Inclusion Criteria:

• Male or female patients 18 years or older
• Diagnosis of mantle cell lymphoma (Stage II, III or IV)
• At least 1 measurable site of disease
• No prior therapies for mantle cell lymphoma
• Not eligible for bone marrow transplantation as assessed by the treating physician. This must be verified with the sponsor study physician.
• Eastern Cooperative Oncology Group status less than or equal to 2
• Absolute neutrophil count greater than or equal to 1500 cells/micro liters
• Platelets greater than or equal to 100,000 cells/micro liters
• Alanine transaminase less than or equal to 3 times the upper limit of normal
• Aspartate transaminase less than or equal to 3 times the upper limit of normal
• Total bilirubin less than or equal to 2 times the upper limit of normal
• Calculated creatinine clearance greater than or equal 20 milliliter/min.
• Female patients must be post menopausal for at least 1 year (must not have had a natural menses for at least 12 months), surgically sterile, or practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double barrier method, contraceptive patch, male partner sterilization) and have a negative serum beta-HCG or urine pregnancy test at screening.
• Male patients must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study.
• All patients (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
• In order to participate in the pharmacogenomic component of this study, patients (or their legally acceptable representative) must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study. Acquisition of tumor sample collections are required for all patients (where available); all other sample collections are optional.

Exclusion Criteria:

• Prior treatment with VELCADE
• Prior anti-neoplastic (including unconjugated therapeutic antibodies), experimental or radiation therapy, radioimmunoconjugates or toxin immunoconjugates for the treatment of mantle cell lymphoma. In the event that a patient has received doxorubicin for the treatment of any condition, other than MCL, the maximum dose and exposure received prior to entry into this study should not exceed 150mg/meters squared.
• Major surgery (at the discretion of the treating physician and in consultation with the sponsor's medical monitor) within 2 weeks before randomization
• Peripheral neuropathy or neuropathic pain of Grade 2 or worse (as per the investigators assessment)
• Diagnosed or treated for a malignancy other than mantle cell lymphoma (MCL) within 1 year of randomization, or who were previously diagnosed with a malignancy other than MCL and have any radiographic or biochemical marker evidence of malignancy. Patients with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are not excluded.
• Active systemic infection requiring treatment
• History of allergic reaction attributable to compounds containing boron, mannitol, or hydroxybenzoates
• Known anaphylaxis or immunoglobulin E-mediated hypersensitivity to murine proteins or to any component of rituximab including polysorbate 80 and sodium citrate dihydrate
• Female or male patients of child-bearing potential who will not use adequate contraception during the course of the study.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Concurrent treatment with another investigational agent.