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