R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

* Pregnant women

* Nursing women

* Men or women of childbearing potential who are unwilling to employ adequate contraception

* NOTE: patients unwilling or unable to do any of the following are also excluded:

* Men must agree to use a latex condom during sexual contact with a female of child-bearing potential even if they have had a successful vasectomy

* Women of child bearing potential must agree to use 2 methods of reliable contraception simultaneously

* All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial; patients with HIV on antiretroviral therapy other than zidovudine (AZT) and/or stavudine and without prior acquired immunodeficiency syndrome (AIDS) defining conditions and adequate CD4 count (\> 400) are eligible

History of myocardial infarction =\< 180 days prior to registration or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm; patients must be \>= 2 weeks from prior anti-lymphoma therapy; the use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed

Other active malignancy =\< 3 years prior to registration; EXCEPTIONS: non-melanotic skin cancer, carcinoma-in-situ of the cervix, or any cancer that, in the judgment of the investigator, has been treated with curative intent and will not interfere with the study treatment plan and response assessment; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment such as radiation, chemotherapy, or immunotherapy for their cancer

Unable or unwilling to take any prophylaxis; patients with history of or new/active deep vein thrombosis/embolism/thrombophilia are allowed to participate if they are on appropriate therapeutic anticoagulation during the treatment on the trial; these patients would not need the aspirin with the lenalidomide unless clinically indicated; therefore, patients must be able and willing to receive anticoagulation (prophylaxis versus therapeutic as clinically indicated)

History of radiation therapy to \>= 25% of the bone marrow for other diseases

Receiving erythroid stimulating agents (epoetin alfa \[EPO\]: Procrit, Aranesp)

Patients with active or prior central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells; NOTE: these patients are usually treated with CNS directed therapy; screening for cerebrospinal fluid (CSF)/CNS involvement is NOT required but can be performed per treating medical doctor (MD) discretion

Active hepatitis B as defined by seropositivity for hepatitis B surface antigen (HBsAg); subjects with positive hepatitis B core antibody titers and normal liver transaminases are allowed provided that antiviral prophylaxis is administered per institutional guidelines; NOTE: subjects with hepatitis C antibody will be eligible provided that they do not have elevated liver transaminases or other evidence of active hepatitis

What this study is about