ≥ 6 RBC units transfused/8 weeks. Results: 153 pts were randomized to luspatercept and 76 to PBO. As of July 1, 2019, 23/66 (34.8%) and 12/66 (18.2%) HTB pts receiving luspatercept achieved a ≥ 50% and ≥ 75% reduction from baseline in RBC transfusion burden over ≥ 24 weeks, respectively, vs 3/33 (9.1%; P = 0.0063) and 1/33 (3.0%; P = 0.0363) pts receiving PBO. 6/66 (9.1%) luspatercept-treated HTB pts and 1/33 (3.0%) PBO-treated HTB pt achieved RBC-transfusion independence (TI) ≥ 8 weeks in Weeks 1–24 (P = 0.2699). The median (range) time to achieve RBC-TI with luspatercept was 50.0 days (1.0–100.0) and median (range) duration of RBC-TI in the luspatercept arm was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 in the luspatercept arm vs 12.4 in the PBO arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) PBO-treated HTB pts reported ≥ 1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) pts, respectively, reported ≥ 1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) PBO-treated pts reported ≥ 1 serious AE. Incidence of grade 3–4 TEAEs in HTB pts was similar between arms (53.0% luspatercept vs 54.5% PBO). Conclusions: Luspatercept treatment resulted in clinically significant reductions in transfusion burden and reduced number of transfusion events in HTB pts with LR-MDS with RS, with an acceptable safety profile consistent with the overall population. Clinical trial information: NCT02631070.