Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Histologically confirmed B-cell non-Hodgkin's lymphoma (NHL) of any of the following subtypes recognized by the World Health Organization (WHO) classification: diffuse large B-cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, or follicular lymphoma; patients with evidence of histological transformation to diffuse large B-cell lymphoma from indolent NHL are eligible

Patients must have received at least one prior therapy; prior autologous stem cell transplant is permitted; patients with diffuse large B-cell lymphoma who have not received high-dose therapy (HDT)/autologous stem cell transplant (ASCT) must be ineligible for HDT/ASCT; prior allogeneic stem cell transplant is not permitted; prior ibrutinib is not permitted

Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of ibrutinib in combination with lenalidomide in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)

Life expectancy of greater than 12 weeks

Patients must have normal organ and marrow function, independent of growth factor or transfusion support; patients should not receive growth factors or transfusions for at least 7 days prior to first dose of study drug, with the exception of pegylated G-CSF (pegfilgrastim) and darbepoeitin which require at least 14 days prior to screening and randomization

Absolute neutrophil count \>= 1,000/mcL in the absence of growth factor administration

Platelets \>= 50,000/mcL in the absence of transfusion support within 7 days prior to determination of eligibility

Total bilirubin =\< 1.5 x upper limit of normal (ULN) unless due to Gilberts disease

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X institutional upper limit of normal unless due to disease

Creatinine =\< 2.0 mg/dL OR creatinine clearance \>= 50 mL/min as determined by the Cockcroft-Gault equation or a 24 hour urine collection

Non-pregnant and non-nursing; due to the known teratogenic potential of lenalidomide and the unknown teratogenic potential of ibrutinib, pregnant or nursing patients may not be enrolled; females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again within 24 hours of starting cycle 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide and for 28 days after the last dose of study drug; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; a FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure

Patients with human immunodeficiency virus (HIV) infection are eligible provided they meet the following criteria: no evidence of co-infection with hepatitis B or C, cluster of differentiation (CD)4 count \>= 400 cells/mm\^3, no resistant viral strains, on highly active antiretroviral treatment (HAART) therapy with a viral load \< 50 RNA copies/ml, and no history of acquired immunodeficiency syndrome (AIDS)-defining conditions

Ability to understand and the willingness to sign a written informed consent document

Curative therapy must have been exhausted or not feasible to administer; patients with diffuse large B-cell lymphoma, germinal center subtype should only enroll on the study if there are no other potentially effective therapeutic options

What this study is about