Background: Most pts with LR-MDS have limited responses to ESAs, thus there is an unmet need to treat anemia and reduce TD. Here we report interim results from the open-label, randomized phase 3 COMMANDS trial (NCT03682536) comparing the efficacy and safety of luspatercept vs epoetin alfa in ESA-naive pts with LR-MDS. Methods: Eligible pts were ≥ 18 years old with IPSS-R-defined LR-MDS with or without RS, < 5% bone marrow blasts, sEPO levels < 500 U/L, required RBC transfusions (defined as 2–6 RBC units/8 weeks [wk] for ≥ 8 wk immediately prior to randomization), and were ESA naive. Pts were randomized 1:1 to receive subcutaneous luspatercept (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 wk or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥ 24 wk. Primary endpoint was achievement of RBC transfusion independence (TI) ≥ 12 wk within the first 24 wk, with a mean hemoglobin increase ≥ 1.5 g/dL. Secondary endpoints included achievement of hematologic improvement-erythroid (HI-E) response ≥ 8 wk per IWG 2006 criteria, RBC-TI 24 wk and ≥ 12 wk, and safety. Results: As of Aug 31, 2022, 178 pts received luspatercept and 176 epoetin alfa, with median treatment durations of 41.6 and 27.0 wk, respectively. Baseline pt characteristics were balanced across treatment arms. Of 301 pts included in the efficacy analysis, 86 (58.5%) pts receiving luspatercept vs 48 (31.2%) epoetin alfa achieved the primary endpoint of RBC-TI ≥ 12 wk with concurrent mean Hb increase ≥ 1.5 g/dL within the first 24 wk (P< 0.0001). HI-E ≥ 8 wk was achieved by 109 (74.1%) luspatercept and 79 (51.3%) epoetin alfa pts (P< 0.0001). Within the first 24 wk of treatment, RBC-TI 24 wk and ≥ 12 wk was achieved by 70 (47.6%) and 98 (66.7%) luspatercept pts, respectively, vs 45 (29.2%) and 71 (46.1%) epoetin alfa pts (P = 0.0006 and 0.0002). Treatment-emergent adverse events (TEAEs; any grade) were reported by 164 (92.1%) luspatercept and 150 (85.2%) epoetin alfa pts; 8 (4.5%) and 4 (2.3%) pts discontinued due to TEAEs. Treatment-related AEs were reported by 54 (30.3%) luspatercept and 31 (17.6%) epoetin alfa pts. AML progression was reported in 4 (2.2%) luspatercept and 5 (2.8%) epoetin alfa pts. Overall rates of death were comparable between arms during treatment and post-treatment (32 [18.0%] luspatercept, 32 [18.2%] epoetin alfa pts). Conclusions: Compared with epoetin alfa, luspatercept led to clinically meaningful and statistically significant improvements in RBC-TI and erythroid response, as well as duration of response. Luspatercept safety results were consistent with previous findings. These data show, for the first time, superiority of an innovative therapy over ESAs in ESA-naive pts with TD LR-MDS. Luspatercept could represent a new standard of care for pts with TD LR-MDS. Clinical trial information: NCT03682536.