Inclusion Criteria:

• Age ≥ 18 years and ≤ 80 years.
• High risk myeloma, which is untreated, defined as any of:
  • ISS stage 3 and gain of chr1q or del17p);
  • bi-allelic deletion of TP53;
  • t(4;14) or t(14;16) and gain of chr1q;
  • t(4;14) or t(14;16) and presence of del17p; or
  • presence of a high-risk gene expression signature on Sky92 assays (Skyline Diagnostics).
• The following laboratory values obtained ≤ 14 days prior to registration.
  • Calculated creatinine clearance (using Cockcroft-Gault equation below)* ≥ 30 mL/min;
  • Absolute neutrophil count (ANC) ≥ 1000/mm^3 (without the use of growth factors);
  • Platelet count ≥ 75000/mm^3;
  • Hemoglobin ≥ 8.0 g/dL;
  • Total bilirubin ≤ 1.5 x ULN;
  • ALT and AST ≤ 3 x ULN;
  • *Cockcroft-Gault Equation:
  • Creatinine clearance for males =
  • (140 - age)(actual body weight in kg)/ (72)(serum creatinine in mg/dL)
  • Creatinine clearance for females =
  • (140 - age)(actual body weight in kg)(0.85)/(72)(serum creatinine in mg/dL).
• LVEF ≥ 40%.
• ECOG performance status (PS) 0 or 1.
• Provide informed written consent. 
• Negative pregnancy test done ≤ 14 days prior to registration, for women of childbearing potential only.
  • Note: All study participants must be registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of the REMS® program.
  • Note: Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
• Willing to follow strict birth control measures as outlined in the protocol.
• Female subjects: If they are of childbearing potential, agree to one of the following:
  • Practice two effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of trial drug, AND must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Male subjects: even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
  • Agree to practice effective barrier contraception during the entire trial treatment period and through 90 days after the last dose of trial drug, OR
  • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject.  (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). 
• Willing to return to enrolling institution for follow-up during the Active Treatment Phase of the trial.
• Able to take aspirin (325 mg) daily as prophylactic anticoagulation. 
  • Note: Subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin.
• Male subjects must agree not to donate sperm for at least 90 days after the last dose of study treatment.
• Willing to provide blood and bone marrow samples for planned research.
• Life expectancy > 6 months.
• Able to take aspirin (325 mg) daily as prophylactic anticoagulation.  Note: Subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin.

Exclusion Criteria:

• MGUS, smoldering myeloma, light chain amyloidosis with organ involvement
• Diagnosed or treated for another malignancy ≤ 1 year prior to registration or previously diagnosed with another malignancy and have any evidence of residual disease.  Note: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol).
• Other co-morbidity which would interfere with subject's ability to participate in trial; e.g., uncontrolled infection, uncompensated heart or lung disease.
• Other concurrent chemotherapy, or any ancillary therapy considered investigational. 
  • NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
• Peripheral neuropathy ≥ Grade 3 on clinical examination or grade 2 with pain ≤ 30 days prior to registration.
• Major surgery ≤ 14 days prior to registration.
• Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.  Note: Prior to trial entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure) or known sensitivity to mammalian-derived products.  Known allergies, hypersensitivity, or intolerance to trial drugs.
• NYHA II, III, IV heart failure
• Known human immunodeficiency virus (HIV) positive.
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).  Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.  Those who are PCR positive will be excluded. 
  • EXCEPTION: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Known or suspected active hepatitis C infection.
• Any medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
• Prior radiation therapy for bony lesions or plasmacytomasKnown allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure) or known sensitivity to mammalian-derived products.  Known allergies, hypersensitivity, or intolerance to trial drugs.
• Inability to comply with protocol/procedures.

Eligibility last updated 3/9/22. Questions regarding updates should be directed to the study team contact.