Luspatercept initiated at the maximum-approved dose in transfusion-dependent lower-risk myelodysplastic syndromes: Interim analysis from maxilus

Abstract Background: Luspatercept is an erythroid-maturation agent approved to treat anemia in patients (pts) with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS) who are erythropoiesis-stimulating agent (ESA)–naive or –exposed. Luspatercept improved red blood cell (RBC) transfusion independence (RBC-TI) in pts in the COMMANDS and MEDALIST studies, with most pts titrating to the maximum-approved dose (1.75 mg/kg). This open-label, phase 3b MAXILUS study (NCT06045689) is being conducted to evaluate luspatercept initiated at the maximum-approved dose in pts with TD LR-MDS. Preliminary results indicated that luspatercept was well-tolerated, with no new safety signals observed and notable ease of administration. We report updated efficacy and safety outcomes from the preplanned interim analysis of the MAXILUS study, with >75% of the study population evaluable based on the 24-week treatment phase. Methods: Eligible pts with non-del(5q) LR-MDS (per IPSS-R) were ≥18 years of age, TD (required ≥1 unit of packed RBCs ≤8 weeks before treatment), and had an ECOG PS score ≤2. Pts were enrolled into cohort 1 (ESA-naive) or cohort 2 (ESA-relapsed/refractory or intolerant [R/R/I]) to receive subcutaneous luspatercept 1.75 mg/kg every 3 weeks. The primary endpoint was RBC-TI ≥8 weeks, with a concurrent mean hemoglobin increase of ≥1.0 g/dL from Weeks 1 to 24. Secondary endpoints included RBC-TI ≥12 weeks (Weeks 1-24) and safety. The data cutoff was April 14, 2025. Results: At data cutoff, 105 pts (ESA-naive, n=52; ESA-R/R/I, n=53) composed the safety population of pts who received ≥1 dose of luspatercept. Median (IQR) duration of follow-up was 5.8 months (3.3-8.2) in the ESA-naive cohort and 7.4 months(5.6-9.2) in the ESA-R/R/I cohort. The median age was 76.0 years in both the ESA-naive and ESA-R/R/I cohorts, and 73.1% (38/52) and 90.6% (48/53) of pts were from Europe, respectively. SF3B1 mutation was present in 51.9% (27/52; ESA-naive) and 56.6% (30/53; ESA-R/R/I) of pts; 40.4% (21/52) and 39.6% (21/53) of pts had ring sideroblast (RS)-negative status; and 73.1% (38/52) and 43.4% (23/53) of pts had baseline serum erythropoietin (sEPO) ≤200 IU/L, respectively. ESA-naive pts: 86.5% of pts were on treatment at data cutoff; 13.5% discontinued treatment, primarily due to withdrawal by the pt (5.8%). Median (range) treatment duration was 25.5 weeks (2.1-50.0). There were 11.5% of pts who required ≥1 dose reduction; 36.5% had ≥1 dose delay. Treatment-emergent adverse events (TEAEs) occurred in 78.8% of pts; 19.2% were treatment-related. Grade 3/4 TEAEs occurred in 34.6% of pts; 3.8% were treatment-related. TEAEs leading to drug interruption occurred in 5.8% of pts. No thromboembolic events (TEEs) were observed, and no pts experienced disease progression to acute myeloid leukemia (AML) or higher-risk MDS (HR-MDS). Among pts who completed the 24-week efficacy-evaluable period at data cutoff (n=30), the primary endpoint was achieved in 73.3% of pts. RBC-TI ≥12 weeks was achieved in 70.0% of all pts, in 61.5% of pts with RS-negative status, and in 85.0% of pts with baseline sEPO ≤200 IU/L. ESA-R/R/I pts: 60.4% of pts were on treatment at data cutoff; 39.6% of pts discontinued treatment, primarily due to a lack of efficacy (13.2%). Median (range) treatment duration was 27.1 weeks (2.1-72.9). There were 13.2% of pts who required ≥1 dose reduction; 39.6% had ≥1 dose delay. TEAEs occurred in 92.5% of pts; 37.7% were treatment-related. Grade 3/4 TEAEs occurred in 47.2% of pts; 5.7% were treatment-related. TEAEs leading to drug interruption occurred in 17.0% of pts. No TEEs were observed, and no pts experienced disease progression to AML; 1 pt experienced disease progression to HR-MDS. Among pts who completed the 24-week efficacy-evaluable period at data cutoff (n=49), the primary endpoint was achieved in 65.3% of pts. RBC-TI ≥12 weeks was achieved in 49.0% of all pts, in 33.3% of pts with RS-negative status, and in 61.9% of pts with baseline sEPO ≤200 IU/L . Conclusions: Starting luspatercept at the maximum-approved dose of 1.75 mg/kg was well-tolerated, with no new safety signals. The high rate of RBC-TI ≥12 weeks in ESA-naive pts suggests that early use of luspatercept may contribute to clinical benefit. In this preplanned interim analysis, luspatercept demonstrated efficacy among pts with LR-MDS, including in those with RS-negative status and baseline sEPO ≤200 IU/L.