This randomized phase II trial studies how well bortezomib works when given after combination chemotherapy, rituximab, and an autologous stem cell transplant in treating patients with mantle cell lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with an autologous stem cell transplant may allow more chemotherapy to be given so that more cancer cells are killed. 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. Giving bortezomib after combination chemotherapy, monoclonal antibody therapy, and an autologous stem cell transplant may kill any remaining cancer cells or keep the cancer from coming back.

Objectives

Primary Objective:

To determine the 18-month progression-free survival (PFS) in patients with previously untreated mantle cell lymphoma who are treated with aggressive chemo-immunotherapy and autologous stem cell transplant followed by randomization to either maintenance or consolidation bortezomib therapy

Secondary Objectives:

• To determine the toxicity profiles of maintenance and consolidation bortezomib by evaluating the number of patients able to complete all maintenance or consolidation therapy
• To determine the complete response rate to intensive chemo-immunotherapy plus maintenance or consolidation bortezomib
• To determine time to progression and overall survival using these two treatment regimens

Correlative/Other Pre-Specified Objectives:

• To determine the importance of p53 mutation or deletion on patient outcome with respect to CR rate, PFS, and OS
• To determine the importance of Ki67, cyclin D1, phosphohistone 3, p27, p21, p16, and PARP p85 expression in pre-treatment tumor biopsies with respect to CR rate, PFS, and OS
• To determine the relationship between proliferation signature and clinical outcome using quantitative real-time RT-PCR
• To evaluate the importance of quantitative cyclin D1 expression and expression of cyclin D1 isoforms in predicting clinical outcome using quantitative real-time RT-PCR
• To evaluate the prognostic significance of microRNAs in mantle cell lymphoma using microRNA arras
• To explore the correlation of selected microRNA polymorphisms with gene target expression with clinical outcomes such as response, PFS, and OS
• To determine changes in gene expression profile from diagnosis to relapse samples to identify genes differentially silenced or over-expressed with disease recurrence
• To determine the importance of early PCR negativity (following Treatment 2) using bcl-1/IgH junction and/or IgH chain gene rearrangement with respect to maintained PFS and the success of maintenance or consolidation therapy to converting patients to PCR negative status

OUTLINE OF INTERVENTIONS:

CHEMOIMMUNOTHERAPY: Patients receive chemoimmunotherapy comprising rituximab* intravenously (IV) over 4-6 hours on day 1, methotrexate (MTX) IV over 4 hours on day 2, cyclophosphamide IV over 2 hours, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3, and prednisone orally (PO) on days 3-7. Beginning 24 hours after completion of MTX, patients receive leucovorin calcium IV every 6 hours until blood levels of MTX are in a safe range. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily (QD) beginning on day 3 and continuing until blood counts recover. Beginning no sooner than day 22, but no later that day 29 of the first course, patients receive a second course of chemoimmunotherapy as above. Patients with > 15% persistent bone marrow involvement may receive a third course of chemoimmunotherapy. Patients are restaged and those with progressive disease are removed from therapy.

NOTE: *During the first course of chemoimmunotherapy, patients receive rituximab only if the number of circulating mantle cells is =< 10,000/mm^3, otherwise, rituximab is omitted during the first course of chemoimmunotherapy.

HIGH-DOSE CONSOLIDATION CHEMOIMMUNOTHERAPY AND PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION: Approximately 4 weeks after completion of chemoimmunotherapy, patients receive high-dose consolidation chemoimmunotherapy comprising cytarabine IV over 2 hours and etoposide phosphate IV continuously on days 1-4, and rituximab IV over 4-6 hours on days 5 and 12 OR 6 and 13. Beginning on day 14 and continuing until completion of PBSC collection, patients receive G-CSF SC QD. Once blood counts recover, patients undergo 1-3 leukapheresis procedures for collection of PBSCs on days 22-25.

HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS PBSC TRANSPLANTATION (PBSCT): Beginning 4-6 weeks after completion of leukapheresis, patients receive carmustine IV over 2 hours on day -6, etoposide phosphate IV over 4 hours on day -4, and cyclophosphamide IV over 2 hours on day -2. Patients undergo autologous PBSCT on day 0. Patients also receive G-CSF SC QD beginning on day 4 and continuing until blood counts recover.

POST-TRANSPLANTATION IMMUNOTHERAPY: Approximately 5 weeks after autologous PBSCT, patients receive rituximab IV over 4-6 hours once weekly for 2 weeks. Approximately 4 weeks after completion of post-transplantation immunotherapy, patients proceed to maintenance therapy or consolidation therapy with bortezomib as described in the Arms section.

After completion of study treatment, patients are followed every 2 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

1. Documentation of Disease

   A. Histologic Documentation:

   • Histologically documented mantle cell lymphoma with co-expression of CD20 (or CD19) and CD5 and lack of CD23 expression by immunophenotyping AND at least one of the following confirmatory tests:

     • positive immunostaining for cyclin D1; OR
     • the presence of t(11;14) on cytogenetic analysis; OR
     • molecular evidence of bcl-1/IgH rearrangement.

   • Cases that are CD5-negative and/or CD23-positive will be eligible provided that the histopathology is consistent with mantle cell lymphoma AND positive for cyclin D1, t(11;14), or bcl-1/IgH rearrangement.A tissue block should be submitted to the CALGB Pathology Coordinating Office for central pathology review.

   • A diagnosis based on peripheral blood or bone marrow is allowed. If the diagnosis is based only on blood, in addition to the immunophenotype and molecular confirmation above, a peripheral blood smear must be available for central pathology review. If the diagnosis is based on a bone marrow biopsy, the tissue block should be submitted.

   • Note: Failure to submit pathology materials within 60 days of patient registration will be considered a major protocol violation.

   B. Extent of Disease:

   • Stage I-IV. Patients with nodular histology mantle cell lymphoma must have Ann Arbor stage III or IV disease to be eligible. Patients with mantle zone histology will not be eligible because of their relatively favorable prognosis. Patients with other mantle cell histologies are eligible regardless of stage.
   • No active CNS disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma. A lumbar puncture demonstrating mantle cell lymphoma at the time of registration to this study is not an exclusion for study enrollment.

2. Prior Treatment:

   A. Patients must be previously untreated or have received no more than one prior cycle of chemotherapy and/or rituximab treatment.

   B. No prior radiation therapy for mantle cell lymphoma.

   C. ≥ 2 weeks since major surgery.

   D. ≥ 3 weeks since prior chemotherapy.

3. Age Eligibility: Age ≥ 18 years and < 70 years

4. Murine Products Hypersensitivity Eligibility: No known hypersensitivity to murine products.

5. Use of Systemic Corticosteroids Eligibility: No medical condition requiring chronic use of systemic corticosteroids.

6. Eligibility Criteria on HIV Infection: No HIV infection. Patients with a history of intravenous drug abuse or any behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus. Patients who test positive or who are known to be infected are not eligible due to an increased risk of infection with this regimen. An HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk.

7. Non-pregnant and non-nursing: Non-pregnant and non-nursing. Treatment under this protocol would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective means of birth control.

8. HepBSAg or HepC Ab Eligibility: Patients who test positive for HepBSAg or HepC Ab are eligible provided all of the following criteria are met:

   A. bilirubin ≤ 2 x upper limit of normal; AND

   B. AST ≤ 3 x upper limit of normal; AND

   C. liver biopsy demonstrates ≤ grade 2 fibrosis and no cirrhosis.

   Hepatitis B surface Ag(+) patients will be treated with lamivudine (3TC) throughout protocol therapy and for 6-12 months thereafter.

9. Secondary Malignancy Eligibility: Patients with a "currently active" second malignancy, other than non-melanoma skin cancers are not eligible. This includes Waldenstrom's Macroglobulinemia, since such patents have experienced transient increases in IgM following initiation of rituximab, with the potential for hyperviscosity syndrome requiring plasmapheresis. Patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, and are considered by their physician to be at less than 30% risk of relapse.

10. Initial Required Laboratory Values:

    • LVEF by MUGA or ECHO ≥ 45%
    • Creatinine ≤ 2.0 mg/dL
    • Total Bilirubin ≤ 2.0 mg/dL (Unless attributable to Gilbert's Disease)
    • u-HCG or serum HCG Negative (If patient of childbearing potential).