Inclusion Criteria:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local study participant privacy regulations.
2. Male or female ≥ 18 years of age, at the time of signing informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia).
4. Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception.
5. In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).
Part 1 Inclusion Criteria
Participants are eligible to be included in Part 1 of the study only if all the following criteria apply:
1. Diagnosis of MDS according to WHO classification that meets International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease.
2. Less than (\<)5percent (%) blasts in bone marrow during the Pretreatment Period.
3. Peripheral blood white blood cell (WBC) count \<13,000/microliter (μL) during the Pretreatment Period.
4. Anemia defined as:
1. In non-transfused participants, having received no RBC transfusions within 8 weeks, Hgb concentration ≤ 10.0 g/dL during the Pretreatment Period OR
2. In LTB participants, having received 1 to 3 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period.
OR
3. In HTB participants, having received ≥ 4 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period.
Part 1 Extension - Abbreviated Inclusion Criteria
Participants from Part 1 are eligible to be included in Part 1 Extension of the study only if all the following criteria apply:
1. Previously completed 4 cycles of elritercept in Part 1 with no dose-limiting toxicities (DLTs).
2. Participant has the potential to benefit from administration of elritercept, in the opinion of the Investigator.
3. \< 5% blasts in bone marrow.
4. Peripheral WBC count \< 13,000/μL during the 28 days prior to cycle 5 day 1 (C5D1).
Part 2 Inclusion Criteria
Participants are eligible to be included in Part 2 of the study only if all the following criteria apply:
1. Cohort A:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* ring sideroblast (RS)-positive as defined by WHO 2016 criteria.
* Requiring at least 2 units of RBC transfusions in the preceding 8 weeks before cycle 1 day 1 (C1D1).
2. Cohort B:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Non-RS as defined by WHO 2016 criteria.
* Requiring at least 2 units of RBC transfusions in the 8 weeks before C1D1.
3. Cohort C:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D1.
4. Cohort D:
* Diagnosis of CMML according to WHO classification.
* Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D1.
* OR
* Received at least 2 units of RBC transfusions for anemia in the 8 weeks before C1D1.
5. Cohort E:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D1.
* Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
* Serum ferritin \> 1000 nanograms per milliliter (ng/mL) on ≥ 2 assessments in the preceding 8 weeks before C1D1.
* Treated with stable dose of iron chelation therapy for ≥ 8 weeks prior to C1D1.
6. Cohort F:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D1.
* Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
* Serum ferritin \> 1000 ng/mL on ≥ 2 assessments in the preceding 8 weeks before C1D1.
* Not treated with iron chelation therapy in the preceding 8 weeks before C1D1 and not eligible to initiate iron chelation therapy in the opinion of the Investigator and in accordance with local treatment guidelines for initiation of iron chelation therapy.
7. Cohort G:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* RS-positive as defined by WHO 2016 criteria OR non-RS as defined by WHO 2016 criteria.
* Relapsed, refractory, or intolerant to frontline luspatercept treatment and have not received an interceding therapy (for example, erythropoiesis-stimulating agent \[ESA\])
* Relapsed is defined as documentation of response to luspatercept therapy and subsequent development of a need for transfusion(s).
* Refractory is defined as documentation of no response with luspatercept ≥ 1 mg/kg administered for ≥ 12 weeks duration.
* Intolerant is defined as documentation of discontinuation of luspatercept therapy due to intolerance or an AE at any time after introduction.
* Requiring ≥ 2 units of RBC transfusions over 8 weeks prior to C1D1.
* Erythropoietin (EPO) \< 500 international units per liter (U/L) at Baseline.
* Last dose of luspatercept is ≥ 3 weeks and \< 12 months from C1D1.
8. \< 5% blasts in bone marrow assessed by bone marrow aspirate during the Pretreatment Period.
Part 1 Exclusion Criteria
Participants are excluded from Part 1 of the study if any of the following criteria apply.
Medical History
1. Diagnosis of MDS with deletion of chromosome 5q (Del5q).
2. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
3. Presence of uncontrolled heart disease or New York Heart Association (NYHA) Class III or IV heart failure.
4. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
5. History of stroke, deep venous thrombosis (DVT), or arterial embolism within 6 months prior to C1D1.
6. Major surgery within 28 days prior to C1D1. Participants must be completely recovered from any previous surgery prior to C1D1.
7. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
8. Any malignancy other than MDS that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C1D1. Diagnosis of secondary MDS (i.e., MDS known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases).
9. History of solid organ or hematological transplantation.
10. Presence of uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
11. Body mass index (BMI) ≥ 40 kilograms per meter square (kg/m\^2) during the Pretreatment Period.
12. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational medicinal product (IMP).
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept.
2. Treatment with ESA within 56 days prior to C1D1.
3. Prior or concurrent chronic treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).
4. Iron chelation therapy if initiated within 8 weeks prior to C1D1.
5. Vitamin B12 therapy initiated within 8 weeks prior to C1D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
6. Treatment with another investigational drug or device or approved therapy for investigational use ≤ 28 days prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
Laboratory Exclusions (during Pretreatment Period)
1. Platelet count \> 450 ✕ 10\^9/L or \< 30 ✕ 10\^9/L.
2. Transferrin saturation \< 15%.
3. Ferritin \< 50 nanograms per milliliter (ng/mL).
4. Folate \< 4.5 nanomoles per liter (nmol/L) (\< 2.0 ng/mL).
5. Vitamin B12 \< 148 picomoles per liter (pmol/L) (\< 200 picograms per milliliter \[pg/mL\]).
6. Estimated glomerular filtration rate (GFR) \< 30 milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2), as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
7. Positive for HIV.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or contract research organization (CRO) employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Part 1 Extension - Exclusion Criteria
Participants from Part 1 are excluded from Part 1 Extension of the study if any of the following criteria apply.
Medical History
1. Discontinuation of IMP in Part 1 for any reason.
2. Has not completed a study visit in the past 12 months.
3. Active infection requiring parenteral antibiotic therapy within 28 days prior to C5D1 or oral antibiotics within 14 days of C5D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
4. Presence of uncontrolled heart disease or NYHA Class III or IV heart failure.
5. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
6. History of stroke, DVT, or arterial embolism within 6 months prior to C5D1.
7. Major surgery within 28 days prior to C5D1. Participants must be completely recovered from any previous surgery prior to C5D1.
8. Known positive for HIV, active infectious HBV, or active infectious HCV. Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
9. Any malignancy other than MDS that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C5D1.
10. History of solid organ or hematological transplantation.
11. Presence of uncontrolled hypertension, defined as systolic BP ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
12. BMI ≥ 40 kg/m\^2 during the 28 days prior to C5D1.
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept.
2. Treatment with ESA within 56 days prior to C5D1.
3. Prior or concurrent chronic treatment with G-CSF or GM-CSF.
4. Iron chelation therapy if initiated within 8 weeks prior to C5D1.
5. Vitamin B12 with treatment initiated within 8 weeks prior to C5D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
6. Treatment with another investigational drug or device or approved therapy for investigational use ≤ 28 days prior to C5D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C5D1, whichever is longer. Previous treatment with elritercept is acceptable.
Laboratory Exclusions (during Abbreviated Pretreatment Period)
1. Platelet count \> 450 × 10\^9/L or \< 30 × 10\^9/L.
2. Transferrin saturation \< 15%.
3. Ferritin \< 50 ng/mL.
4. Folate \< 4.5 nmol/L (\< 2.0 ng/mL).
5. Vitamin B12 \< 148 pmol/L (\< 200 pg/mL).
6. Estimated GFR \< 30 mL/min/1.73 m\^2, as determined by the CKD-EPI equation.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or CRO employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Part 2 Exclusion Criteria
Participants are excluded from Part 2 of the study if any of the following criteria apply.
Medical History
1. Diagnosis of MDS with Del5q.
2. Diagnosis of secondary MDS (i.e., MDS known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases).
3. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
4. Presence of the following cardiac conditions:
1. Presence of uncontrolled heart disease or NYHA Class III or IV heart failure.
2. QTcF (QT interval corrected by Fridericia's formula) \> 500 msec on the screening or C1D1 electrocardiogram (ECG; mean of 3 measurements).
3. Uncontrolled clinically significant arrhythmia (participants with rate-controlled atrial fibrillation are not excluded).
4. Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to C1D1.
5. Presence of uncontrolled hypertension, defined as systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
6. History of stroke, DVT, or arterial embolism within 6 months prior to C1D1.
7. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
8. Major surgery within 28 days prior to C1D1. Participants must be completely recovered from any previous surgery prior to C1D1.
9. Any malignancy other than MDS or CMML that has not been in remission and/or has required major surgery or systemic therapy including radiation, chemotherapy, targeted therapy, or hormonal therapy within 1 year prior to C1D1.
10. History of solid organ or hematological transplantation.
11. Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenital disorders as a cause of the participant's anemia.
12. NCI-CTCAE Grade ≥ 2 bleeding events within the 3 months prior to C1D1.
13. Receipt of an RBC or platelet transfusion for any reason(s) or combination of reasons other than underlying MDS within the 16 weeks prior to C1D1. If a participant requires a transfusion for an unanticipated reason during the Pretreatment Period, a prolonged screening period may be considered after discussion with the Medical Monitor.
14. Known positive for HIV, active infectious HBV with positive viral load (HBV DNA), or active infectious HCV with positive viral load (HCV RNA). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
15. BMI ≥ 40 kg/m\^2.
16. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the IMP.
17. Diagnosis of cirrhosis, non-alcoholic steatohepatitis, alcoholic liver disease, hepatitis, or other liver disease (acute or chronic) meeting Child-Pugh C criteria for hepatic impairment. Participants with elevated liver enzymes are allowed if the liver enzyme elevation is suspected to be due to iron-overload or iron chelation, and other hepatic causes have been ruled out, in the opinion of the Investigator.
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, or sotatercept.
2. Prior treatment with luspatercept (Cohorts A, B, C, D, E, and F only).
3. Treatment with ESA within 8 weeks prior to C1D1.
4. Prior or concurrent chronic treatment with G-CSF or GM-CSF, for reasons other than for treatment of MDS.
a. Note: Previous treatment with G-CSF or GM-CSF for MDS, which has been discontinued ≥ 8 weeks prior to C1D1 is allowed.
5. Iron chelation therapy if initiated within 8 weeks prior to C1D1. Participants on stable doses of iron chelation therapy for ≥ 8 weeks are allowed.
6. Vitamin B12 and/or folate therapy initiated within 8 weeks prior to C1D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
7. Any need to receive a prohibited medication.
8. Treatment with another investigational drug or device or approved therapy for investigational use within 8 weeks prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
Laboratory Exclusions (during Pretreatment Period)
1. Peripheral WBC count ≥ 13,000/μL.
2. Platelet count \> 450 × 10\^9/L or \< 25 × 10\^9/L.
3. Transferrin saturation \< 15%.
4. Ferritin \< 50 ng/mL.
5. Folate \< 4.5 nmol/L (\< 2.0 ng/mL).
6. Vitamin B12 \< 148 pmol/L (\< 200 pg/mL).
7. Estimated GFR \< 30 mL/min/1.73 m\^2 as determined by the CKD-EPI equation.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or CRO employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
For Cohort G ONLY:
1. Any luspatercept related AE Grade ≥ 3 that has not resolved to baseline or Grade ≤ 1.
2. No history of allergy/anaphylaxis/hypersensitivity to luspatercept.
3. No prior treatment with imetelstat.
