Multiple myeloma (MM), a multifocal plasma cell neoplasm, remains incurable despite conventional high-dose chemotherapy. The development of rational-based therapeutics for MM requires a detailed knowledge of the mutations driving this malignancy. It stands to reason that a more complete view of these genetic lesions would increase opportunities for cancer drug development. It is equally imperative that biological systems be developed to better validate these target genes. Genomic studies Our laboratory is working to identify the genetic events leading to MM. To this end, we have developed a thorough molecular profile of MM pathogenesis by analyzing cancer-associated alterations in the DNA and RNA of clinically annotated specimens and established cell lines. This oncogenomic analysis has yielded genetic elements of MM with strong biological and clinical correlates to other tumor types, to survival, and to known oncogenes and tumor suppressor genes, or their homologues, not previously implicated in MM pathogenesis. Biological systems - our next challenge is to identify which genes within newly identified loci are myeloma oncogenes or tumor suppressor genes, and to understand the role that these genes play in the genesis and progression of MM. To characterize these genes, we are conducting functional studies that include in vitro cell-based assays as well as hematopoietic stem cell transplantation and genetically engineered mice. Biologic correlates - in conjunction with the Pathology Department at Brigham and Women's Hospital, we are also examining a series of MM bone marrow tumors to evaluate the expression of novel disease markers. In addition, we are engaged in translational studies to develop novel markers for diagnosis and prognostication in MM patients. The increasing availability of small-molecule inhibitors of protein interaction may open the door to a series of clinical trials.