Assessment of Effectiveness and Safety of Luspatercept in Patients Suffering From Lower-risk Myelodysplastic Syndrome.

Inclusion Criteria:

1. Subject is 18 years of age or older at the time of signing the informed consent form (ICF)

2. Subject is able to understand and voluntarily sign the ICF prior to anystudy-related assessments/procedures being conducted

3. Subject has documented diagnosis of MDS according to WHO classification that meetsIPSS-R classification[3] of very low-, low-, or intermediate-risk disease, and thefollowing:

• Ring sideroblasts (RS) ≥ 15% of erythroid precursors in bone marrow or ≥ 5% ifSF3B1 mutation is present

• Less than 5% blasts in bone marrow

• Peripheral blood white blood cell (WBC) count < 13,000/μL

4. Subject must be one of the following:

• Refractory to prior ESA treatment: Documentation of non-response or responsethat was no longer maintained to prior ESA-containing regimen, either as asingle agent or in combination (e.g. with granulocyte colony-stimulating factor [G-CSF]). The ESA regimen must be either:

• Recombinant human erythropoietin ≥ 40,000 IU/week for at least 8 weeks (=doses) or equivalent; or

• Darbepoetin-α ≥ 500 μg q3w for at least 4 doses or equivalent

• Intolerant to prior ESA treatment: Documentation of discontinuation of priorESA containing regimen, either as a single agent or in combination (e.g. withG-CSF), at any time after introduction due to intolerance or an adverse event (AE)

• ESA ineligible: Low chance of response to ESA based on endogenous serumerythropoietin (EPO) level > 200 U/L for subjects not previously treated withESAs

• Refractory to- /relapsed after prior HMA treatment1: Treatment failure/relapseafter at least six (azacitidine) or four (decitabine) 4-week treatment cyclesexcept for del(5q) MDS

• Refractory to- /relapsed after prior lenalidomide treatment1 except for del(5q)MDS

5. If previously treated with ESAs or G-CSF/granulocyte-macrophage colony-stimulatingfactor (GM-CSF), both agents must be discontinued ≥ 4 weeks prior to the date ofstarting treatment with the Investigational medicinal Product (IMP) in this study

6. Required RBC transfusions, as documented by the following criteria:

• Average transfusion requirement of ≥ 2 units/8 weeks of packed RBCs confirmedfor a minimum period of 16 weeks immediately preceding start of treatment withIMP

• Hemoglobin (Hb) levels at the time of or within 7 days prior to administrationof an RBC transfusion must be ≤ 10.0 g/dL in order for the transfusion to becounted towards meeting eligibility criteria. RBC transfusions administeredwhen Hb levels are > 10 g/dL and/or RBC transfusions administered for electivesurgery do not qualify as a required transfusion for the purpose of meetingeligibility criteria

• No consecutive 56-day period that is RBC transfusion-free during the 16 weeksimmediately prior to starting treatment with IMP

7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2

8. A female of childbearing potential (FCBP) for this study is defined as a sexuallymature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) is not naturally postmenopausal (amenorrhea following cancer therapy does notrule out childbearing potential) for at least 24 consecutive months (i.e. had mensesat any time in the preceding 24 consecutive months). An FCBP participating in thestudy must:

• Have 2 negative pregnancy tests as verified by the investigator prior tostarting IMP (unless the screening pregnancy test is done within 72 hours ofCycle 1 Day 1). She must agree to ongoing pregnancy testing during the courseof the study and after end of treatment (EOT).

• If sexually active, agree to use, and be able to comply with, highly effectivecontraception** without interruption, 5 weeks prior to starting IMP, duringtreatment with IMP (including dose interruptions), and for 12 weeks afterdiscontinuation of IMP. ** Highly effective contraception is defined in thisprotocol as the following (information also appears in the ICF): Hormonalcontraception (e.g. birth control pills, injection, implant, transdermal patch,vaginal ring), intrauterine device, tubal ligation, or a partner with avasectomy

9. Male subjects must agree to use a condom, defined as a male latex condom or nonlatexcondom NOT made out of natural (animal) membrane (e.g. polyurethane), during sexualcontact with a pregnant female or an FCBP while participating in the study, duringdose interruptions, and for at least 12 weeks following IMP discontinuation, even ifhe has undergone a successful vasectomy

10. Subject is willing and able to adhere to the study visit schedule and other protocolrequirements

Exclusion Criteria:

1. Prior therapy with disease modifying agents other than HMA or LEN for underlying MDSdisease

2. Previously treated with either luspatercept or sotatercept

3. Secondary MDS, i.e. MDS that is known to have arisen as the result of chemicalinjury or treatment with chemotherapy and/or radiation for other diseases

4. Known clinically significant anemia due to iron, vitamin B12, or folatedeficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinalbleeding

• Iron deficiency to be determined by local laboratory via serum ferritin ≤ 15 μg/Land additional testing if clinically indicated (e.g. calculated transferrinsaturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stainfor iron)

5. Prior allogeneic or autologous stem cell transplant

6. Known history of diagnosis of acute myeloid leukemia (AML)

7. Use of any of the following within 5 weeks prior to the first dose of the IMP inthis study:

• Anticancer cytotoxic chemotherapeutic agent or treatment

• Corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 weekprior to the first dose of IMP for medical conditions other than MDS ICT,except for subjects on a stable or decreasing dose for at least 8 weeks priorto the first dose of IMP

• Other RBC hematopoietic growth factors (e.g. interleukin [IL]-3)

• Investigational drug or device, or approved therapy for investigational use. Ifthe half-life of the previous study drug is known, the use of it within 5 timesthe half-life prior to the first dose of IMP or within 5 weeks, whichever islonger, is excluded

8. Uncontrolled hypertension, defined as repeated elevations of diastolic bloodpressure (DBP) ≥ 100 mmHg despite adequate treatment

9. Platelet count < 30,000/μL (30 × 109/L)

10. Estimated glomerular filtration rate or creatinine clearance < 40 mL/min

11. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) oralanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≥ 3.0 ×upper limit of normal (ULN)

12. Total bilirubin ≥ 2.0 × ULN

• Higher levels are acceptable if these can be attributed to active RBC precursordestruction within the bone marrow (i.e. ineffective erythropoiesis) or in thepresence of known history of Gilbert Syndrome

• Subjects are excluded if there is evidence of autoimmune hemolytic anemiamanifested as a corrected reticulocyte count of > 2% with either a positiveCoombs test or over 50% indirect bilirubin

13. Prior history of malignancies, other than MDS, unless the subject is free of thedisease (including completion of any active or adjuvant treatment for priormalignancy) for ≥ 5 years. However, subjects with the following history/concurrentconditions 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 clinical staging system)

14. Major surgery within 8 weeks prior to the first dose of IMP. Subjects must becompletely recovered from any previous surgery prior to the first dose of IMP

15. History of stroke, deep venous thrombosis, pulmonary or arterial embolism within 6months prior to the first dose of IMP

16. Pregnant or breast-feeding females

17. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, oruncontrolled cardiac arrhythmia as determined by the investigator within 6 monthsprior to the first dose of IMP. Subjects with a known ejection fraction of ˂ 35%,confirmed by a local echocardiography or multigated acquisition scan (MUGA)performed within 6 months prior to the first dose of IMP, are excluded

18. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoingsigns/symptoms related to the infection without improvement despite appropriateantibiotics, antiviral therapy, and/or other treatment), known humanimmunodeficiency virus (HIV), known evidence of active infectious hepatitis B,and/or known evidence of active hepatitis C

19. History of severe allergic or anaphylactic reactions or hypersensitivity torecombinant proteins or excipients in the IMP

20. Subject is in custody by order of an authority or a court of law

21. Participation in another interventional clinical study within the last 3 monthsprior to signing the ICF or simultaneous participation in other clinical studies

22. Close affiliation with the investigator (e.g. a close relative) or persons workingat the study site

23. Subject is an employee of the sponsor or involved Contract research Organization (CRO)

24. Criteria which in the opinion of the investigator preclude participation forscientific reasons, for reasons of compliance, or for reasons of the subject'ssafety