The goal of this clinical research study is to learn if bortezomib when given in combination with cyclophosphamide and rituximab can help to control mantle cell lymphoma. The safety of this drug combination will also continue to be studied.

The Study Drugs:

Bortezomib is designed to block a protein that plays a role in cell function and growth. This may cause cancer cells to die.

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Rituximab is designed to attach to lymphoma cells, which may cause them to die.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive all of the study drugs preferably through a central venous catheter (CVC) that will be left in place the entire time that you are receiving the study drugs. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. You will sign a separate consent form for this procedure, which will describe the procedure and the risk in more detail.

You will receive rituximab by vein over 6 hours on Day 1 of every 21-day study cycle.

You will receive bortezomib by vein over 3 to 5 seconds, after you have received rituximab on Day 1 of every cycle. You will also receive bortezomib on Days 4, 8, and 11 of every cycle.

You will receive cyclophosphamide by vein over 3 hours 2 times each day (6 hours total each day) on Days 2, 3, and 4 of every cycle. On these days, you will also receive mesna by vein non-stop. Mesna is a drug that protects the bladder from damage by chemotherapy drugs. It is used to decrease the risk of bleeding in the bladder.

You will receive G-CSF (filgrastim - a drug that is used to help build your white blood cell counts and prevent infections) as an injection under the skin starting 24-36 hours after you receive bortezomib. You will receive filgrastim 1 time each day until your white blood cell counts recover.

Study Visits:

At each study visit, you will be asked about how you are feeling and about any other drugs that you may be taking.

Throughout the study, blood (about 1 tablespoon each time) will be drawn 2-3 times a week for routine tests.

Within 2 days before each cycle, the following tests and procedures will be performed:

• You will have a physical exam, including measurement of your weight and vital signs.
• You will complete the questionnaire about nervous system side effects.
• Your performance status will be recorded.
• Blood (about 2 tablespoons) will be drawn for routine tests.

After every 2 cycles, the following tests and procedures will be performed:

• You will have a physical exam, including measurement of your weight and vital signs.
• Your performance status will be recorded.
• You will have a chest x-ray or CT scans to check the status of the disease. These scans may be of your head, neck, chest, stomach, and/or pelvis. The CT scan at Cycle 4 will only occur if the doctor thinks it is needed.
• Blood (about 5 teaspoons) will be drawn for routine tests.
• If your doctor thinks it is needed, you will have a bone marrow biopsy/aspirate to check the status of the disease.
• If your doctor thinks it is needed, you will have an ECHO or a multigated radionuclide angiography (MUGA) scan and/or an ECG.

You will have an exam of the colon (colonoscopy) to check the status of the disease after Cycle 2. Biopsy samples (about 3-6) of the colon will be taken during this exam to check the status of the disease.

After Cycles 2, 6, and/or 8, if your doctor thinks it is needed, you will have a positron emission tomography (PET) scan to check the status of the disease.

After Cycle 6, you will be taken off study if the disease is in "complete remission" (if the disease has disappeared). Otherwise, you may receive 2 more cycles of study treatment.

If you are receiving 2 more cycles, if colonoscopy was done after Cycle 2 and it showed lymphoma, you will have another colonoscopy after Cycle 6 and Cycle 8 to check the status of the disease. Biopsy samples (about 3-6) of the colon will be taken during this exam to check the status of the disease.

Length of Study:

You will receive the study drugs for up to 8 cycles (about 8 months). You will be taken off study early if the disease gets worse or intolerable side effects occur before Cycle 8, or if the disease is in complete remission after Cycle 6.

End-of-Treatment Visit:

After you have finished receiving the study drugs, the following tests and procedures will be performed:

• You will have a physical exam, including measurement of your weight and vital signs.
• You will complete the questionnaire about nervous system side effects.
• Your performance status will be recorded.
• You will have a chest x-ray or CT scans to check the status of the disease.
• Blood (about 5 teaspoons) will be drawn for routine tests.
• If your doctor thinks it is needed, you will have a bone marrow biopsy/aspirate to check the status of the disease.
• If your doctor thinks it is needed, you will have an ECHO or a MUGA scan and/or an ECG.

Follow-Up Visits:

After you have finished receiving the study drugs, you will have follow-up visits according to the following schedule:

• Every 3 months during Year 1 after treatment.
• Every 4 months during Year 2 after treatment
• Every 6 months during Years 3-4 after treatment.
• Every 12 months after Year 4 after treatment.

At each of the follow-up visits, the following tests and procedures will be performed:

• You will have a complete physical exam, including measurement of your weight and vital signs.
• You will complete the questionnaire about nervous system side effects.
• Your medical history will be recorded
• Your performance status will be recorded.
• Blood (around 1 tablespoon) will be drawn for routine tests.
• You will have a chest x-ray to check the status of the disease.
• You will have CT scans of the head, neck, chest, abdomen, and pelvis to check the status of the disease.
• If the doctor thinks it is needed, you will have a bone marrow aspirate/biopsy to check the status of the disease.

This is an investigational study. All of the drugs used in this study are FDA approved and commercially available for the treatment of various types of lymphoma. The use of this drug combination is investigational.

Up to 46 patients will take part in this multicenter study. All will be enrolled at M. D. Anderson.

Inclusion Criteria:

1. Confirmed diagnosis mantle cell lymphoma and its variants, excluding marginal zone and disease exclusively in the GI system. Patients should have measurable disease based on Cheson Criteria or Bone Marrow/tissue sample positive for mantle cell lymphoma. No prior therapy with a combination of bortezomib, cyclophosphamide and rituximab.
2. Patients with performance status of 2 or less (Zubrod).
3. Serum bilirubin <1.5 mg/dl and serum creatinine < 2.0 mg/dl unless due to lymphoma; absolute neutrophil count (ANC) >1000/mm^3 and platelets >100,000/mm^3 unless due to lymphoma.
4. Cardiac ejection fraction 50% or greater.
5. Ages 18 to 85.
6. Patients must be willing to receive transfusions of blood products.
7. Signed consent form.
8. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
9. Female subject is either post-menopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) from the time of signing the informed consent form through 30 days after the last dose of VELCADE, or agree to completely abstain from heterosexual intercourse.
10. Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse.

Exclusion Criteria:

1. Human immunodeficiency virus (HIV) infection.
2. Central nervous system (CNS) involvement.
3. Patient has a platelet count of < 100 K (eg <30 x 10^9/L for studies with bortezomib alone) within 14 days before enrollment.
4. Patient has an absolute neutrophil count of ANC (eg <1.0 x 10^9/L for studies with bortezomib alone)> within 14 days before enrollment.
5. Patient has > 1.5 times Total Bilirubin
6. Patient has a calculated or measured creatinine clearance of < 20 mL/minute creatinine clearance (eg <20 mL/minute for studies with bortezomib alone) > within 14 days before enrollment.
7. Patient has >/= Grade 2 peripheral neuropathy within 14 days before enrollment.
8. Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
9. Patient has hypersensitivity to bortezomib, boron or mannitol.
10. Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum Beta-human chorionic gonadotropin (Beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
11. Participation in clinical trials with other investigational agents not included in this trial, within 14 days the start of this trial and throughout the duration of this trial.
12. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
13. Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.
14. Concurrent or previous malignancy whose prognosis is poor (< 90% probability of survival at 5 years).

One participant of 21 participants was not treated and is therefore excluded from baseline demographics.

Adverse event collection performed with each cycle of chemotherapy every 21 days, up to 8 cycles with those who received at least one cycle considered assessable for adverse events. Overall study period: August 2009 to March 19, 2014.