The phase 3b MAXILUS trial (NCT06045689) is underway to assess the safety and efficacy of initiating treatment with luspatercept (Reblozyl) at the maximum approved dose in patients with lower-risk myelodysplastic syndromes (MDS). This study seeks to optimize the dosing strategy for luspatercept, an erythroid maturation agent, in this patient population.
Rory Shallis, MD, from Yale School of Medicine, noted that enthusiasm for luspatercept stemmed from the phase 3 MEDALIST trial (NCT02631070), which studied patients with lower-risk MDS who were refractory to or unlikely to respond to erythropoiesis-stimulating agents (ESAs). Luspatercept received its initial FDA approval in April 2020 for anemia in adults with very low- to intermediate-risk MDS who failed an ESA and required at least 2 red blood cell (RBC) units over 8 weeks. The indication expanded in August 2023 to include first-line treatment of anemia in similar patients who may require regular RBC transfusions; these approvals were based on the MEDALIST and COMMANDS trials.
Luspatercept's Clinical Foundation
The MEDALIST trial was a multicenter, double-blind, placebo-controlled study involving patients with very low-, low-, or intermediate-risk MDS per Revised International Prognostic Scoring System (IPSS-R) criteria. Patients had to have an inadequate response to prior ESA therapy or be intolerant, or have serum erythropoietin levels exceeding 200 U/L. Exclusion criteria included 5q deletions, high white blood cell counts, low neutrophil or platelet levels, and prior treatment with disease-modifying agents for MDS.
Patients were randomized 2:1 to luspatercept or placebo. Luspatercept was initiated at 1 mg/kg subcutaneously every 3 weeks, with potential dose increases to 1.33 mg/kg and 1.75 mg/kg after the first two cycles if needed. All patients received best supportive care, including RBC transfusions.
Data supporting the initial FDA approval showed that 37.9% of patients on luspatercept achieved RBC transfusion independence for at least 8 weeks during weeks 1-24, compared to 13.2% in the placebo arm (P < .0001). The 12-week RBC transfusion independence rates during weeks 1-24 were 28.1% and 7.9%, respectively (P = .0002), and during weeks 1-48, 33.3% and 11.8%, respectively (P = .0003).
Following MEDALIST, the COMMANDS trial directly compared luspatercept to epoetin alfa in ESA-naive, transfusion-dependent, lower-risk MDS patients. This open-label study enrolled adults with very low-, low-, or intermediate-risk MDS who were RBC transfusion dependent and ESA-naive, requiring 2 to 6 packed RBC units per 8 weeks for at least 8 weeks prior to randomization. Patients also needed an endogenous serum erythropoietin concentration below 500 U/L.
Patients were randomized 1:1 to luspatercept or epoetin alfa. Luspatercept was administered subcutaneously at a starting dose of 1.0 mg/kg every 3 weeks, with possible titration to 1.33 mg/kg and 1.75 mg/kg. Epoetin alfa was given weekly at a starting dose of 450 IU/kg, with potential increases to 787.5 IU/kg and 1050 IU/kg, up to a total dose of 80,000 IU.
The primary endpoint was 12-week RBC transfusion independence with a concurrent mean hemoglobin increase of at least 1.5 g/dL during weeks 1-24. Key secondary endpoints included hematological improvement-erythroid (HI-E) for at least 8 weeks, as well as 24- and 12-week RBC transfusion independence.
COMMANDS data showed that at a median follow-up of 17.2 months in the luspatercept arm and 16.9 months in the epoetin alfa arm, 60% of patients in the luspatercept arm reached the primary endpoint vs 35% in the epoetin alfa arm (OR, 3.1; 95% CI, 2.0-4.8; P < .0001). HI-E response rates were 74% vs 53%, respectively (OR, 2.8; 95% CI, 1.8-4.5; P < .0001). The 24-week RBC transfusion independence rates during weeks 1-24 were 48% vs 31%, respectively (OR, 2.3; 95% CI, 1.4-3.7; P = .0003), and the 12-week rates were 68% vs 49%, respectively (OR, 2.5; 95% CI, 1.6-4.0; P < .0001). The respective 24-week RBC transfusion independence rates during weeks 1-48 were 64% vs 42% (OR, 2.7; 95% CI, 1.7-4.4; P < .0001).
Guillermo Garcia-Manero, MD, from The University of Texas MD Anderson Cancer Center, highlighted the favorable toxicity profile of luspatercept observed in MEDALIST and COMMANDS, with no increased risk of transformation to acute leukemia.
MAXILUS Trial Design
MAXILUS is a global, open-label, nonrandomized study enrolling adults with very low-, low-, or intermediate-risk MDS according to IPSS-R criteria. Eligible patients must have an ECOG performance status of 2 or less and require RBC transfusions per study criteria. Exclusion criteria include clinically significant anemia, a history of acute myeloid leukemia (AML), uncontrolled hypertension, and prior stem cell transplant.
Eligible patients are divided into two cohorts: cohort 1 includes ESA-naive patients, and cohort 2 includes patients relapsed or refractory to prior ESA treatment. All patients receive subcutaneous luspatercept every 3 weeks at a starting dose of 1.75 mg/kg, with dose reductions based on tolerance and safety.
The primary endpoint is RBC transfusion independence for 8 weeks with a simultaneous mean hemoglobin increase of at least 1 g/dL from week 1 to 24. Secondary endpoints include safety, the number of patients who progress to AML, time to AML progression, and additional RBC transfusion independence outcomes.
MAXILUS will enroll approximately 100 patients, with an estimated primary completion date of January 2026.
