AbstractPatients with myelodysplastic syndromes and ring sideroblasts (MDS RS) are clinically characterized by severe anemia and transfusion need. Erythropoiesis‐stimulating agents (ESAs), which stimulate hemoglobin production and early maturation of erythroid precursors, are effective only in a portion of patients and for limited time. Luspatercept, an inhibitor of the TGF‐beta pathway, is beneficial in unblocking late‐stage erythropoiesis and has been approved for MDS RS patients failing or not‐candidate to ESAs. ESAs and/or luspatercept failure represents an unmet clinical need and most patients become life‐long transfusion dependent. Here, we describe the clinical combination of luspatercept with ESAs (subcutaneous epoetin alpha 40–80 000 IU/week) in seven MDS RS patients. Two patients had ESAs as pre‐existing therapy, while five were re‐challenged with ESAs as add‐on treatment due to luspatercept failure. Three patients achieved hematologic improvement, and one became transfusion independent. No adverse events were noted. This is the first clinical evidence that stimulating both early and late‐stage erythropoiesis may offer a further option for this challenging patient population.