Myelodysplastic syndromes, primarily affecting older adults, are a heterogeneous group of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis that manifest clinically as anemia, neutropenia, and/or thrombocytopenia of variable severity; these often result in RBC- transfusion dependent (TD) anemia, increased risk of infection, and/or hemorrhage, as well as a potential to progress to acute myeloid leukemia (AML). Lenalidomide is approved for red blood cell transfusion-dependent (RBC TD) anemia due to low-risk myelodysplastic syndromes (MDS) with a chromosome 5q deletion (del5q) with or without additional cytogenetic abnormalities. About one third of patients are refractory/resistant/intolerant and will require further treatment options. Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion protein consisting of a modified form of the extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the Fc portion of human immunoglobulin G1 (IgG1-Fc). Luspatercept acts on endogenous inhibitors of late-stage erythropoiesis (eg, growth differentiation factor 11, GDF11) to increase release of mature erythrocytes into circulation. Nonclinical data have demonstrated that luspatercept binds to negative regulators governing late-stage erythroid development to inhibit their action, thereby promoting the maturation of erythrocytes in the bone marrow. Luspatercept is indicated for the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia and due to very low, low and intermediate-risk MDS with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based-therapy. It is not indicated for other MDS subtypes. Unfortunately, patients with MDS with del5q refractory/resistant/intolerant to lenalidomide are excluded from clinical trials that evaluate novel treatments for the anemia of RBC TD lower risk MDS. Therefore, treatment of anemia in such patients is an unmet need. QOL-ONE Phoenix is a Phase 2, multicenter, single arm, prospective study. The primary objective of the study is to evaluate the effect of luspatercept on RBC TI in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and \< 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and who require RBC transfusions. The study is divided into a Screening Period, a 2-year Treatment Period and a 3-year Follow-up Period. Primary objective is to evaluate the effect of luspatercept on RBC TI (lack of transfusions for 8 consecutive weeks within the first 24 weeks) in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and \< 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and RBC TD.