Background: Management of anemia is a common therapeutic challenge in pts with MDS. Approx. 30% of MDS pts have ≥ 15% RS in the bone marrow (BM) accompanied by ineffective erythropoiesis. Luspatercept (ACE-536), a novel activin type IIB receptor fusion protein, regulates late-stage erythroid differentiation. Preliminary phase 2 data suggest luspatercept improves erythropoiesis in lower-risk MDS pts with promising activity in pts with RS, with achievement of hematologic improvement and reduced need for transfusion in 55% and 39%, respectively, at doses ≥ 0.75 mg/kg. MEDALIST is a phase 3, randomized, double-blind, placebo (PBO)-controlled, multicenter study to determine the efficacy and safety of luspatercept for treatment of anemia in pts with lower-risk MDS ( < 5% BM blasts) and RS ( ≥ 15%) requiring RBC transfusion (average ≥ 2 units packed RBCs/8 weeks [wks]) who are refractory/intolerant or have a low chance of response to erythropoiesis-stimulating agents (serum erythropoietin > 200 IU/L). Methods: Pts aged ≥ 18 years are randomized 2:1 to luspatercept 1.0 mg/kg starting dose or PBO subcutaneously every 3 wks for ≥ 24 wks; no crossover between treatment arms is allowed. Stratification is by baseline RBC transfusion burden ( ≥ 6 RBC units/8 wks vs < 6 RBC units/8 wks) and baseline IPSS-R risk category (Very Low/Low vs Intermediate). Primary endpoint is rate of RBC transfusion independence (RBC-TI) ≥ 8 wks during the first 24 wks of treatment. Secondary endpoints include RBC-TI ≥ 12 wks, safety, quality of life, duration of RBC-TI, AML progression, overall survival, and mean hemoglobin increase ≥ 1.0 g/dL. Pts with evidence of clinical benefit and no progression to IPSS-R High/Very High-risk MDS or AML at wk 25 enter a double-blind extension phase until loss of clinical benefit, unacceptable toxicity, disease progression, or other discontinuation criteria. Post-treatment long-term follow-up is ≥ 2 years. The study is open to enrollment as of Dec 2015; target enrollment is 210 pts. Clinical trial information: NCT02631070