The following criteria is provided for health care professionals.

Inclusion Criteria:

• Diagnosis

  • Phase I: confirmed diagnosis of relapsed or refractory multiple myeloma
  • Phase II: confirmed diagnosis of active multiple myeloma and must be newly diagnosed
  • NOTE: all tests for establishing disease status must be completed =< 28 days prior to registration
  • Measurable disease =< 28 days prior to registration, defined by at least one of the following:
    • Serum monoclonal protein >= 1.0 g/dL
    • > 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
    • Serum immunoglobulin free light chain > 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
    • Monoclonal bone marrow plasmacytosis > 30% (evaluable disease)

• Prior treatment

  • Phase I: exposure to 2-3 prior lines of therapy or no therapeutic options
  • Phase II: previously untreated for symptomatic MM
  • EXCEPTION: =< 7 days with pulse steroids or localized radiation therapy, without curative intent, for a myeloma-related complication prior to registration is allowed, as considered necessary by the treating physician

• Myeloma Frailty Score:

  • NOTE: this will include calculating a frailty score (based on age, activities of daily living, instrumental activities of daily living and Charlson comorbidity index)
    • Phase I: "intermediate fitness" or "frail"; NOTE: no "fit" patients will be included in the phase 1 portion of the trial which is being done to determine the MTD of the 3-drug combination
    • Phase II: transplant-ineligible as per their treating physician; NOTE: all the patients with "intermediate fitness" or "frail" status will be considered transplant-ineligible; other reasons to consider transplant ineligibility may include, but are not limited to: financial constraints or patient preference; in case such patients have a frailty score of "fit", it should be duly noted by the treating physician
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Absolute neutrophil count (ANC) >= 1,000 cell/mm^3 without growth factor support
• Platelets >= 50,000 cells/mm^3 for patients who have bone marrow
• Plasmacytosis < 50% or >= 30,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50%
• Calculated or measured creatinine clearance >= 30 ml/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN
• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 X ULN
• Provide informed written consent
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Persons able to become pregnant must be willing to adhere to the scheduled pregnancy testing as required in the REVLIMID Risk Evaluation and Mitigation Strategy (REMS) program
• Willing to be registered into the mandatory REVLIMID REMS program, and willing and able to comply with the requirements of the REVLIMID REMS program
• Ability to complete study-related (QoL, pill diary) questionnaire(s) by themselves or with assistance
• Willing to provide bone marrow aspirate and core, and blood samples for correlative research purposes

Exclusion Criteria:

• Non-secretory MM or known amyloid light-chain (AL) amyloidosis
• Clinically significant active infection requiring intravenous antibiotics =< 14 days prior to registration
• >= grade 3 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Other prior malignancy; EXCEPTIONS:
  • Adequately treated basal cell or squamous cell skin cancer
  • Any in situ cancer
  • Adequately treated stage I or II cancer from which the patient is currently in complete remission, or
  • Any other cancer from which the patient has been disease-free for >= at least three years prior to registration
• Concurrent therapy considered to be investigational; NOTE: patients must not be planning to receive any radiation therapy (except localized radiation for palliative care that must be completed prior to starting cycle 1, day 1)
• Any of the following:
  • Pregnant women
  • Nursing women (lactating females are eligible provided that they agree not to breast feed while taking lenalidomide)
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
• Requires treatment with a strong cytochrome (CYP) 3A4/5 inhibitor
• Major surgery =< 4 weeks prior to registration
• History of stroke/intracranial hemorrhage =< 6 months prior to registration
• Requires use of therapeutic anticoagulation prior to registration
  • NOTE: thromboprophylaxis with any agent is permitted
• History of clinically significant bleeding or known platelet or coagulation disorder
• Clinically significant cardiac illness including New York Heart Association (NYHA) class III or class IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or >= grade 3 cardiac arrhythmias noted =< 14 days prior to registration
• Hepatic impairment:
  • Phase I: any currently active, clinically significant hepatic impairment (Child-Pugh class A, B, or C according to the Child Pugh classification)
  • Phase II: currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification
• Known human immunodeficiency virus (HIV) positive (+) patients; EXCEPTION: if they meet the following additional criteria =< 28 days prior to registration:
  • CD4 cells >= 500/mm^3
  • Viral load of < 50 copies HIV messenger (m) ribonucleic acid (RNA)/mm^3 if on combination antiretroviral therapy (cART) or < 10,000 copies HIV mRNA if not on cART • No zidovudine or stavudine as part of cART
• Known hepatitis B or hepatitis C infection; EXCEPTION: if viral load < 800,000 IU/L
• Phase I: active dermatologic disease >= grade 3