Smart Start: A Phase II Study of Rituximab, Lenalidomide, and Ibrutinib

Inclusion Criteria: * Histopathologically confirmed diagnosis of previously untreated DLBCL of the non-GCB DLBCL subtype * No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids =\< 25 mg daily of prednisone equivalent which must cease prior to day 1 of cycle 1, and/or cyclophosphamide for an urgent lymphoma related problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome) * Patient or durable power of attorney (DPA) for healthcare must be able to understand and voluntarily sign an Institutional Review Board (IRB) -approved informed consent form * Patients must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of \>= 1.5 cm * Patients with performance status of =\< 3 (3 only allowed if decline in status is deemed related to lymphoma and felt potentially reversible by the treating physician) * Serum bilirubin \< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome as defined by \> 80% unconjugated bilirubin * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x ULN or \< 5 x ULN if hepatic metastases are present * Absolute neutrophil count (ANC) \> 1000/mm\^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician * Platelets \> 100,000/…