The drug treatment of multiple myeloma is rapidly evolving, with four active classes of drugs (alkylating agents, glucocorticoids, proteasome inhibitors and Imids) being used in combinations with remarkable efficacy. Despite a high rate of remission, relapses still occur. This project seeks to use a novel transgenic Vk*MYC mouse model of myeloma to understand the molecular mechanism underlying drug response and optimize the drug treatment of patients with multiple myeloma (MM). Presumably because of its pathogenic fidelity the Vk*MYC model results in a tumor with close phenotypic fidelity to human MM, characterized by indolent bone marrow localized monoclonal plasma cells that respond to drugs much like human MM. We hypothesize that many fundamental aspects of MM cell biology are conserved between mouse and human MM, including important shared aspects of normal plasma cell biology. We propose to use our ability to manipulate the Vk*MYC MM genome in a controlled fashion in order to identify genetic changes associated with drug resistant MM that will be generated in vivo. We will then take a comparative pharmaco-oncogenomic approach and will query existing human MM genomic datasets for relevance of genetic changes identified in the mouse to human MM drug response. We will identify the genetic (DNA copy and GEP) changes in paired samples from patients before and after relapse from drug treatment and compare to similarly matched mouse samples. We will validate the relevance to in vivo drug resistance of the genetic changes identified. We will use lentiviral shRNA to target these genetic changes in Vk*MYC MM cells transplanted into recipient mice, and determine their relative drug sensitivity. In addition to examining the role of these genetic modifiers of drug response, we will examine pharmacologic modifiers of drug response implicated in clinical studies as a positive control for future studies. We will use response rate and time to progression in Vk*MYC MM to study in vivo drug combinations with proteasome inhibitors, seeking pre-clinical evidence of synergy in this model to support its use for the pre- clinical evaluations of combinations for use in the treatment of MM patients. In conclusion this proposal takes advantage of a novel faithful mouse model amenable to rapid genetic manipulation to understand and improve the drug treatment of MM patients