The combination of lenalidomide (Revlimid) and luspatercept-aamt (Reblozyl) has shown early signs of safety and efficacy in patients with non-del(5q) myelodysplastic syndrome (MDS), according to data from a phase 1b trial (NCT04532936) presented at the 2024 ASH Annual Meeting.
The study, led by Mikkael A. Sekeres, MD, MS, from the University of Miami Health System, Sylvester Comprehensive Cancer Center, explored the potential of combining these two agents, both of which are already approved as monotherapies for MDS. The rationale was to potentially achieve higher transfusion independence rates than either drug could achieve alone.
Trial Design and Patient Population
The phase 1b/2 multicenter study enrolled patients with very low-, low-, or intermediate-risk MDS (per Revised International Prognostic Scoring System [IPSS-R] criteria) who were transfusion-dependent, requiring at least 2 packed red blood cell (RBC) units over 16 weeks. Patients could not have the del(5q) abnormality and were allowed prior treatment with an erythropoiesis-stimulating agent (ESA) or a hypomethylating agent (HMA), but not with lenalidomide or luspatercept. The ECOG performance status had to be between 0 and 2.
During the phase 1b portion, three different dose levels of lenalidomide were tested (2.5 mg, 5 mg, or 10 mg daily) in combination with luspatercept at a starting dose of 1.0 mg/kg subcutaneously on day 1 of each 21-day cycle. Luspatercept dose titrations were permitted based on response. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).
Safety and Efficacy Findings
At a median follow-up of 22.5 weeks, no dose-limiting toxicities (DLTs) were observed among the 12 treated patients, and the MTD was not reached. Among the 10 evaluable patients, 50% experienced hematologic improvement. Specifically, the rates of hematologic improvement–erythroid (HI-E), red blood cell (RBC) transfusion independence, and HI-platelet were 40%, 30%, and 10%, respectively.
The most common hematologic adverse events (AEs) included decreased absolute neutrophil count (n = 16), decreased platelet count (n = 9), and decreased hemoglobin (n = 6). Non-hematologic AEs included diarrhea (n = 5), muscle cramps (n = 4), and fatigue and lung infection (n = 3 each). Most non-hematologic AEs were grade 1 or 2, with only four grade 3 events reported (pneumonia, agitation, and a fall).
Implications and Next Steps
Based on these findings, the RP2D was established as lenalidomide 10 mg orally once daily and luspatercept 1.0 mg/kg subcutaneously on day 1 of a 21-day cycle. Enrollment for the phase 2 arm of the trial is ongoing.
"The next step forward is to start to combine drugs for patients with lower-risk MDS, and that's what we've done with this trial," said Dr. Sekeres.
These early results suggest that the combination of luspatercept and lenalidomide may offer a valuable treatment option for patients with lower-risk, non-del(5q) MDS, potentially improving hematologic parameters and reducing transfusion burden.
