Inclusion Criteria:

- Histologically confirmed DLBCL expressing cluster of differentiation (CD)20 antigen
(Journal of Clinical Oncology [J Clin Oncol] 17[4]:1244-53, 1999); patients with
known primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; similarly,
patients with known v-myc myelocytomatosis viral oncogene homolog (avian) (c-myc)
translocation (by fluorescence in situ hybridization) positive DLBCL are encouraged
to participate in trials specifically designed for these patients; however patients
with known c-myc positive are NOT excluded from this study; c-myc testing prior to
study enrollment is NOT required

- Stages II bulky disease (defined as mass size of more than 10 cm), stage III, or IV
(Ann Arbor Staging); patients with stage I and stage II non-bulky disease are
excluded from this study

- A tumor tissue specimen from the initial diagnostic biopsy has been located and ready
to ship to the Eastern Cooperative Oncology Group (ECOG) Pathology Coordinating
Office within 30 days following registration; patients must have paraffin-embedded
tumor specimen available for central pathology review and defined laboratory research
studies; archived formalin fixed paraffin embedded (FFPE) tumor tissue block is
required; if the block is unavailable for submission, please submit the below
alternative requirements:

- One (1) hematoxylin & eosin (H&E) slide, and

- Twenty (20) 4 um unstained air-dried plus slides, and

- One (1) or more core punches (minimum of 4 mm diameter)

- International Prognostic Index (IPI) of 2 or greater

- ECOG performance status 0-2

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

- Previously untreated and not receiving any other agent that would be considered as a
treatment for the lymphoma

- No known central nervous system (CNS) lymphoma or cerebrospinal fluid involvement
with malignant lymphoma cells; 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

- 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

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

- Absence of history of myocardial infarction =< 6 months, or congestive heart failure
requiring use of ongoing maintenance therapy for life-threatening ventricular
arrhythmias

- Absence of history of deep venous thrombosis/embolism, threatening thromboembolism or
known thrombophilia; patients with history of deep vein
thrombosis/embolism/thrombophilia may participate if they are on full anticoagulation
during the treatment (warfarin or low molecular weight heparin at therapeutic doses)

- Patient must be able and willing to receive anticoagulation therapy with aspirin 325
mg daily prophylaxis, low molecular weight heparin, or warfarin; patients unable or
unwilling to take any prophylaxis are NOT eligible

- Absence of history of acquired immune deficiency syndrome (AIDS)-related conditions
(other than the presenting DLBCL) or posttransplant 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 another active malignancy requiring therapy such as radiation, chemotherapy, or
immunotherapy; exceptions to this are as follows: localized nonmelanotic 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 (erythropoietin [EPO]:
Procrit, Aranesp)

- Patient must be willing to provide informed written consent and to return to
enrolling institution for follow-up

- 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