Dr Shallis on the Utility of Luspatercept in the ELEMENT-MDS Trial in MDS

Rory Shallis, MD, assistant professor, medicine (hematology), Yale School of Medicine, Yale New Haven Health, discusses the utility of luspatercept-aamt (Reblozyl) as evaluated in the phase 3 ELEMENT-MDS trial (NCT05949684) for patients with myelodysplastic syndrome (MDS).

In August 2023, the FDA approved treatment with luspatercept for adult patients with anemia who present with very low– to intermediate-risk MDS) and may require regular red blood cell (RBC) transfusions; these patients will not have had prior treatment with an erythropoiesis-stimulating agent (ESA). The initial excitement for luspatercept in this patient population emerged from the phase 3 MEDALIST trial (NCT02631070), Shallis begins. The trial showed impressive responses in a placebo-controlled setting and was followed by the phase 3 COMMANDS trial (NCT03682536), he reports.

COMMANDS enrolled RBC-dependent patients with MDS who had not previously received ESAs, Shallis continues, adding that patients were randomly assigned to receive either luspatercept or an ESA. The primary end point, which was achieved in the luspatercept arm, measured at least 12 weeks of transfusion independence across various patient subgroups, including those with low endogenous erythropoietin (EPO) levels or low transfusion burdens, he states. Those 2 patient characteristics sparked investigators’ interest in using luspatercept earlier in treatment, Shallis emphasizes.

The ELEMENT-MDS trial will assess whether luspatercept can be introduced before patients become transfusion dependent, a common situation for patients with low-risk MDS at diagnosis, he explains. This randomized trial focuses on reducing progression to transfusion dependence in ESA-naive, non–transfusion-dependent patients with low-risk MDS, Shallis imparts. Low risk is defined using the revised International Prognostic Scoring System (IPSS-R), and the trial excludes patients with low-risk MDS with deletion 5q.

Patients must have a baseline EPO level below 500 U/L to be eligible for enrollment. The trial stratifies patients by baseline EPO level, ring sideroblast status, and IPSS-R risk category, he expands. ELEMENT-MDS will include some patients with intermediate-risk MDS per IPSS-R, who represent approximately 20% of all low-risk MDS cases, Shallis notes. The primary end point will evaluate the proportion of patients who become transfusion dependent during any continuous 16-week period in weeks 1 to 96.

There is confidence that using luspatercept earlier could prevent patients from becoming transfusion dependent, theoretically delaying the accumulation of significant transfusion burdens, he says. This delay is important as it may improve post-transplant outcomes by reducing iron overload, a factor that negatively affects stem cell transplant success, Shallis concludes.