Updated overall survival (OS) and long-term transfusion-independence (TI) from the phase 3 COMMANDS trial in erythropoiesis-stimulating agent (ESA)–naive patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS).

6566 Background: In the phase 3 COMMANDS trial (NCT03682536), luspatercept (LUSPA) significantly improved RBC-TI ≥12 wks with concurrent mean hemoglobin (Hb) increase ≥1.5 g/dL during wks 1-24 (primary endpoint) vs epoetin alfa (EA) in pts with ESA-naive transfusion-dependent (TD) LR-MDS. Longer follow-up (>2.5 yrs) showed a favorable OS trend and durable TI responses with LUSPA vs EA. We report updated results with 6 additional mos of follow-up (>3 yrs). Methods: Eligible pts (≥18 yrs; ESA-naive; TD; LR-MDS) were stratified by baseline (BL) transfusion burden (TB), ring sideroblasts (RS), and serum erythropoietin (sEPO). Pts were randomized 1:1 to LUSPA (1.0-1.75 mg/kg; SC Q3W) or EA (450-1050 IU/kg; SC QW) for ≥24 wks. OS (from randomization), RBC-TI responses and Hb improvement (all from wk 1 to end of treatment), predictive BL biomarkers of OS, and safety were evaluated. Results: At cutoff (Oct 6, 2025), median (min-max) follow-up was 35.9 (1-73; LUSPA) and 30.8 (0-77; EA) mos. Median OS was not reached (NR) for LUSPA and 46.0 mos for EA (HR, 0.78; 95% CI, 0.56-1.09), with similar trends in subgroups (Table). RBC-TI ≥12 wks (LUSPA vs EA) occurred in 76.4% vs 55.8% of pts, and in 60.4% vs 39.2% with concurrent mean Hb ≥10 g/dL. Median cumulative duration (95% CI) of RBC-TI ≥12 wks was 184.4 (118.4-NE) wks for LUSPA and 95.1 (74.9-180.1) wks for EA (HR, 0.54; 95% CI, 0.36-0.80). RBC-TI ≥2.5 yrs (LUSPA vs EA) was achieved by 25.3% vs 10.5% of pts. Mean Hb increase ≥1.5 g/dL (LUSPA vs EA) was achieved by 80.2% vs 58.6% of pts; median duration (95% CI) of Hb increase ≥1.5 g/dL was 72.9 (53.9-89.9) and 47.9 (35.9-60.0) wks (HR, 0.61; 95% CI, 0.44-0.85). Improved OS was associated with BL biomarkers of favorable immune (LUSPA) and CV function (LUSPA and EA), less aggressive disease (EA), and preserved megakaryopoiesis (EA); these characteristics may enhance response to therapy. At cutoff, 17.6% (LUSPA) and 7.8% (EA) of pts remained on treatment; 84.6% and 83.2% had ≥1 dose escalation. No new safety concerns emerged. Deaths (any cause) occurred (LUSPA, 36.3%; EA, 43.0%), fewer LUSPA pts progressed to HR-MDS (3.3%; 7.3%), and AML progression was comparable (4.9%; 5.5%). Conclusions: Long-term follow-up demonstrated improved OS trends and sustained responses with LUSPA vs EA, overall and in subgroups. No new safety concerns emerged, reinforcing superior clinical benefit as first-line treatment in LR-MDS. Clinical trial information: NCT03682536 . Median OS, mos LUSPA EA HR (95% CI) Overall (n=182)NR (n=181)46.0 0.78(0.56-1.09) Stratification subgroup TB <4 RBC U/8 wks (n=118)57.5 (n=111)47.2 0.87(0.57-1.33) TB ≥4 RBC U/8 wks (n=64)NR (n=70)39.9 0.62(0.37-1.05) RS+ (n=133)NR (n=130)47.2 0.70(0.47-1.04) RS− (n=49)54.8 (n=50)46.2 0.96(0.53-1.72) sEPO ≤200 U/L (n=145)NR (n=144)51.4 0.81(0.55-1.20) sEPO >200 U/L (n=37)43.0 (n=37)35.4 0.67(0.35-1.28)