Rituximab and Combination Chemotherapy With or Without Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Diffuse Large B Cell Lymphoma

Absence of history of acquired immune deficiency syndrome (AIDS)-related conditions (other than the presenting DLBCL) or post-transplant lymphoproliferative disorder (PTLD) in immunocompromised patients; patients with human immunodeficiency virus (HIV) on antiretroviral therapy other than zidovudine (AZT) and/or stavudine and without prior AIDS defining conditions and adequate CD4 count (\> 400) are eligible

No other active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy; exceptions to this are as follows: localized non-melanotic skin cancer and 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

No history of radiation therapy to \>= 25% of the bone marrow for other diseases or history of anthracycline therapy

Patients must not be receiving erythroid stimulating agents (EPO: Procrit, Aranesp)

RANDOMIZATION (STEP 1)

Patient meets the eligibility criteria outlined above

Site has received notification from Mayo Clinic - Rochester Division of Hematopathology of the central confirmation of diagnosis and tissue adequacy for mandatory research studies

Patients must have measurable disease (at least 1 lesion of \>= 1.5 cm in one diameter) as detected by computed tomography (CT) or the CT images of the positron emission tomography (PET)/CT

International Prognostic Index (IPI) of 2 or greater

Ejection fraction of \>= 45% by either multi-gated acquisition (MUGA) scan or echocardiogram (ECHO)

Absence of 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

Absolute neutrophil count (ANC) \>= 1500

Platelets (PLT) \>= 100,000

Total bilirubin =\< 1.5 x upper limit of normal (ULN) or if total bilirubin is \> 1.5 x ULN, the direct bilirubin must be normal

Alkaline (Alk.) phosphatase =\< 3 x ULN unless evidence of the direct liver involvement by lymphoma - then =\< 5 x ULN

Aspartate aminotransferase (AST) =\< 3 x ULN unless evidence of the direct liver involvement by lymphoma - then =\< 5 x ULN

Creatinine =\< 2 x ULN or creatinine clearance (CrCl) \> 30 ml/min

Women must not be pregnant or breast-feeding

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 lenalidomide 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, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

What this study is about