Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma

Inclusion Criteria (Induction):

* Histologically confirmed (biopsy-proven) diagnosis of follicular B-cell non-Hodgkin lymphoma with no evidence of transformation to large cell histology

  * Patients having both diffuse and follicular architectural elements are eligible if the histology is predominantly follicular (i.e., ≥ 50% of the cross-sectional area) and there is no evidence of transformation to a large cell histology
  * Diagnostic confirmation (i.e., core needle or excisional lymph node biopsy) required if the interval since tissue diagnosis of low-grade malignant lymphoma is \> 24 months

    * Bone marrow biopsy alone not acceptable
* Stage II, III, or IV AND grade 1, 2, or 3a disease
* Must meet criteria for High Tumor Burden (higher risk) as defined by either the Groupe D'Etude des Lymphomes Follicularies (GELF) criteria OR the follicular lymphoma international prognostic index (FLIPI) as defined below:

  * Patient must meet ≥ 1 of the following GELF criteria:

    * Nodal or extranodal mass ≥ 7 cm
    * At least 3 nodal masses \> 3.0 cm in diameter
    * Systemic symptoms due to lymphoma or B symptoms
    * Splenomegaly with spleen \> 16 cm by CT scan
    * Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) or pleural or peritoneal serous effusion due to lymphoma (irrespective of cell content)
    * Leukemic presentation (≥ 5.0 x 10\^9/L malignant circulating follicular cells)
    * Cytopenias (polymorphonuclear leukocytes \< 1.0 X 10\^9/L, hemoglobin \< 10 g/dL, and/or platelets \< 100 x 10\^9/L)
  * Patient must have a FLIPI-1 score of 3, 4, or 5 (1 point per criterion below):

    * Age ≥ 60 years
    * Stage III-IV disease
    * Hemoglobin level \< 12 g/dL
    * \> 4 nodal areas
    * Serum lactate dehydrogenase (LDH) level above normal
* At least 1 objective measurable disease parameter

  * Baseline measurements and evaluations (PET and CT) obtained within 6 weeks of randomization
  * Measurable disease in the liver is required if the liver is the only site of lymphoma
* HIV-positive patients must meet all of the following criteria:

  * HIV is sensitive to antiretroviral therapy
  * Must be willing to take effective antiretroviral therapy if indicated
  * No history of CD4 \< 300 cells/mm³ prior to or at the time of lymphoma diagnosis
  * No history of AIDS-defining conditions
  * If on antiretroviral therapy, must not be taking zidovudine or stavudine
  * Must be willing to take prophylaxis for Pneumocystis jiroveci pneumonia (PCP) during therapy and ≥ 2 months following completion of study therapy or until the CD4 cells recover to over 250 cells/mm³
* ECOG performance status 0-2
* Absolute neutrophil count (ANC) ≥ 1,500/mm³ (includes neutrophils and bands)
* Platelet count ≥ 100,000/mm³
* Creatinine ≤ 2.0 mg/dL
* Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 5 x upper limit of normal (ULN)
* Alkaline phosphatase ≤ 5 x ULN
* Total bilirubin ≤ 1.5 x ULN (patients with known Gilbert disease should contact the study PI)
* Negative pregnancy test
* Fertile patients must use 2 effective methods (1 highly effective and 1 additional effective method) of contraception ≥ 28 days before, during, and for ≥ 28 days after completing study treatment
* Must register into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist® (for patients randomized to arm C and proceed onto arm F)

Exclusion Criteria (Induction):

* Prior chemotherapy, radiotherapy, or immunotherapy for lymphoma

  * Prednisone or other corticosteroids used for non-lymphomatous conditions will not be considered as prior chemotherapy
  * A prior/recent short course (\< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms is allowed
* Recent history of malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for ≥ 2 years
* Pregnant or nursing
* Active, uncontrolled infections (afebrile for \> 48 hours off antibiotics)
* ≥ grade 2 neuropathy
* Myocardial infarction within the past 6 months
* NYHA class III-IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
* Serious medical or psychiatric illness likely to interfere with participation in this clinical study
* Known hypersensitivity to boron or mannitol
* Chronic carriers of hepatitis B virus (HBV) with positive hepatitis surface antigen (HBsAg +)

Inclusion Criteria (Continuation):

* Patient must have improved their response or have had no interval change in their tumor measurements with restaging from Induction cycle 3 to 6 as determined at Cycle 6 restaging.
* Adequate organ function
* ECOG performance status 0-2
* Patients with a prior history of HBV infection, but immune, with only IgG hepatitis core antibody positive (HBcAb+), must receive antiviral prophylaxis (e.g., lamivudine 100 mg po daily) for ≥ 1 week prior to course 1 and throughout induction and continuation therapy and for ≥ 12 months after the last rituximab dose
* Additional requirements for Arm C induction patients registering to arm F:

  * Patients must be willing to take deep vein thrombosis (DVT) prophylaxis. Subjects with a history of a thrombotic vascular event will be required to have full anticoagulation, therapeutic doses of low molecular weight heparin or warfarin to maintain an INR between 2.0 - 3.0, or any other accepted full anticoagulation regimen (e.g. direct thrombin inhibitors or Factor Xa inhibitors) with appropriate monitoring for that agent. Subjects without a history of a thromboembolic event are required to take a daily aspirin (81 mg or 325 mg) for DVT prophylaxis. Subjects who are unable to tolerate aspirin should receive low molecular weight heparin therapy or warfarin treatment or another accepted full anticoagulation regimen.
  * Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study/lenalidomide: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation/stopping lenalidomide. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device (IUD), hormonal \[birth control pills, injections, or implants\], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed.
  * Patient must agree to abstain from donating blood during study participation and for at least 28 days after discontinuation from protocol treatment.
  * All males, regardless of whether they have undergone a successful vasectomy, must agree to use a latex condom during sexual contact with a female of childbearing potential, or to practice complete abstinence from heterosexual intercourse with any female of childbearing potential during the cycles of continuation therapy of which lenalidomide are taken and for at least 28 days after discontinuation/stopping lenalidomide. Patient must agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from protocol treatment.
  * Must register into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist®

Exclusion Criteria (Continuation):

* Active, uncontrolled infections (afebrile for \> 48 hours off antibiotics)
* ≥ grade 2 neuropathy
* Additional requirements for Arm C induction patients registering to arm F:

  * Not pregnant or breast-feeding