Multiple myeloma (MM) is a fatal neoplastic disease whose genetic mechanisms of origin, progression, and clinical behavior are poorly understood. The proposed studies are based on the hypothesis that detailed genetic characterization of MM utilizing currently-available cutting-edge technologies will enable a new understanding of the biology and clinical behavior of this important hematopoietic malignancy. In these studies, we propose to combine the two novel molecular cytogenetic techniques, spectral karyotyping (SKY) and comparative genomic hybridization (CGH), with those of cloning and characterization of genes deregulated in chromosomal translocations. This applicatin has three Specific Aims: 1. Define chromosomal changes in MM using CGH and SKY We will apply the molecular cytogenetic techniques SKY and CGH to a series of prospectively ascertained MM tumor samples seen for diagnostic evaluation and entered on Memorial Hospital (MH treatment protocols in order to fully characterize structural rearrangements (SKY) and numerical abnormalities (CGH) at all stages of the disease. 2. Isolate novel genes deregulated by rearrangement with IG genes. We will isolate and characterize the candidate deregulated genes from novel 14q32 (IGH)-associated chromosomal translocations. The two translocations, t(12;14)(q24;q32) and t(14;20)(q32;q11), discovered in the first SKY study of these tumors by us will be initially targeted for cloning. 3. Develop a new genetic prognostic model for MM. We will develop a genetic prognostic model for MM utilizing data from SKY and CGH on recurring rearrangements, breakpoints, and gains and losses of chromosomal regions, along with conventional prognostic markers such as levels of beta2-microglobulin, serum IL-2-6, and C-reactive protein, on patients entered on Memorial Hospital treatment protocols. The subregional gains and losses identified by CGH may also identify sites of genes whose amplification or inactivation may influence clinical outcome. Our preliminary studies of MM and our previous success with similar goals in the analysis of B-cell non-Hodgkin's lymnphoma (NHL), give us the confidence that we will be successful in the studies proposed in this application.