Multiple myeloma is a malignancy of the plasma cell, the final stage of differentiation of the B-lymphocyte. The average age-adjusted incidence of multiple myeloma in the US is 3.0/100,000. Multiple myeloma is the second most common lymphoid malignancy in whites, and the most common lymphoid malignancy in blacks. A major contributor to the morbidity and mortality of multiple myeloma is the unregulated production of immunoglobulin resulting in renal failure, hyperviscosity, and amyloid deposition with end-organ damage. Hence, treatment strategies directed not only at growth inhibition of the malignant cell, but also inhibition of immunoglobulin secretion may alter both morbidity and mortality of multiple myeloma. The multifunctional cytokine IL-6 has been proposed as an autocrine or paracrine mediator of myeloma cell growth and immunoglobulin secretion. Previous work in our laboratory has shown that in vitro glucocorticoids and the polysulfonated napthylurea suramin synergistically inhibit the growth of human multiple myeloma cell lines. In addition, we have demonstrated that both these agents inhibit immunoglobulin secretion in human multiple myeloma cell lines at minimally growth inhibitory (IC10) concentrations. This proposal is aimed at directly experimentally testing the following specific hypotheses: 1. The lymphokine IL-6 is an autocrine or paracrine growth factor for both growth and immunoglobulin production in multiple myeloma. 2. Glucocorticoids and/or suramin exert inhibitory effects on myeloma growth and immunoglobulin secretion by interfering with the action of IL-6. Objectives: 1. A panel of human, B-cell, immunoglobulin-secreting, glucocorticoid sensitive multiple myeloma cell lines will be selected and characterized for both in vitro and in vivo studies. 2. The expression of IL-6 protein, mRNA and receptor sites will be determined in this panel of cell lines in response to treatment with glucocorticoids and suramin to test the hypothesis that these agents block IL-6 dependent growth and immunoglobulin secretion. 3. The mechanism by which suramin and glucocorticoids inhibit the elaboration of immunoglobulin from human myeloma cells will be examined. 4. The ability of an available IL-6-binding polyclonal antibody to block immunoglobulin secretion will be determined to test the hypothesis that IL- 6 functions as an autocrine or paracrine stimulator of immunoglobulin secretion in multiple myeloma. 5. An animal model (NIH-3 mouse) will be established for in-vivo study of inhibition of growth and immunoglobulin secretion and the growth regulatory role of IL-6 in heterografted human multiple myeloma cells.
