Luspatercept

JAK inhibitor monotherapy successes in myelofibrosis led to development of combination regimens aiming to increase spleen volume reduction (SVR) and decrease symptom burden. Momelotinib, approved by the FDA in 2023 for myelofibrosis with anemia, showed noninferiority to ruxolitinib in SVR but not in total symptom score (TSS) reduction. Clinical data from SIMPLIFY-1 and MOMENTUM trials supported its use, particularly in patients with anemia. Momelotinib offers advantages over older JAK inhibitors by improving anemia without exacerbating thrombocytopenia. Future therapeutic targets and combination strategies with JAK inhibitors are promising, focusing on comprehensive disease control and patient-specific benefits.

Dr. Bertrand Y. Tuan discusses therapies for low-risk MDS, including erythropoietin-stimulating agents, luspatercept-aamt, and the newly FDA-approved telomerase inhibitor, imetelstat.

Luspatercept-aamt (Reblozyl) continues to be studied for MDS, with phase 3b MAXILUS aiming to assess its safety and efficacy at the maximum approved dose in lower-risk MDS patients. The agent's use stems from the MEDALIST trial, which demonstrated RBC transfusion independence in ESA-refractory patients. FDA approvals in 2020 and 2023 expanded its indications. MAXILUS will evaluate starting luspatercept at 1.75 mg/kg, aiming for RBC transfusion independence and hemoglobin increase.

The FDA's approval of luspatercept for first-line treatment of anemia in lower-risk MDS patients without prior ESA use expands treatment options, emphasizing efficacy and QOL. Jorge Cortes highlights the need to balance these factors, noting luspatercept's significant impact on QOL compared to ESAs. The ultimate goal is to improve symptoms and QOL, though MDS remains incurable, with ongoing research focusing on altering the disease's natural history.