Disease Characteristics:

• Histologically confirmed untreated mantle cell lymphoma (MCL), with documented cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH)
• Patients must have at least one objective measurable disease parameter
  • Abnormal PET scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging
  • Measurable disease in the liver is required if the liver is the only site of lymphoma
• Patient must have no CNS involvement

Patient Characteristics:

• ECOG performance status 0-2
• ANC ≥ 1,500/mcL (1.5 x 10^9/L)*
• Platelets ≥ 100,000/mcL (100 x 10^9/L)* NOTE: *Unless due to marrow involvement.
• AST/ALT ≤ 2 times upper limit of normal (ULN)
• Bilirubin ≤ 2 times ULN
• Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min
• Women (sexually mature female) must not be pregnant or breast-feeding
• Negative pregnancy test
• Women of childbearing potential and sexually active males use an accepted and effective method of contraception
  • Men must agree to use a latex condom during sexual contact with a female of child-bearing potential, 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
• No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma, or any surgically or radiation-cured malignancy continuously disease free for ≥ 5 years so as not to interfere with interpretation of radiographic response
• Patient agrees that if randomized to Arms C or D, and proceed onto Arms G or H, they must register into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®
  • Patients must have no medical contra-indications to, and be willing to take, deep vein thrombosis (DVT) prophylaxis as all patients registering to the lenalidomide/rituximab Arms G and H will be required to have DVT prophylaxis
    • Patients randomized to Arms G or H who have a history of a thrombotic vascular event will be required to have therapeutic doses of low-molecular weight heparin or warfarin to maintain an INR between 2.0 - 3.0
    • Patients on Arms G and H without a history of a thromboembolic event are required to take a daily aspirin (81 mg or 325 mg) for DVT prophylaxis
      • Patients who are unable to tolerate aspirin should receive low molecular weight heparin therapy or warfarin treatment
  • Women must agree to abstain from donating blood during study participation and for at least 28 days after discontinuation from protocol treatment
  • Males must agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from protocol treatment
• HIV-positive patients are not excluded but, to enroll, must meet all of the below criteria:
  • HIV is sensitive to antiretroviral therapy
  • Must be willing to take effective antiretroviral therapy, if indicated
  • No history of CD4 prior to or at the time of lymphoma diagnosis < 300 cells/mm³
  • 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 until at least 2 months following the completion of therapy or until the CD4 cells recover to over 250 cells/mm³, whichever occurs later
• Patients must not have grade 2 or greater peripheral neuropathy
• Patients must not have NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia
• Patients must not have hypersensitivity to bortezomib, boron, or mannitol
• Patients must not have a serious medical or psychiatric illness likely to interfere with study participation

Prior Concurrent Therapy:

• No prior therapy for MCL, except < 1 week of steroid therapy for symptom control
• HIV-positive patients are not excluded, but to enroll, must meet all of the below criteria:
  • Must be willing to take effective antiretroviral therapy if indicated
  • If on antiretroviral therapy, must not be taking zidovudine or stavudine
• Patients must not be participating in any other clinical trial or taking any other experimental medications within 14 days prior to registration