DESCRIPTION: (Applicant's Description) Multiple myeloma remains an incurable disease, in spite of the considerable progress made in increasing the rate of complete remissions achieved by patients. Relapses are caused by the myeloma cells with self-renewal capacity. These cells are able to survive even the most aggressive treatment. Interactions of the myeloma cells with their microenvironment through adhesion molecules and cytokines provides the myeloma cells with a sanctuary, protecting the cells from spontaneous and drug-induced apoptosis. The long-term goals of this project are to elucidate the biology of myeloma at the molecular and cellular level as a guide to better clinical management of the disease. The central hypothesis this project addresses is: Myeloma and stroma interactions result in a supportive microenvironment that allows the myeloma plasma cells to achieve a state of inexhaustible proliferation and disease subsistence, and to eventually develop resistance to drug therapy. By targeting the myeloma plasma cells directly and by interfering with elements of the supportive and protective micro-environment, we can develop effective therapies against myeloma. Our specific aims are: (1) To control the growth of myeloma and its manifestations by changing the bone marrow environment. We will determine whether normal bone marrow stroma can support sustained proliferation of myeloma cells. We will identify elements of the supportive micro-environment required for myeloma cell growth by disrupting the functions of the osteoclasts and vascular endothelial cells and determine the effects on the survival and the growth of the myeloma cells and on the cytokine milieu. These studies will reveal the importance of osteoclasts and vascular endothelial cells, in supporting myeloma. (2) To prevent emergence of drug resistance in myeloma. We will determine if the bone marrow stromal environment facilitates emergence of drug resistance, and investigate if the molecular mechanisms of in vivo drug resistance are the same as have been reported for in vitro resistance. These studies will shed light on the development of drug resistance in vivo, and will point to strategies that will increase treatment efficacy. (3) To determine the role of pre-plasmacytic cells in the blood and bone marrow of myeloma patients in sustaining the disease process. We will determine the ability of purified myeloma plasma cells to achieve a state of inexhaustible proliferation and production of myeloma manifestations in the SCID-hu host, and whether the preplasmacytic cells in the bone marrow and blood of patients are able and required to produce sustained symptomatic myeloma in the SCID-hu host. These findings will determine if therapy needs to consider preplasmacytic cells as an important component of the myeloma disease process. By its conclusion, work under this project will have determined the significance of reported anomalies in the myeloma bone marrow microenvironment to the disease process, elucidated the role of osteoclasts and vascular endothelial cells in supporting myeloma cells, determined whether disrupting osteoclast function and interfering with neo-angiogenesis inhibits growth of myeloma cells and increases the efficacy of treatment, demonstrated the ability of myeloma plasma cells to maintain the disease process, and determined whether preplasmacytic clonal cells have a continuous active role in sustaining the disease process.