Inclusion Criteria:

Subjects must satisfy the following criteria to be randomized in the study:

1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).

2. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.

3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.

4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that
meets IPSS-R classification of very low, low, or intermediate risk disease, and:

• < 5% blasts in bone marrow. 5. Subject has an endogenous serum erythropoietin (sEPO) level of 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC
transfusions administered for elective surgery, infections or bleeding events
will not qualify as a required transfusion for the purpose of meeting eligibility
criteria or stratification.

- The hemoglobin level after the last RBC transfusion prior to randomization must
be < 11.0 g/dL (centrally or locally analyzed). 7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. 8. Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must: - Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. - If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy. 9. Male subjects must: - Practice true abstinence (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy. Exclusion Criteria: The presence of any of the following will exclude a subject from randomization (with the randomization date defined as the date in which the subject is randomized in IRT): 1. Subject with the any of the following prior treatments: - Erythropoiesis-stimulating agents (ESAs) - Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for treatment of febrile neutropenia - Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide] - Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from randomization, at the investigator's discretion. - Hypomethylating agents - Subjects may be randomized at the investigator's discretion contingent that the subject received no more than 2 doses of HMA. The last dose must be ≥ 8 weeks from the date of randomization. - Luspatercept (ACE-536) or sotatercept (ACE-011) - Immunosuppressive therapy for MDS - Hematopoietic cell transplant 2. Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification. 3. Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia (JMML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), MDS/MPN unclassifiable. 4. Subject with secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases. 5. Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate). • Iron deficiency to be determined by serum ferritin < 100 μg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron). 6. Subject with known history of diagnosis of AML. 7. Subject receiving any of the following treatment within 8 weeks prior to randomization: - Anticancer cytotoxic chemotherapeutic agent or treatment - Systemic corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS - Iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization - Other RBC hematopoietic growth factors (eg, Interleukin-3) - Androgens, unless to treat hypogonadism - Hydroxyurea - Oral retinoids (except for topical retinoids) - Arsenic trioxide - Interferon and interleukins - Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug) 8. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment. 9. Subject with any of the following laboratory abnormalities: - Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L) - Platelet count < 50,000/μL (50 x 109/L) - Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [MDRD] formula) - Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) - Total bilirubin ≥ 2.0 x ULN. - Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome. 10. Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed: - Basal or squamous cell carcinoma of the skin - Carcinoma in situ of the cervix - Carcinoma in situ of the breast - Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) 11. Subject with major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization. 12. Subject with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis within 6 months prior to randomization Note: prior superficial thrombophlebitis is not an exclusion criterion. 13. New-onset seizures or poorly controlled seizures within 12 weeks prior to randomization. 14. Subject with the following cardiac conditions within 6 months prior to randomization: myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New York Heart Association (NYHA) Class III-IV heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator. Subjects with a known ejection fraction ˂ 35%, confirmed by a local echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan performed within 6 months prior to randomization. 15. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment). 16. Subject with known human immunodeficiency virus (HIV), known evidence of active infectious Hepatitis B, and/or known evidence of active Hepatitis C. 17. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in luspatercept (see Investigator's Brochure). 18. Subject with known hypersensitivity to the active substance or to any of the excipients in epoetin alfa. 19. Subjects with history of pure red cell aplasia (PRCA) and/or antibody against erythropoietin. 20. Pregnant or breastfeeding females. 21. Subject has any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study. 22. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 23. Subject has any condition or receives concomitant medication that confounds the ability to interpret data from the study.