A Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Participants Who Require Red Blood Cell Transfusions and Are ESA Naïve

Percentage of participants who are RBC transfusion-free for any 12-week period associated with a concurrent mean hemoglobin (Hgb) increase ≥ 1.5 g/dL compared to baseline. After applying below 14/3-day rule, the baseline Hgb value is defined as the lowest Hgb value from the central, local laboratory, or pre transfusion Hgb from transfusion records that is within 56 days on or prior to the first dose of treatment, or randomization date if participants were not treated. 4/3-day rule: only Hgb values that are at least 14 days after a transfusion may be used unless there is another transfusion within 3 days after the Hgb assessment. If this occurs, that Hgb value will be used despite being \< 14 days after the previous transfusion.

Time frame: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Time frame: Day 1 on week 4, 10, 16, 22, and every 12 weeks (±14 days) from the 24-Week MDS Assessment visit for up to one year from the first dose

The EORTC QLQ-C30 is composed of 30 items that includes a global health status score ranging from: 1-7 as well as scores for 5 functional scales (physical, role, emotional, cognitive and social), 3 symptom scales (fatigue, nausea/vomiting, and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) all ranging from 1-4. Subscale scores are transformed to a 0 to 100 scale. A high score for a functional scale represents a high or healthy level of functioning; a high score for the global health status/health related quality of life (HRQoL) represents a high overall HRQoL; but a high score for a symptom scale represents a high level of symptomatology or problems. Baseline is defined as the last value on or before the first dose of study drug.

Time frame: Baseline and week 24.

Population: All randomized participants who completed the EORTC QLQ-C30 assessment at baseline and post-baseline assessment at the respective visit.

The Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire includes 47 items rating on a 5-point Likert scale from 0 (not at all) to 4 (very much) (so that 0 is considered worse quality of life and 4 is good response) on five primary subscales: * Physical well-being (sum of 7 items, score range from 0-28) * Social/Family well-being (sum of 7 items, score range from 0-28) * Emotional well-being (sum of 6 items, score range from 0-24) * Functional well-being (sum of 7 items, score range from 0-28) * Anemia-related symptoms (sum of 20 items, score range from 0-80) A total score for the FACT-An can be calculated by summing the five primary subscales with a score range from 0-188. Higher scores representing better quality of life. Baseline is defined as the last value on or before the first dose of study drug.

Time frame: Baseline, Day 1 on weeks 7,13,19, and 24.

Population: All randomized participants who completed the Fact-An assessment at baseline and post-baseline assessment at the respective visit.

Maximum duration of RBC transfusion independence for participants who achieve RBC-TI ≥ 84 days.

Time frame: Week 1 through End of Treatment (Up to approximately an average of 66 weeks and a maximum of 202 weeks)

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) who were RBC-TI \>= 12 Weeks (Week 1-24) responders

Time frame: Day 1 on week 4, 10, 16, 22, and every 12 weeks (±14 days) from the 24-Week MDS Assessment visit for up to one year from the first dose

Mean hemoglobin (Hgb) change over the 24-week period of Week 1 through Week 24 compared to baseline. After applying below 14/3-day rule, the baseline Hgb value is defined as the lowest Hgb value from the central, local laboratory, or pre transfusion Hgb from transfusion records that is within 56 days on or prior to the first dose of treatment, or randomization date if participants were not treated. 4/3-day rule: only Hgb values that are at least 14 days after a transfusion may be used unless there is another transfusion within 3 days after the Hgb assessment. If this occurs, that Hgb value will be used despite being \< 14 days after the previous transfusion.

Time frame: Week 1 through Week 24

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) with baseline measurements.

Time to AML progression is defined as the time between randomization and first diagnosis of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with diagnosis of AML will be considered to have had an event. Participants who have not progressed to AML at the time of analysis will be censored at the last assessment date which does not indicate progression to AML estimated by Kaplan-Meier method.

Time frame: From randomization to first diagnosis of AML up to 5 years from first dose or 3 years from last dose (whichever occurs later), unless the participant withdraws consent from the study, dies or is lost to follow-up. (Up to approximately 221 weeks)

Population: ITT Population: all randomized participants regardless of whether or not the participant received treatment

Number of participants under each ADA positive category. A participant is counted as 'Treatment-Emergent' if there is a positive post-baseline sample while the baseline sample is ADA negative, or there is a positive post-baseline sample with a titer \>= 4-fold of the baseline titer while the baseline sample is ADA positive. A participant is counted as 'Preexisting' if the baseline sample is ADA positive and the participant is not qualified for 'Treatment-Emergent'. If the participant was discontinued from study treatment earlier than one year from the first dose, additional samples will be collected if last ADA is positive. Baseline is defined as the last value on or before the first dose of study drug.

Time frame: Day 1 on week 4, 10, 16, 22, and every 12 weeks (±14 days) from the 24-Week MDS Assessment visit for up to one year from the first dose

Population: Safety Population (all participants who were randomized and received at least one dose of treatment) with baseline and at least one post-baseline immunogenicity assessment result. - Luspatercept Arm Only.

Time from date of randomization to death due to any cause

Time frame: Randomization to death due to any cause up to 5 years from first dose or 3 years from last dose (whichever occurs later), unless the participant withdraws consent from the study, dies or is lost to follow-up. (Up to approximately 221 weeks)

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

The percentage of participants meeting the modified HI-E criteria per the International Working Group (IWG) sustained over any consecutive 56-day period in Week 1-24: For participants with baseline red blood cell (RBC) transfusion burden of \>= 4 units/8 weeks, a reduction of at least 4 units RBC transfusion; for participants with baseline RBC transfusion burden of \< 4 units/8 weeks, mean increase of hemoglobin of at least 1.5 g/dL in the absence of transfusions.

Time frame: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Percentage of participants who are RBC transfusion-free over a consecutive 84-day period.

Time frame: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Defined as percentage of participants achieving RBC-TI for \>= 56 days during any consecutive 56-day period from Week 1 through Week 24.

Time frame: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Defined as percentage of participants achieving RBC-TI for \>= 168 days during any consecutive 168-day period from Week 1 through Week 48.

Time frame: Week 1 through Week 48

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) whose first dose date is at least 337 days from the cutoff date or discontinued early are included in this analysis.

Red blood cell transfusion independence (RBC-TI) for 24 weeks is defined as the percentage of participants who did not receive RBC transfusions from Week 1 through Week 24.

Time frame: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Progression to AML is defined as a diagnosis of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow.

Time frame: From randomization to 5 years from first dose or 3 years from last dose (whichever occurs later), unless the participant withdraws consent from the study, dies or is lost to follow-up. (Up to approximately 221 weeks)

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Treatment-emergent adverse events include adverse events that started on or after the first dose of treatment until 42 days after the last dose of treatment, as well as those serious adverse events (SAEs) made known to the investigator at any time thereafter that are suspected of being related to treatment. The severity/intensity of AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0). Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.

Time frame: From first dose to 42 days post last dose (Up to approximately an average of 72 weeks and a maximum of 208 weeks)

Population: Safety Population - all participants who were randomized and received at least one dose of treatment.

RBC transfusion burden on treatment is defined as total number of packed red blood cell (pRBC) units transfused within the first 24 weeks of treatment since Week 1.

Time frame: Week 1 through Week 24

Population: All participants who were randomized and received at least one dose.

Time to first RBC transfusion is defined as time from Week 1 to first RBC transfusion on treatment. Participants who maintain RBC-TI through the end of the Treatment Period or time of analysis will be censored at EOT visit date, subsequent MDS therapy start date, study discontinuation date, analysis cutoff date or death, whichever occurs first. Median is from un-stratified Kaplan-Meier method.

Time frame: Week 1 through End of Treatment (Up to approximately an average of 66 weeks and a maximum of 202 weeks)

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Time from first dose to first onset of achieving modified HI-E. The modified HI-E criteria per the International Working Group (IWG) sustained over any consecutive 56-day period in Week 1-24: For participants with baseline red blood cell (RBC) transfusion burden of \>= 4 units/8 weeks, a reduction of at least 4 units RBC transfusion; for participants with baseline RBC transfusion burden of \< 4 units/8 weeks, mean increase of hemoglobin of at least 1.5 g/dL in the absence of transfusions.

Time frame: Week 1 through Week 24

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) who achieve HI-E response (Week 1-24)

Time from first dose to first onset of transfusion independence ≥ 84 days.

Time frame: Week 1 through Week 24

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) who were RBC-TI \>= 12 Weeks (Week 1-24) responders