Waldenstrom's macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy. This condition is considered to correspond to the lymphoplasmacytoid lymphoma as defined by the REAL2 and WHO classification systems. WM is a rare disease, with an incidence that is less frequent than multiple myeloma, and accounts for approximately 2% of all hematologic malignancies. The age-adjusted incidence rate is 3.4 per million among males and 1.7 per million among females in the US, with a geometrical increase with age. Despite continuing advances in the therapy of WM, the disease remains incurable with a median survival of 5 to 8 years from the time of diagnosis thereby necessitating the development and evaluation of novel therapeutics. Overall response rates (ORR) of 30-70% with complete response (CR) rates of up to 10% have been reported with the use of alkylator agents (e.g. chlorambucil), nucleoside analogues (cladribine or fludarabine), and the monoclonal antibody rituximab these therapeutic agents in the upfront therapy of WM with median durations of response averaging 2-3 years. Higher response rates including CR rates of up to 20% have been reported in studies combining nucleoside analogues with rituximab, and/or alkylator agents. Importantly, individual patients including the presence of cytopenias, need for more rapid disease control, age, and in particular candidacy for autologous transplant therapy should be taken into account in making the choice of first line therapy. For patients who are candidates for autologous transplant therapy, and in whom such therapy is seriously considered, exposure to alkylator or nucleoside analogue therapy should be limited. Monoclonal antibodies have been successfully used to treat patients with Waldenstrom's macroglobulinemia (WM). Most of these efforts to date have focused on the use of rituximab, a chimeric IgG1 monoclonal antibody which targets CD20, an antigen which is widely expressed in WM. Several studies employing standard dose rituximab therapy have demonstrated major response (>50% reduction in serum IgM) rates of 30%, and durations of response of about 8 months13-17. More recently, the use of extended schedule rituximab has been evaluated. Time to response after rituximab is slow and exceeds 3 months on the average. In many patients a transient increase of serum IgM may occur immediately following initiation of rituximab. Such an increase does not herald treatment failure and most patients will return to their baseline serum IgM by 12 weeks. However, patients with baseline serum IgM levels of >50g/L may be particularly at risk for a hyperviscosity-related event. Bortezomib is a small molecule proteasome inhibitor developed by Millennium Pharmaceuticals, Inc., (MPI) as a novel agent to treat human malignancies. Bortezomib is currently approved by the US FDA and by the European EMEA for the treatment of multiple myeloma. By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling pathways. The anti-neoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration and angiogenesis. Thus, the mechanisms by which bortezomib elicits its anti-tumor activity may vary among tumor types, and the extent to which each affected pathway is critical to the inhibition of tumor growth could also differ. The mechanism of anti-tumor activity in NHL is not known; however, bortezomib inhibits the growth of various human lymphoma cell lines, as well as the survival primary WM cells. Bortezomib has been administered to patients with WM in the context of prospective studies. Chen et al administered bortezomib to 16 patients with either untreated or pretreated WM who had received ≤3 prior regimens. Six of 13 evaluable patients (46%) achieved a partial response. Dimopoulos et al administered bortezomib to 10 patients with relapsed or refractory WM. Six of these patients achieved a partial response which occurred at a median of 1 month. The median time to progression in the responding patients is expected to exceed 11months. The more common toxicities were mild or moderate thrombocytopenia, fever and fatigue; peripheral neuropathy occurred in 3 patients. The WM Clinical Trials Group (WMCTG) conducted a Phase II Study (DFCI Protocol 03-248) of single-agent bortezomib in 27 patients with relapsed or refractory WM. In an interim analysis, the safety and efficacy results for 15 patients who completed at least 2 cycles of therapy were reported.37 Eight and 7 of these patients had relapsed and refractory disease, respectively. With a median of 3 completed cycles (range 2-8), 12 of 15 (80%) patients have demonstrated a response with 5 partial responses (>50% decrease in serum IgM) and 7 minor responses (>25% decrease in serum IgM) observed. Three other patients remain with stable disease. Therapy was generally well tolerated with greater than grade II adverse events as follows: neuropathy (n=3; 20%); neutropenia (n=3; 20%); thrombocytopenia (n=1; 7%); and rash (n=1; 7%). Adverse events were generally reversible and returned to baseline after holding or dose modifying the study drug.