PROJECT 1 SUMMARY/ABSTRACT Despite recent advances in therapy the majority of multiple myeloma (MM) patients are not cured but rather suffer from a chronic relapsing, yet ultimately fatal disease. Two challenges immediately become evident. Most urgent is the need to find alternative therapies for patients who fail existing potent drug classes. Second, is to understand why patients may be resistant in the first place and to seek methodologies, dosing strategies and new drug combinations which can prevent or overcome drug-resistant relapse. We propose an innovative strategy of “direct to drug” screening of 500 primary patient samples with chemogenomic interrogation which addresses both of these two big questions. Our hypothesis is that a direct to drug analysis of individual patients will improve response rates, lower unnecessary toxicity and reduce drug costs through identification of the most effective combinations of FDA approved drugs for each patient. This strategy will also, for the purposes of this proposal, provide a database of samples and clinical data sets from which to explore genomic or clinical correlates of drug sensitivity and resistance. Our goal will be attained through the successful pursuit of three specific aims, building upon extensive cell line and primary patient sample data. First, we will measure the in vitro sensitivity of 79 MM therapeutics including CTEP compounds in 500 primary myeloma patient samples. Second, we will conduct combination screens to seek synergistic combinations of IMiDs and proteasome inhibitors as base compounds with other active MM therapeutics such as bromodomain inhibitors which can be tested in animal models such as the human CRBN mouse in project 2. Third, using our M3P mutation panels, we will conduct a chemogenomic interrogation to examine specific correlates of drug sensitivity and resistance utilizing pre-treatment and surviving cells from primary patient robotic screens. These studies will determine the frequency of specific genetic mutation or cellular subsets resistant to the most active drugs or drug combinations used in MM therapy and will be shared throughout the program for further epigenetic and transcriptional analysis and bi-directional feedback derived from both Projects 2 and 3. Critical to the current U54 application this strategy will provide a database of 500 multiple myeloma samples and linked clinical data sets which together build a mosaic of drug sensitivity and clinical phenotype from which all elements of this program grant can exploit to explore genomic or clinical correlates of drug sensitivity and resistance.