Although drugs that are used for the treatment of multiple myeloma, asuch as alkylating agents and steroids, can kill myeloma cells, they do so with limited specificity. Thus the toxicity that they induce in normal tissue limits the dosing that can be used in patients. To develop the next generation if treatment for multiple myeloma it is necessary to identify particular intracellular pathways that are activated inappropriately in myeloma, and which would be desirable targets for therapeutic inhibition. Evidence has accrued in recent years that two transcription factors, STAT3 and NF-kB, are activated in tumor cells from the vast majority of myeloma patients. Furthermore, these proteins are necessary for the continued survival of myeloma cells. By contrast, inhibition of these molecules in normal cells leads to little if any toxicity. Thus they represent extremely attractive molecules for specific targeted therapy of myeloma. To identify compounds that can inhibit the function of these transcription factors, our laboratory has developed a cell based system to screen for drug-like molecules that can specifically inhibit their function. We have already used these systems to successfully identify potent and specific modulators of STAT family transcription factors. We now propose to use these systems to screen the Myeloma Collection for molecules that can specifically inhibit STAT3 and NF-kB. Given that the screening systems have been established and validated, and have already identified active compounds, it is highly likely that the Myeloma Collection can successfully and accurately be screened to identify drugs that alone or in combination, will enhance the therapy of multiple myeloma. Furthermore, since STAT3 and NF-kB play a prominent role in the resistance of myeloma cells to therapy, inhibitors of these transcription factors will likely act synergistically with treatments currently in use. As many of the compounds in the Myeloma Collection are already approved by the FDA, active agents can be introduced rapidly into rationally designed clinical trials for patients with myeloma.