Sotatercept, Lenalidomide or Pomalidomide, and Dexamethasone in Treating Patients with Relapsed or Refractory Multiple Myeloma

Inclusion Criteria

• Relapsed or relapsed/refractory multiple myeloma (MM) with progressive disease (PD) parameters according to International Myeloma Working Group (IMWG) criteria * Refractory is defined as experiencing less than minimal response to or PD within 60 days of the most recent line therapy * Relapsed is defined as patients requiring salvage therapy for PD who are not refractory to the most recent line of therapy
• Relapsed patients must have measurable disease; patients without measurable disease may be considered after discussion with principal investigator
• Participant must have received at least one prior line of treatment of multiple myeloma; for pomalidomide-containing arm(s), patients must have received at least one prior line of treatment and must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of proteasome inhibitor (either in separate regimens or within the same regimen) unless not a candidate
• For participants treated with local radiotherapy with or without concomitant exposure to steroids, for pain control or management of cord/nerve root compression, two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field; participants who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and two weeks have passed since the last date of therapy
• Eastern Cooperative Oncology Group (ECOG) performance status of zero to two unless decline is due to bony disease
• Serum bilirubin less than two times the institutional upper limits of normal (ULN); higher levels are acceptable if these can be attributed to active hemolysis, ineffective erythropoiesis, or Gilbert’s disease
• Serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) less than three times the upper limits of normal (ULN)
• Absolute neutrophil count (ANC) >= 1000/uL
• Platelet count >= 50,000/ul; for patients with >= 50% plasma cell involvement of the bone marrow, platelet count >= 30,000/ul is acceptable
• Creatinine clearance >= 30 mL/min
• Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test within 7 days of starting study drug; in addition, sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; or barrier contraceptive with spermicide) while on study drug; WCBP must agree to have pregnancy tests every 4 weeks while on study drug
• Hemoglobin 8-13 g/dL (patients with hemoglobin > 13 g/dL are excluded)
• All study participants must be registered into the mandatory pomalidomide (POMALYST) Risk Evaluation and Mitigation Strategy (REMS) program and be willing and able to comply with the requirements of the POMALYST REMS program
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the POMALYST REMS program
• Ability to understand and the willingness to sign a written informed consent document
• The effects of sotatercept on the developing human fetus are unknown; for this reason and because IMiDs are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

Exclusion Criteria

• Prior pomalidomide treatment (for patients on the pomalidomide arm)
• Participants who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Participants may not have received treatment with another investigational drug or device within 28 days prior to day 1, or if the half-life of the previous product is known, within 5 times the half-life prior to dosing, whichever may be longer
• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to sotatercept, lenalidomide, pomalidomide, or dexamethasone; participants with a prior history of allergic reaction to lenalidomide (grade 1-2) may be allowed to participate in the pomalidomide arm, after discussion with the principal investigator and if the use of pomalidomide would reflect standard practice
• Bisphosphonates will not be allowed on the study while the participant is receiving sotatercept; prior bisphosphonate use is allowed
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because lenalidomide and pomalidomide are IMiDs with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with lenalidomide or pomalidomide, breastfeeding should be discontinued if the mother is treated with lenalidomide or pomalidomide; these potential risks may also apply to other agents used in this study
• Individuals with a history of a malignancy (other than multiple myeloma) are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy
• Individuals with the following non-invasive cancers are eligible: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
• History of major surgery within 30 days prior to trial initiation
• Human immunodeficiency virus (HIV) infection
• Active hepatitis B infection
• Active hepatitis C infection