The objective of this Program Project is to develop therapeutic strategies that achieve sustained CR, based on insights gained from fundamental research and carefully controlled clinical trials. The research activities of this Program Project are based on the hypothesis that ultimate growth control of multiple myeloma can be achieved only through novel therapeutic interventions in the context of fundamental research of disease genetics and the biological mechanisms that sustain myeloma cell survival and progression. Six projects are proposed in this competing renewal application. The roles of anti-angiogenesis therapy with thalidomide and dose-intensified consolidation therapy will be investigated via clinical trials in newly diagnosed patients (Proj 1), given our knowledge about critical obstacles to cure and the demonstrated efficacy of these treatment modalities. In patients treated previously for myeloma (Proj 2), standard melphalan-based stem cell transplantation will be compared to chemoangiotherapy. We expect that molecular identification of myeloma tumor suppressor gene(s), associated with the high risk chromosome 13 entity, will ultimately lead to better diagnosis and staging, as well as discovery of potentially novel growth-regulatory molecules (Proj 3). As standard and high-dose therapies have both been shown to induce myelodysplasia (MDS) in a considerable fraction of patients, this adverse consequence of effective myeloma therapy will be studied prospectively in relationship to host and treatment variables (Proj 4). Biological and clinical observations of the roles of normal host accessory cells for the survival and expansion of myeloma cells can now be explored in the SCID-hu model, which lends itself to studying stromal-directed therapies that lead to tumor cell inactivation, such as pamidronate and thalidomide (Proj 5). Delineation of the mechanisms underlying the growth- inhibiting and bone-stimulating properties of syndecan-1 should lead to therapeutic exploitation either of this or related molecules (Proj 6). Three cores are proposed: Research Coordination and Administration; Biostatistics and Data Operations; and Cell Analysis. Thus, in the pursuit of achieving Growth Control in Multiple Myeloma, the collective work of basic and clinical scientists will shed light on the fundamental cellular and molecular mechanisms of myeloma growth and identify new means of tumor cell inactivation, thus aiding the design of rational, more effective, and safer therapeutic interventions.
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