Luspatercept + Darbepoetin in MDS

Inclusion Criteria: 1. Ability to understand and the willingness to sign a written informed consent document. 2. Participant is 18 years or older at the time of signing informed consent. 3. Participant has lower-risk myelodysplastic syndrome (MDS) defined as very low, low and intermediate risk by International Prognostic Scoring System-Revised (IPSS-R) criteria (3). 4. Bone marrow biopsy within 90 days of screening demonstrated less than 5% blasts in the aspirate and/or core biopsy. If no bone marrow biopsy was done within 90 days of screening it is mandatory to repeat it at screening. Otherwise, bone marrow biopsy is optional at screening to obtain correlative study samples. 5. Absence of SF3B1 mutation and del5q. 6. Endogenous serum erythropoietin alfa (EPO) level \< 500 IU/L. 7. Participant is transfusion dependent defined as ≥ 2 packed red blood cell (PRBC) units/8 weeks for a minimum of eight weeks immediately prior to screening. The maximum consecutive timeframe participants may be RBC transfusion-free within this 8-week time period is six weeks. a. Red blood cell transfusions administered when hemoglobin levels were \> 9.0 g/dL and/or RBC transfusions administered for elective surgery, infections or bleeding events will not be counted in above. 8. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 (Appendix 1. ECOG Performance Status Scale). 9. Participant has adequate organ function defined as: 1. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered due to organ involvement by the participant's myeloid malignancy (in that case a cut off ≤ 5 x ULN will be used). 2. Serum direct bilirubin \< 1.5 x ULN. 3. Creatinine clearance \> 30 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation. 10. Participants must adhere to the following reproductive and contraceptive requirements while on study treatment and for three months after the last dose of luspatercept and darbepoetin alfa: a. General Requirements: i. Participants must not be pregnant or breastfeeding. ii. Participants must not donate gametes (i.e., eggs or sperm) or freeze gametes for future use related to assisted reproduction. b. For participants of childbearing potential: i. Participant of childbearing potential is defined as an individual who is premenopausal and capable of becoming pregnant, including those using contraception, those who are single, or those with partners who have had a vasectomy. ii. A negative highly sensitive pregnancy test must be obtained at screening, and a negative serum or urine pregnancy test must be obtained within 72 hours starting on treatment, and participants must agree to further pregnancy tests throughout the study as required per the site's institutional guidelines. iii. Participants must agree to use two methods of contraception of which one must be highly effective for three months after the last dose of luspatercept and darbepoetin alfa. c. For Partners of Participants: i. If the participant's partner is of childbearing potential, the partner must also practice a highly effective method of contraception while the participant is on study treatment and for three months after the last dose of luspatercept and darbepoetin alfa, unless the participant is vasectomized. d. Highly effective methods of contraception include, but are not limited to: i. Combined hormonal contraception (estrogen and progestogen) that inhibits ovulation (oral, intravaginal, or transdermal). ii. Progestogen-only hormonal contraception that inhibits ovulation (oral, injectable, or implantable). iii. Non-hormonal (cooper) intrauterine device (IUD). iv. Intrauterine hormone-releasing system. v. Bilateral tubal occlusion. vi. Sexual abstinence (the reliability of abstinence must be evaluated concerning the duration of the clinical study and the participant's lifestyle). vii. A vasectomized partner (provided the partner is the sole sexual partner of the study participant of childbearing potential and that the vasectomized partner has received medical confirmation of the surgical success). Exclusion Criteria: 1. Prior treatment with ESA, luspatercept, hypomethylating agents or lenalidomide/thalidomide/other immunomodulating drug (IMiDs). 1. Exception 1: Participants can have received ≤ 2 doses of prior epoetin alfa or ≤ 1 dose darbepoetin alfa if ≥ 8 weeks from date of consent. 2. Exception 2: Participants can have received ≤ 1 week of treatment with lenalidomide ≥ 8 weeks from the date of consent, at the sponsor-investigator's discretion. 3. After signing consent, the participants are not allowed to receive any of these drugs: other RBC hematopoietic growth factors (e.g., Interleukin-3), granulocyte colony stimulating factors (i.e., G-CSF, GM-CSF), except in cases of neutropenic fever, cytotoxic, chemotherapeutic, targeted or investigational agents/therapies, azacitidine, decitabine or other hypomethylating agents, lenalidomide, thalidomide and other immunomodulating drugs (IMiDs), hydroxyurea, androgens, unless to treat hypogonadism, oral retinoids (topical retinoids are permitted), arsenic trioxide, interferon and interleukins. 2. Participants with history of seizures at any time. 3. Participants with any of the following conditions within six months prior to screening: 1. Stroke. 2. Thrombosis/thromboembolism. 3. Myocardial infarction. 4. Uncontrolled angina. 5. Acute decompensated cardiac failure or New York Heart Association (NYHA) Class III-IV heart failure. 6. Uncontrolled cardiac arrhythmia as determined by the investigator. 4. Participant has immediate life-threatening, severe complications of their myeloid malignancy such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation. 5. Participants with uncontrolled hypertension defined as systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment. Participant with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack. 6. Participant has active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or active infection with hepatitis C virus (HCV). Participants with HIV that is controlled (not detectable viral load) with highly active antiretroviral therapy (HAART) are eligible to participate. 7. Participant has active 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). 8. Participant who is pregnant or lactating. 1. Pregnant participants are excluded from this study because luspatercept has shown in animal studies to be potentially associated with fetal harm. 2. Because there is an unknown but potential risk for AE in nursing infants secondary to treatment, lactating participants are excluded from this study. 9. Participant with prior history of malignancies, other than MDS, unless the participant has been free of the disease for ≥ 5 years. However, participants with the following history/concurrent conditions are allowed: 1. Basal or squamous cell carcinoma of the skin. 2. Carcinoma in situ of the cervix. 3. Carcinoma in situ of the breast. 4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis TNM clinical staging system).