Patients previously diagnosed with diabetes must not have uncontrolled diabetes (defined as a hemoglobin [Hg] A1C > 7% within 28 days prior to registration)
Patients must have newly diagnosed active multiple myeloma (MM); except where otherwise indicated below that assessment is required within 14 days, all tests for establishing baseline disease status must be completed within 28 days prior to registration for patients with no prior therapy, or within 28 days prior to initiation of first Induction course for patients with prior therapy
For the Phase II portion only, patients must have high-risk MM based on one or more of the following criteria at the time of initial diagnosis (prior to any chemotherapy):* Poor-risk genomic signature according to the University of Arkansas 70-gene model (available clinically as myeloma prognostic risk score [MyPRS] score, Signal Genetics, Inc) AND/OR* Translocation (14;16), and/or translocation (14;20), and/or deletion (17p) by fluorescence in-situ hybridization (FISH) or cytogenetics AND/OR* Primary plasma cell leukemia (defined by either >= 2,000 plasma cells/mL of peripheral blood, or 20% on a manual differential count) AND/OR* Serum lactate dehydrogenase (LDH) >= 2 x institutional upper limit of normal (IULN) AND/OR* 1q21 amplification by FISH analysis AND/OR* High risk by the SKY92 signature* All tests for establishing high risk status must be completed within 28 days prior to registration for patients with no prior therapy, or within 28 days prior to initiation of first Induction course for patients with prior therapy
Patients must have measurable disease within 28 days prior to registration (or prior to initiation of first induction course for patients with prior therapy)
Patients must have Barcelona Clinic Liver Cancer (BCLC) stage: intermediate (B) or advanced (C) within 28 days prior to study entry
STEP I: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 28 days after stopping lenalidomide; male subjects must also agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from lenalidomide; male subjects must be willing to use condoms for 90 days after discontinuation of carfilzomib
STEP II: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 28 days after stopping lenalidomide; male subjects must also agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from lenalidomide; males must agree to use contraception and agree to not donate sperm for at least 90 days after the last day of carfilzomib
Any of the following prior therapies:* Chemotherapy =< 28 days prior to registration* Mitomycin C/nitrosoureas =< 42 days prior to registration* Immunotherapy =< 28 days prior to registration* Biologic therapy =< 28 days prior to registration* Radiation therapy =< 28 days prior to registration* Investigational therapy or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA] approved indication and in the context of a research investigation) =< 28 days prior to registration* Prior poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor therapy
Patients with melanoma must have a serum lactate dehydrogenase (LDH) test performed within 28 days prior to registration
Any number of the following prior therapies is allowed:* Chemotherapy >= 28 days prior to registration* Mitomycin C/nitrosoureas >= 42 days prior to registration* Immunotherapy >= 28 days prior to registration* Biologic therapy >= 28 days prior to registration* Targeted therapy >= 28 days prior to registration* Radiation therapy >= 28 days prior to registration* Radiation to < 25% of bone marrow
Registration Step 3  Maintenance: Patients must have adequate marrow function as evidenced by ANC >= 750/mcl within 28 days prior to registration
The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration
Documentation of steroid doses within 28 days prior to step 2 registration
Patients who received systemic corticosteroids within 28 days of enrollment on this protocol, except as specified, are not eligible
Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration
Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information
Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist
Serum lactate dehydrogenase (LDH) < 10 X ULN (patients with LDH > 10 X ULN are felt to have aggressive disease and should be considered for BRAF inhibitor therapy off protocol), obtained within 4 weeks prior to randomization
Concomitant use of warfarin or other vitamin K antagonists within the last 28 days
Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug
Performance status of 0, 1 or 2 within 28 days prior to registration
Adequate oxygen saturation via pulse oximeter within 28 days prior to registration (i.e., patient can NOT have CTCAE hypoxia grade 2 or greater)
Serum lactate dehydrogenase (LDH) =< 10 X ULN
Patients must not have cavitating pulmonary lesions; patients must not have tumor invading the gastrointestinal (GI) tract or evidence of endotracheal or endobronchial tumor within 28 days prior to registration
Received anticoagulation therapy with warfarin, or equivalent vitamin K antagonists, within the last 28 days prior to day 1 of ibrutinib; patients with familial coagulopathic diseases (e.g. hemophilia, von Willebrand disease) are also excluded; if applicable, subjects must discontinue fish oil and vitamin E supplements within 7 days prior to initiating ibrutinib therapy
Patients must not have received any immunotherapy, biologic or any investigational drug within 28 days prior to registration; patients must not have received bevacizumab within 42 days prior to registration
Patient history: patients who have any of the following are NOT eligible:* Central nervous system (CNS): Symptomatic, untreated, or uncontrolled brain metastases present* Heme: Active bleeding or bleeding diathesis* Gastrointestinal (GI):** Abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days prior to registration** Acute GI bleed within 28 days of registration* Diabetes mellitus: Patients with diabetes mellitus with inadequate control, based on either a glycosylated hemoglobin (Hgb A1c) of > 7.0 or fasting blood glucose above or equal to 130 mg/dL* Cardiac and vascular disorders:** History of congenital long QT syndrome or torsades de pointes** Any arrhythmia that is currently not rate-controlled (rate between 60 and 100)** Prolongation of corrected QT interval via Fridericias formula (QTcF) > 480 msec** Ongoing unstable angina** Symptomatic peripheral vascular disease** Arterial thrombosis within 28 days of registration including transient ischemic attack (TIA), cerebrovascular accident (CVA), myocardial infarction (MI)** Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) must be on a stable dose of anticoagulation for 14 days prior to registration** Uncontrolled hypertension, defined as blood pressure (BP) > 140/90** Multi gated acquisition scan (MUGA) with ejection fraction (EF), 50% or echocardiogram (echo) with low EF** Class III or IV congestive heart failure (CHF) within 28 days of registration
Anemia (hematocrit < 28%)
Prestudy history and physical must be obtained within 90 days prior to registration; patients must have a complete blood count (CBC) and basic metabolic panel including creatinine, potassium, chloride, blood urea nitrogen (BUN), carbon dioxide (CO2) and glucose within 28 days prior to registration
Patients must have lactate dehydrogenase (LDH) performed within 28 days prior to registration
Patients with autoimmune disease who are otherwise eligible must not have received steroid and immunosuppressive therapy within 28 days prior to registration
Within 28 days prior to registration: ANC >= 1,000/mcL
Patients must have adequate adrenal axis function, as evidenced by adrenocorticotropic hormone (ACTH) values within the institutional normal ranges OR cortisol levels within institutional normal ranges (ante meridiem [AM] cortisol preferred), within 28 days prior to registration
Patients must have a baseline electrocardiograph (ECG) performed within 42 days prior to registration
Patients who have had significant traumatic injury within 28 days prior to enrollment are not eligible
Activated partial thromboplastin time (aPTT) =< 2.0 x IULN if not using anticoagulants within 28 days prior to registration; if using anticoagulants, then the value must be within therapeutic range according to the condition for which the patient is being treated within 28 days prior to registration
Patients must have lactate dehydrogenase (LDH) obtained prior to registration