Multiple myeloma (MM) is an incurable malignancy of plasma cells that evolves from clinically benign precursor conditions, including the premalignant condition monoclonal gammopathy of undetermined significance (MGUS) and an asymptomatic stage called smoldering MM (SMM). The progression from MGUS to SMM and overt, full-blown MM is quite variable. The reason(s) why some patients progress whereas others live out their lives without ever developing MM remains an important clinical question. The overall goal of this highly integrated program is to elucidate the causes of progression from MGUS -> SMM -> MM -> relapsed MM to learn how best to clinically approach each stage of the disease. In Project 1, Dr. Rajkumar proposes to identify predictors of progression permitting definition of a subset of MGUS patients with a risk of progression high enough to warrant intervention; and the premalignant stage responsible for light chain-only MM. He will also examine the role of genetic or familial factors in MGUS and the epidemiology of smoldering myeloma. In Project 2, Dr. Jelinek hypothesizes that intraclonal heterogeneity, a hallmark feature of the monoclonal gammopathies, includes heterogeneity in tumor cell growth potential. The hypothesized proliferative subset is suggested to exist within the monoclonal (as defined by immunoglobulin sequence) PC pool at all phases of disease, i.e., MGUS -> SMM -> MM -> relapsed MM, and this population of cells may utilize some mechanisms employed by normal hematopoietic stem cells and/or early B cell progenitors. She will therefore study intraclonal heterogeneity in MGUS/SMM plasma cells and during disease progression. She will also isolate and characterize proliferating cells and study the role of two specific pathways linked to oncogenesis and growth control of normal stem cells in MGUS/SMM/MM cells. In Project 3, Dr. Fonseca will determine if IgH translocations are seminal events in the pathogenesis of some PC neoplasms and if so, what are their transcriptional consequences. He will also use molecular cytogenetics to elucidate pathogenic pathways in both MGUS and MM and whether MGUS/MM patients have an underlying susceptibility to acquire IgH translocations. Core A will centralize data and sample collection and processing providing appropriate materials for each project. Core B will play a key role in project design and will provide statistical analysis of individual project data. Core C will provide an administrative structure to enhance interaction and support regular internal and external scientific review. The major Specific Aim of this Program Project continues to be obtaining a better understanding of the pathophysiology of the monoclonal gammopathies. We believe that these results will ultimately translate into improved and novel therapeutic strategies.