Support is requested to advance the therapy of patients with multiple myeloma with developing a prognostic factor model for various therapeutic endpoints, such as remission induction, response duration and survival, so that novel treatment can be investigated in poor risk patients. In approaching this goal, a prognostic factor model will be established on a historical data base of 201 previously untreated patients receiving standard combination chemotherapy. In a second step, the model will be validated, using a cohort of 50 recently treated patients and 30 patients to be treated over the first year. After confirmation of the model, treatment will be stratified, so that standard therapy will be administered to good risk patients, whereas investigational treatment will be reserved for high risk patients, both for remission induction and for maintenance. The prognostic variables to be investigated include standard clinical and laboratory parameters. In addition, major emphasis will be placed on the further development of cellular biological parameters some of which have already demonstrated clinical usefulness. Thus, RNA content as determined by flow cytometry of acridine orange -stained marrow cells, is associated with remission induction; and the cytometrically defined proportion of tumor cells in the marrow affects survival duration. In addition, the relationship between cellular expression of RNA and CIg and myeloma protein concentration in the serum and urine will be investigated, in an effort to identify a biological basis for the known clinical heterogeneity of myeloma. With the notion that DNA synthetic rate seems to affect remission induction, a BUdR monoclonal antibody immunofluorescence assay will be adopted to assess DNA synthesis rate by flow cytometry. We will also quantitate the receptor expression on myeloma cells for glucocorticosteroids and interferon and correlate these findings with in vivo response to these agents. Likewise, adriamycin cellular uptake will be measured by flow cytometry, using either a direct assay or a competitive binding assay with Hoechst 33342. While the aforementioned studies will serve to develop a treatment model for myeloma, efforts will also be devoted to the development of new therapy, including phase I-II chemotherapy agents, interferon, and high dose chemotherapy + total body irradiation supported by marrow transplantation.
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