RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 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 together with gemcitabine hydrochloride and rituximab may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of bortezomib and gemcitabine hydrochloride when given together with rituximab and to see how well they work in treating patients with progressive or relapsed B-cell non-Hodgkin lymphoma.

OBJECTIVES:

Primary:

I. To evaluate the safety and feasibility of combining VELCADE (bortezomib) with gemcitabine (gemcitabine hydrochloride) in patients with recurrent lymphoma after standard therapy.

II. To define the maximum tolerated dose (MTD) of gemcitabine and Rituxan (rituximab) administered in combination with VELCADE given on a 21-day (old schema - Schema I) or 28-day (amended schema - Schema II) schedule.

Secondary:

I. To obtain preliminary data for response to this regimen in this patient population.

OUTLINE: This is a phase I, dose-escalation study of bortezomib and gemcitabine hydrochloride followed by a phase II study.

Patients receive bortezomib intravenously (IV), gemcitabine hydrochloride IV over 3-4 hours, and rituximab IV on days 1 and 15. Treatment repeats every 28 days for at least 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed intermediate or high grade B-cell Non-Hodgkin lymphoma with primary progressive or relapsed disease
• Patients may have had up to 4 prior chemo-and-or radiation therapy regiments, including one autologous transplant based protocol; any prior therapy (chemotherapy or radiation) must have been completed at least 4 weeks prior to start of this protocol; for prior high-dose chemotherapy with stem cell transplant, a 6-week interval is required; all side effects must have resolved
• Karnofsky performance status >= 60%
• Life expectancy of greater than 3 months
• Absolute neutrophil count >= 1,500 mm^3
• Platelets >= 50,000 mm^3
• Total bilirubin =< 1.5 mg/dl
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min for creatinine levels above institutional normal (calculated or measured)
• Cardiac ejection fraction of > 40% by echocardiogram or multi gated acquisition (MUGA) scan
• Have no serious or intercurrent medical illness
• 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, intra-uterine 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 a platelet count of < 20 x 10^9/L with 7 days before enrollment
• Patient has an absolute neutrophil count of < 1.0 x 10^9/L within 7 days before enrollment
• Patient has a calculated or measured creatinine clearance of < 30 ml/min with 14 days before enrollment
• Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment
• Patient has hypersensitivity to bortezomib, boron, or mannitol
• Female subject is pregnant or breastfeeding; 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 postmenopausal or surgically sterilized women
• Patient has received other investigational drugs with 14 days before enrollment
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Patients who have had more than 4 prior different chemotherapy regimens will be excluded; patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for autologous transplant regimens) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients may not have previously received VELCADE or gemcitabine
• Patients with active central nervous system (CNS) involvement are not eligible
• Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Adverse events occurred over a period of 3 years.

"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.