John A. Lust, M.D., Ph.D.
John A. Lust, M.D., Ph.D.
Multiple myeloma (MM) is a universally fatal B cell malignancy despite aggressive treatment approaches. Approximately 50,000 Americans currently have the disease and it accounts for 1-2% of all cancer deaths. Newer therapeutic strategies are clearly needed for this disease and these are likely to arise from a better understanding of the biology of myeloma.
Comparison of the spectrum of clinical disease between MM and its clinically benign precursor condition, monoclonal gammopathy of undetermined significance (MGUS) have provided direction into the investigation of those changes that may be important in the pathogenesis of myeloma. During long-term follow-up of 241 patients with MGUS, 59 patients (24.5%) went on to develop MM or a related plasmaproliferative disorder. A potential role for the acquired expression of various cytokines such as interleukin-1 beta (IL-1beta) and other cellular factors in the monoclonal plasma cells has been implicated in the progression of MGUS to MM. In this regard, the IL-1beta gene is not expressed in normal plasma cells, but we have shown that IL-1beta is expressed by plasma cells obtained from virtually all myeloma patients. In contrast, plasma cell IL-1beta expression was observed in less than 25% of patients with MGUS. Functionally, IL-1beta has potent osteoclast activating factor activity, can increase the expression of adhesion molecules, and can induce paracrine IL-6 production. These biologic effects of IL-1beta closely parallel several of the clinical features of human myeloma such as osteolytic bone lesions, ?homing? of myeloma cells to the bone marrow, and IL-6 induced cell growth. Since MGUS is relatively common in the general population and myeloma is incurable in virtually all cases, identification of those MGUS patients likely to progress to active myeloma will be important in the development of new therapeutic strategies. The above observations suggest that treatment of patients with an effective IL-1beta inhibitor may be a rational therapeutic approach in individuals with early myeloma or high-risk MGUS. We anticipate initiating clinical trials with an IL-1 inhibitor in 2002.
In addition, we are attempting to target myeloma cells using novel antibody engineering techniques. We have successfully constructed a single chain variable fragment (scFv) gene specific for the CD38 molecule, the most common antigen on myeloma cells. This was accomplished by fusing the anti-CD38 hybridoma immunoglobulin heavy chain gene with the light chain gene. We are using the scFv protein as a carrier to introduce "toxin" genes into myeloma cells. Preliminary results suggest that the scFv binds to CD38 and is internalized. We are currently investigating those factors important in scFv internalization and in the stability of the scFv in vivo.
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