INFUSIONAL 8 CHLORO CYCLIC AMP IN TREATMENT OF MULTIPLE MYELOMA

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This project builds upon growing laboratory evidence identifying distinct, but convergent pathways in the induction of apoptosis in lymphoid cell lines. One of these paths is initiated by glucocorticoid receptor binding and one initiated by cyclic AMP. Having now observed in our laboratory a consistent and marked efficacy of cAMP in inducing cell death in glucocorticoid-sensitive and glucocorticoid-resistant myeloma cells, we propose a pilot study evaluating infusional dibutyryl cAMP as a single agent in relapsed and resistant myeloma. Our studies have shown that, unlike the method of cell death induced by glucocorticoids in myeloma cell lines, the cell death induced by cAMP exposure is not resisted or deterred by exogenous supply of IL-6. Dibutyryl cAMP infusion has been previously employed at the doses utilized here in the treatment of congestive heart failure. As one would predict from its known range of activities on vascular smooth muscle and myocardium, it is associated with an increase in heart rate, an increase in caridac output, and a decrease in systemic vascular resistance. In prior pharmacologic trials it has not been associated with hypotension or arrhythmia other than sinus tachycardia. Our plan is to utilize this therapy in patients who have relapsed or been refractory to first line therapy for myeloma. The best single agent in this setting is dexamethasone, which offers a 30% response. Since our laboratory data suggest superiority to dexamethasone alone in inducing cell death in myeloma cell lines, we hope to appreciate any similar rate of efficiency for this agent alone.