This phase I/II trial studies the side effects and best dose of lenalidomide when given after combination chemotherapy with or without rituximab and stem cell transplant and to see how well it works in treating patients with non-Hodgkin lymphoma that has not responded to treatment or has returned after a period of improvement and is resistant to chemotherapy. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as carmustine, etoposide, cytarabine, and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, may block cancer growth by targeting certain cells. Giving lenalidomide after combination chemotherapy with or without rituximab may work better in treating patients with non-Hodgkin lymphoma.

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) of lenalidomide given in the post-transplant setting for a 12 month maintenance period.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of the 1-year response rate, event-free and overall survival using this regimen.

OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study.

PRE-CONDITIONING (patients with cluster of differentiation [CD]20+ non-Hodgkin lymphoma): Patients receive rituximab intravenously (IV) per standard of care.

PREPARATIVE REGIMEN: Patients receive carmustine IV on day -6, etoposide IV twice daily (BID) and cytarabine IV BID on days -5 through -2, and melphalan IV on day -1.

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo stem cell infusion on day 0.

MAINTENANCE THERAPY: Beginning approximately 100 days post-transplant, patients receive lenalidomide orally (PO) on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

• Persistent, or relapsed non-Hodgkin's lymphoma (NHL) (any histology) that is chemo-resistant (< a partial response [PR]), subjects who have received >= 3 prior chemotherapy regimens, or subjects with lymphomas that have a high relapse rate following autologous or syngeneic stem cell transplantation (transformed NHL, peripheral T-cell lymphoma [PTCL], mantle cell lymphoma, anaplastic lymphoma kinase [ALK]-negative anaplastic large cell lymphoma [ALCL, alk neg]), intermediate International Prognostic Index (IPI) or high risk IPI or subjects with a positive positron emission tomography (PET) scan prior to transplant, and otherwise eligible for transplantation with adequate end-organ function
• Subjects that relapse within one year of diagnosis
• Able to collect >= 1.5 x 10^6 CD34+/kg cell for transplantation
• Absolute neutrophil count (ANC) >= 1000 cells/mm^3 and platelet count >= 60 K when maintenance lenalidomide is started (day 100 post-transplant)
• Subjects must have calculated creatinine clearance >= 30 ml/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN
• Subjects who are seropositive because of hepatitis B virus vaccine
• Subjects must be willing to give written informed consent, and sign an institutionally approved consent form before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
• Able to adhere to the study visit schedule and other protocol requirements
• Expected survival duration of >= six months
• Karnofsky performance status >= 70
• Subjects > age 60 or with clinical signs of heart disease must have ejection fraction >= 45% left ventricular ejection fraction (LVEF) pre-transplant
• Subjects with clinical signs of pulmonary insufficiency must have diffusion capacity of the lung for carbon monoxide (DLCO) to be measured at >= 50% of predicted value
• No serious disease or condition that, in the opinion of the investigator, would compromise the subject's ability to participate in the study
• Disease free of prior malignancies for >= 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast or low risk prostate cancer after curative therapy
• All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of Revlimid REMS program
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and 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, as least 28 days before she starts taking lenalidomide; 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
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (subjects intolerant to acetylsalicylic acid [ASA] may use warfarin or low molecular weight heparin)
• Male subject agrees to use an acceptable method for contraception for the duration of the study

Exclusion Criteria:

• Chemosensitive NHL, except subjects receiving >= 3 prior chemotherapy regimens, or subjects having transformed NHL, PTCL, mantle cell lymphoma (MCL) or ALCL, alk neg
• End-organ function not appropriate for transplantation
• Inability to collect adequate stem cells
• Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type B (HBV) or C (HCV) or active hepatitis
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
• Pregnant or breast feeding females; (lactating females must agree not to breast feed while taking lenalidomide)
• Known hypersensitivity to thalidomide or lenalidomide (if applicable)
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
• Any prior use of lenalidomide
• Concurrent use of other anti-cancer agents or treatments
• Serum creatinine > 2.0 mg/dL or calculated creatinine clearance < 30 ml/min
• Active infection at the start of lenalidomide
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
• History of life threatening or recurrent thrombosis/embolism; subjects may participate if they are adequately anticoagulated during the treatment
• Subject has > grade 2 peripheral neuropathy within 14 days before enrollment