A Trial Comparing Three Different Treatment Options for Adults With Low-Risk Myelodysplasia and Anemia (A MyeloMATCH Treatment Trial)

Inclusion Criteria: * Participants must have been registered to Master Screening and Re-Assessment Protocol (MYELOMATCH) prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox Protocol Assignment Team, prior to registration to this study. Participants must have agreed to have specimens submitted for translational medicine and must be offered the opportunity to submit biosamples for banking for future research as per MYELOMATCH * Participants must have pathologically confirmed MDS according to World Health Organization (WHO) 2022 classification, without excess blasts * Lower risk MDS with a revised international prognostic scoring system (IPSS-R) score of less than or equal to 3.5 * Symptomatic anemia defined as either red blood cell (RBC) transfusion dependent, or hemoglobin \< 95 g/L with subjective fatigue or dyspnea * Age 18 years or greater * No prior therapy for myelodysplasia; including no luspatercept, imetelstat, emavusertib, lenalidomide, hypomethylating or immunosuppressive agents. Patients may have received up to 2 prior doses of erythropoietin stimulating agents (epoetin alfa or darbepoetin) if at least 8 weeks have elapsed between the prior therapy and study enrollment * No concurrent radiotherapy, biological, or any other investigational agents within 30 days prior to enrollment * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 * Absolute neutrophil count ≥ 0.5 x 10\^9/L * Platelet count ≥ 50 x 10\^9/L * Bilirubin ≤ 3.0 x upper limit of normal (ULN) * If confirmed Gilbert's, eligible providing direct bilirubin ≤ 3.0 x ULN * Alanine aminotransferase (ALT) ≤ 3.0 x ULN * Erythropoeitin ≤ 500 IU/L * Creatinine clearance \> 30 mL/min * Creatinine clearance to be measured directly by 24-hour urine sampling or as calculated by Cockcroft and Gault equation * Participant consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrollment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedure * Participants must be accessible for treatment and follow-up. Participants enrolled on this trial must be treated and followed at the participating center. Investigators must assure themselves the participants enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. Participants must agree to return to their primary care facility for any adverse events which may occur through the course of the trial * In accordance with Canadian Cancer Trials Group (CCTG) policy, protocol treatment is to begin within 7 working days of participant enrollment * Males and females of reproductive potential must have agreed to use a highly effective contraceptive method during study treatment and for 3 months afterwards. A participant is considered to be of "childbearing potential" if they have had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate participant chooses to become sexually active during the time period for use of contraceptive measures, they are responsible for beginning contraceptive measures. Participants of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumor production of human chorionic gonadotropin (hCG), as seen with some cancers. Participant will be considered eligible if an ultrasound is negative for pregnancy Exclusion Criteria: * Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * MDS with del(5q) * Concurrent use of hematopoietic growth factors (other than protocol specified) * Known hypersensitivity to either luspatercept, erythropoietin, or emavusertib therapy * Participants who are unable to take oral medication regularly, with active gastroparesis, short gut syndrome, or other malabsorption syndrome * Active, uncontrolled bacterial, fungal, or viral infection within 14 days prior to enrollment. * Participants with hepatitis B core antibody positive suggestive of past infection are eligible if they are hepatitis B virus (HBV) deoxyribonucleic acid (DNA) negative and concurrently treated with anti-viral therapy. Participants who are hepatitis B surface antigen positive should be referred for appropriate care and considered eligible if hepatitis B DNA becomes negative. * Participants with a history of hepatitis C which has been treated and is no longer active are eligible. Patients who have not been treated should be referred for appropriate care. * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * Participants on prophylactic antimicrobials need not be excluded, although specific agents may be excluded for drug-to-drug interactions or overlapping toxicities. * Participants who do not meet these eligibility criteria should be referred for appropriate care and may be considered in the future if eligibility criteria are met * Participants with serious illnesses or medical conditions which would not permit the participant to be managed according to protocol including but not limited to: * Uncontrolled hypertension, defined as repeated systolic blood pressure greater than 160 and/or diastolic greater than 100 mmHg despite adequate treatments, * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better * Iron deficiency defined as ferritin of \< 50 ug/L * Live attenuated vaccination administered within 30 days prior to enrollment * Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and not allowed * Participants who are pregnant or breast-feeding are excluded from this study because luspatercept was found to be hazardous to the fetus in pregnant animals and was found in the milk of treated lactating rats. Emavusertib and epoetin alfa have not been evaluated in pregnant or lactating individuals, and potential risks to the fetus are unknown