Luspatercept and Lenalidomide (L2) in Lower-risk, Non-del(5q) MDS Patients

Inclusion Criteria: 1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF). 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. 3. Documented diagnosis of MDS according to World Health Organization (WHO) / French-American-British (FAB) classification that meets International Prognostic Scoring System Revised (IPSS-R) classification (Greenberg, 2012) of very low, low, or intermediate risk disease; intermediate patients must have a blast percentage \<5% to be enrolled. 4. Subjects can be ESA-naïve, or refractory or intolerant to, or ineligible for, prior ESA treatment, as defined by any one of the following: * Refractory to prior ESA treatment - documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF); ESA regimen must have been either: * recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent; OR * darbepoetin alpha ≥ 200-500 μg Q1-3W for at least 4 doses or equivalent; * Intolerant to prior ESA treatment - documentation of discontinuation of prior ESAcontaining regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event * ESA ineligible - Low chance of response to ESA based on endogenous serum erythropoietin level \> 200 U/L for subjects not previously treated with ESAs 5. If previously treated with ESAs, agents must have been discontinued ≥ 4 weeks prior to date of C1D1. 6. Requires RBC transfusions, as documented by the following criteria: * average transfusion requirement of ≥ 2 units/8 weeks of packed Red Blood Cells (pRBC)s preceding C1D1. * Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 10.0 g/dL for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were \> 10.0 g/dL and/or RBC transfusions administered for elective surgery will not qualify as a required transfusion for the purpose of meeting eligibility criteria. 7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 (Appendix 1) 8. Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) 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), must: * Have two negative pregnancy tests (urine or serum) as verified by the Investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of C1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. * If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy. 9. Male subjects must: * Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (for example, polyurethane), 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 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy. 10. Subject must have a negative Coronavirus Disease of 2019 (COVID-19) test completed ≤7 days prior to administration of protocol therapy. 11. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: 1. Prior therapy with Lenalidomide. 2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011) 3. MDS associated with del 5q cytogenetic abnormality 4. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding * iron deficiency to be determined by serum ferritin ≤ 15 μg/L and additional testing if clinically indicated (eg, calculated transferrin saturation \[iron/total iron binding capacity ≤ 20%\] or bone marrow aspirate stain for iron). 5. Prior allogeneic stem cell transplant 6. Known history of diagnosis of AML 7. Use of any of the following within 4 weeks prior to C1D1: * anticancer cytotoxic chemotherapeutic agent or treatment * other RBC hematopoietic growth factors (eg, Interleukin-3) * investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the half-life prior to C1D1 or within 5 weeks, whichever is longer is excluded. 8. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment. 9. Prior history of malignancies, other than MDS, unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 1 year. However, subjects with the following history/concurrent conditions involving in situ cancer (or similar) are allowed: * Basal or squamous cell carcinoma of the skin * Carcinoma in situ of the cervix * Carcinoma in situ of the breast * Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis (TNM) clinical staging system) 10. Major surgery within 4 weeks prior to C1D1. Subjects must have completely recovered from any previous surgery prior to C1D1 11. History of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within 6 months prior to C1D1 12. Pregnant or breastfeeding females 13. Subject has any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that, in the opinion of the Investigator, would prevent the subject from participating in the study.