RATIONALE: Lenalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with rituximab, cyclophosphamide, and dexamethasone may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving lenalidomide together with rituximab, cyclophosphamide, and dexamethasone works in treating patients with previously untreated low-grade non-Hodgkin lymphoma.

OBJECTIVES:

Primary

• To assess tumor response to lenalidomide, rituximab, cyclophosphamide, and dexamethasone in patients with symptomatic previously untreated low-grade non-Hodgkin lymphoma.

Secondary

• To describe the adverse event profile of this regimen.
• To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure associated with this regimen.
• To estimate tumor response to lenalidomide, rituximab, cyclophosphamide and dexamethasone in the subgroup of patients with lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia).

OUTLINE: This is a multicenter study.

Patients receive oral lenalidomide once daily on days 1-21, rituximab IV on day 1, oral cyclophosphamide once daily on days 1, 8, and 15, and oral dexamethasone once daily on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 3 months for 5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed symptomatic non-Hodgkin lymphoma by biopsy within the past 6 months

  • Any of the following subtypes allowed:

    • Grade 1 or 2 lymphoma
    • Small lymphocytic lymphoma
    • Marginal zone lymphoma
    • Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia [WM])

• Previously untreated disease that, in the investigator's opinion, requires treatment

• Measurable disease by CT or MRI scans with lymph nodes ≥ 2.0 cm in ≥ 1 dimension

  • WM patients without lymphadenopathy must meet the following criteria:

    • More than 10% lymphocytes, lymphoplasmacytic cells, or plasma cells on a bone marrow aspirate/biopsy
    • Quantitative Immunoglobulin M ≥ 400 mg/dL NOTE: A new classification scheme for adult non-Hodgkin lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• ANC ≥ 1,400/mm^3

• Platelet count ≥ 100,000/mm^3

• Creatinine ≤ 2.0 mg/dL

• Total or direct bilirubin ≤ 1.5 mg/dL

• AST and ALT ≤ 2 times upper limit of normal (ULN) (5 times ULN if hepatic metastases are present)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective double-method contraception at least 28 days prior to, during, and for 28 days after completion of study therapy

• Able to take acetylsalicylic acid (ASA) 325 mg/day as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin)

• No known hypersensitivity to thalidomide

• No development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance with study requirements

• No myocardial infarction within the past 6 months

• No other active malignancy requiring treatment, except for localized nonmelanomatous skin cancer or any cancer that, in the judgement of the investigator, has been treated with curative intent and will not interfere with the study treatment plan and response assessment

• No co-morbid systemic illnesses or other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate for entry into the study or would interfere significantly with the proper assessment of safety and toxicity of study treatment

• No known positivity for HIV or infectious hepatitis A, B, or C

• No serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent

• Willing to return to Mayo Clinic enrolling institution for follow up

• Registered into the RevAssist® program and willing and able to comply with the requirements of RevAssist®

PRIOR CONCURRENT THERAPY:

• No prior lenalidomide
• No prior irradiation to ≥ 25% of the bone marrow
• More than 28 days since prior experimental drug or therapy
• No concurrent radiotherapy, chemotherapy, or immunotherapy
• No other concurrent anticancer agents or treatments, including thalidomide or investigational agents