In this study, we are trying to find out if the combination of these two drugs is effective in treating Waldenstrom's macroglobulinemia (WM). The combination of these two drugs has not been studied for patients with relapsed or refractory macroglobulinemia. The U.S. Food and Drug Administration (FDA) has approved bortezomib for the treatment of multiple myeloma, a cancer that is closely related to Waldenstrom's macroglobulinemia.

• Participants will receive 6 cycles of the study treatment with bortezomib and rituximab. Each cycle is 28 days long (4 weeks).
• Participants will receive Rituximab intravenously once a week for the first and fourth cycles only. Participants will receive bortezomib once a week for three weeks on and one week off every cycle, for a total of 6 cycles.
• During the rituximab infusion, the participants blood pressure and pulse will be monitored frequently. The rate of infusion may be decreased depending upon the side effects that are experienced.
• Blood samples will be collected before the first dose and on follow up with every cycle. Blood counts will also be performed every week.
• Routine physical exams will be performed at each evaluation. A PET/CAT scan of the chest, abdomen and pelvis at the end of treatment. This scan is required to assess the response of the participants disease.
• In order to learn more on how bortezomib and rituximab affect WM, a bone marrow biopsy will be performed.
• We anticipate that participants will complete the active therapy over a period of 6 cycles provided that they are benefiting from therapy and have not had any serious side effects. The participant will be followed every three months for 2 years for office visits and laboratory tests.

Inclusion Criteria:

• 18 years of age or older
• Patients with previously untreated WM and those who have received prior therapy are eligible
• Must have received prior therapy for their WM and have relapsed or refractory WM.
• CD20 positive disease based on any previous bone marrow immuno-histochemistry or flow cytometric analysis performed up to 3 months prior to enrollment.
• Measurable disease
• ECOG Performance Status 0,1, or 2
• Total bilirubin < 2.0 mg/dl
• AST < 3 x ULN
• Life expectancy of greater than 12 weeks

Exclusion Criteria:

• Uncontrolled infection
• Other active malignancies
• Cytotoxic chemotherapy less than 3 weeks, or biologic therapy less than 2 weeks, or corticosteroids less than 2 weeks, prior to registration.
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational
• Known to be HIV positive or HEP B positive
• Radiation therapy less than 2 weeks prior to registration
• Grade 2 or greater peripheral neuropathy
• Myocardial infarction within 6 months rior to enrollment or has NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Hypersensitivity to bortezomib, boron, or mannitol
• Pregnant or breast feeding women
• Other investigational drugs within 14 days of enrollment
• Serious medical or psychiatric illness likely to interfere with participation