Study of Bortezomib in Combination With Cyclophosphamide and Rituximab

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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.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).