Future Directions: Next Steps in the Treatment of Lower-Risk MDS

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The expanding therapeutic landscape for lower-risk myelodysplastic syndrome (MDS) has created exciting opportunities but also important questions about optimal treatment sequencing. Key uncertainties include determining the best second-line therapy post-luspatercept failure, with emerging data supporting imetelstat efficacy similar to the general population from the IMERGE trial. Additionally, phase 2 clinical trial data are emerging for combination therapy using erythropoiesis-stimulating agents (ESAs) plus luspatercept, which conceptually makes sense given that luspatercept promotes late-stage erythropoiesis while ESAs drive early-stage red blood cell proliferation, though this combination lacks FDA approval currently.

The intriguing survival trend favoring luspatercept from American Society of Clinical Oncology 2025 long-term follow-up data raises fundamental questions about the drug’s mechanisms beyond erythroid maturation. Luspatercept may potentially play a role in innate immunity, which could explain the observed survival benefit that doesn’t appear attributable to transfusion independence or disease progression prevention alone. This hypothesis requires further investigation and could reshape understanding of how targeted therapies influence overall outcomes in patients with MDS beyond their primary intended mechanisms.

The upcoming ELEMENT trial results are anticipated to provide crucial guidance on optimal luspatercept timing in frontline settings. This phase 3 trial evaluates luspatercept vs ESA therapies in patients with lower-risk MDS with baseline hemoglobin less than or equal to 9.5 g/dL who are transfusion-independent, potentially informing evidence-based recommendations for when to initiate luspatercept in treatment-naive patients. Clinical pearls for community practitioners include expecting dose escalation in approximately 80% of patients, with 50% reaching maximum doses, emphasizing the importance of patient counseling about treatment duration and the common need for dose adjustments throughout the therapeutic journey.