• Ability to understand and the willingness to sign a written informed consent document.

• Participant is 18 years or older at the time of signing informed consent.

• 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).

• 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.

• Absence of SF3B1 mutation and del5q.

• Endogenous serum erythropoietin alfa (EPO) level \< 500 IU/L.

• 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.

• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 (Appendix 1. ECOG Performance Status Scale).

• Participant has adequate organ function defined as:

∙ 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).

‣ Serum direct bilirubin \< 1.5 x ULN.

‣ Creatinine clearance \> 30 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation.

⁃ 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).