The purpose of the study is to see if participants with anemia due to their type of MDS or MDS/MPN will experience a more decreased need for regular blood transfusions if they take luspatercept plus best supportive care, and what effect, good and/or bad, luspatercept has on them and their anemia due to MDS or MDS/MPN. The safety and tolerability of luspatercept will also be evaluated in this study.

Inclusion Criteria:

1. Participant is ≥18 years at the time of signing the informed consent form

2. Participant is willing and able to adhere to the study visit schedule and other protocol requirements

3. Documented diagnosis of MDS or non-proliferative MDS/MPN (WBC < 13,000 U/L)

   1. According to WHO 2016 classification
   2. Meets IPSS-R classification of very low, low, or intermediate risk disease

4. Documented acquired splicing gene mutation

   1. Cohort 1: detectable splicing mutation other than SF3B1: (SRSF2, U2AF1, ZRSR2)
   2. Cohort 2: SF3B1 mutation with prior treatment with hypomethylating agent and or lenalidomide

5. <5% blasts in bone marrow

6. Refractory, intolerant to, or ineligible for, prior ESA treatment, as defined by any one of the following:

   1. Refractory to prior ESA treatment - non-response or response that is no longer maintained. ESA regimen must have been either:

      • rHu EPO ≥ 40,000 IU/wk for at least 8 doses or equivalent Or darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent

   2. Intolerant to prior ESA treatment - discontinuation of prior ESA-containing regimen, at any time after introduction due to intolerance or AE

   3. ESA ineligible - Low chance of response to ESA based on endogenous serum EPO > 200 U/L for subjects not previously treated with ESAs

7. Discontinuation of ESAs, G-CSF, GM-CSF ≥ 4 weeks prior to start of study treatment

8. Require RBC transfusions

   a. Average of ≥ 2 units/8 weeks of pRBCs confirmed for a minimum of 16 weeks immediately preceding registration

9. Applies to on treatment subjects only - females of childbearing potential (FCBP) defined as a sexually mature woman who:

   1. has achieved menarche at some point,

   2. has not undergone a hysterectomy or bilateral oophorectomy, or

   3. 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) and must:

      • Have two negative pregnancy tests 48 hours apart as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact.
      • Either commit to true abstinence*from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with highly effective, contraception without interruption, 35 days prior to starting

10. investigational product (IP), during the study therapy (including dose interruptions), and for 84 days after discontinuation of study therapy

11. Applies to on treatment subjects only - Male subjects must:

    1. Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom 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 84 days following investigational product discontinuation even if he has undergone a successful vasectomy. * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).

Exclusion Criteria:

1. Prior allogeneic or autologous stem cell transplant
2. MDS associated with del 5q cytogenetic abnormality if no prior lenalidomide treatment
3. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment
4. ANC < 500/μL (0.5 x 109/L)
5. Platelet count ˂50,000/μL (50 x 109/L)
6. Active other malignancies
7. Severe renal impairment (eGFR < 30 mL/min/1.73 m2)
8. ALT or AST ≥ 3 × ULN
9. Prior treatment with Luspatercept or Sotatercept
10. Pregnant or breastfeeding females