The purpose of this study is to find out if the combination of bortezomib (Velcade), dexamethasone (Decadron) and rituximab (Rituxan) is effective in treating Waldenstrom's macroglobulinemia.

• This is an open-label study which means both the patient and the doctor will know what drugs and doses the patient is receiving throughout the study.
• Patients will receive 8 cycles of study treatment with bortezomib, dexamethasone and rituximab. Each cycle is 21 days long. Therapy is given on the first, fourth, eighth and eleventh day of each cycle, followed by a 10 day rest period. The first 4 cycles will be given one after the other. Three months after completing the fourth cycle of therapy, patients will receive one cycle of therapy every three months for a total of four more cycles.
• On the first, fourth, eighth and eleventh day of each cycle, the patient will receive bortezomib and dexamethasone as an intravenous injection through a needle in your vein. On the eleventh day only, the patient will also receive rituximab as an intravenous infusion after getting bortezomib and dexamethasone.
• Prior to each infusion of rituximab therapy, the patient will be asked to take some medications to prevent or reduce side effects of rituximab. These medications are benadryl, tylenol, and possibly more steroids. The doctor will determine which of these drugs are appropriate for the individual patient.
• During the rituximab infusion, the patients blood pressure and pulse will be monitored frequently and the infusion rate may be decreased depending upon the side effects experienced.
• After therapy is completed, the patient will be followed every three months for 2 more years for office visits and laboratory tests to determine how well they are doing and if the therapy continues to benefit them.

Inclusion Criteria:

• Clinicopathological diagnosis of Waldenstrom's macroglobulinemia (WM)
• No previous therapy for WM
• Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level of greater than or equal to 2 times the upper limit of each institution's normal value
• CD20 positive disease based on any previous bone marrow immuno-histochemistry or flow cytometric analysis performed up to 3 months prior to enrollment
• Karnofsky performance status > 60
• Life expectancy > 3 months
• AST (SGOT) < 3 x ULN
• ALT (SGPT) < 3 x ULN
• Total bilirubin < 2 x ULN
• Calculated or measured creatinine clearance > 30mL/minute
• Serum sodium > 130 mmol/L
• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control
• Male subject agrees to use an acceptable method for contraception for the duration of the study

Exclusion Criteria:

• Previous therapy for Waldenstrom's macroglobulinemia
• Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association 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 dexamethasone, boron or mannitol
• Pregnant or breast-feeding women
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study