Ibrutinib, Lenalidomide, and Dexamethasone in Treating Patients With Multiple Myeloma Ineligible for Transplant

Inclusion Criteria:

Age >= 18 years

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 (obtained =< 14 days prior to registration)
Platelets >= 50,000 cells/mm^3 for patients who have bone marrow (obtained =< 14 days prior to registration)
Plasmacytosis < 50% or >= 30,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50% (obtained =< 14 days prior to registration)
Calculated or measured creatinine clearance >= 30 ml/min (obtained =< 14 days prior to registration)
Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome (obtained =< 14 days prior to registration)
Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN (obtained =< 14 days prior to registration)
Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 X ULN (obtained =< 14 days prior to registration)
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