Approximately 25% of patients with clinically benign monoclonal gammopathy of undetermined significance (MGUIS) will eventually progress to active multiple myeloma (MM). We have shown that interleukin-1beta (IL-1beta, which is not expressed by normal plasma cells, is abnormally produced by plasma cells obtained from virtually all myeloma patients and approximately 25% of patients with MGUS. The importance of Il-1beta production by myeloma cells comes from its ability to induce IL-6 by bone marrow stromal cells. Because IL-6 is the central growth factor for myeloma cells, the IL-1beta induced Il=6 serves to maintain and perpetuate the myeloma clone in the bone marrow. We hypothesize that treatment of patients with smoldering or indolent multiple myeloma (SMM/MM), who are at high risk for progression to active MM, with IL-1 receptor antagonist (IL-1Ra) will inhibit paracrine Il-6 production and myeloma cell growth. Using stromal IL-6 production as a surrogate biomarker for IL-1beta activity, preliminary results demonstrate that bone marrow cells from myeloma patients induce IL-6 levels that are significantly higher than the levels generated by MGUS patients (p. 0.001). In patients with these elevated IL-6 levels, IL-1Ra can inhibit IL-6 production by >90% in vitro. Base on these preclinical results, we have developed a Phase II clinical trial using IL-Ra in patients with smoldering/indolent myeloma that do not require chemotherapy but are at high risk for progression to active myeloma.