Inclusion Criteria:

• Histologically confirmed diagnosis of CD20 positive, diffuse large B-cell NHL; de novo or transformed histologies are acceptable
• Patient must have relapsed after or not responded to at least one standard, upfront multi-agent chemotherapy for DLBCL
• Measurable PET positive disease, as defined by tumor mass > 1.5 cm in one dimension
• Stage II, III, or IV disease
• Age > 18 years
• Adequate liver and kidney function (total bilirubin < 2 x ULN and creatinine < 2.0 mg/dl, unless abnormalities are related to lymphoma or Gilbert's disease
• Adequate bone marrow reserves (absolute neutrophil count >1500 cells/mm3 and platelet count > 100,000, unless cytopenias are the result of marrow infiltration by lymphoma
• ECOG performance status < 2
• Life expectancy of at least 3 months
• Bortezomib-naive
• 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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
• Male subject agrees to use an acceptable method for contraception for the duration of the study.

Exclusion Criteria:

• Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrollment.
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 8.4), 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.
• Patient has hypersensitivity to boron or mannitol
• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. (Pregnancy testing is not required for post-menopausal or surgically sterilized women)
• Patient has received other investigational drugs or cytotoxic chemotherapy within 14 days of enrollment
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Known HIV infection
• Active Hepatitis B or C as defined by positive Hepatitis B surface antigen or hepatitis C RNA
• Known CNS disease
• Pregnant or nursing women
• Concurrent treatment with other chemotherapy or anti-lymphoma therapy, including corticosteroids, unless on a stable dose of corticosteroids less than the equivalent of 20 mg of prednisone each day for treatment of disease not related to lymphoma
• Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
• Any condition that, in the opinion of the investigator, would prevent the subject from being fully compliant with the protocol.