Although multiple myeloma is clinically defined as the accumulation of clonal, malignant plasma cells in the bone marrow, the disease shows significant heterogeneity with regard to progression and therapeutic response. The hypothesis addressed in this proposal is that functional genetic polymorphisms are associated with tumor growth control, drug metabolism/detoxification, and DNA repair mechanisms that will influence chemotoxicity and the course of the disease. Cell and DNA banks from 3 phase Ill clinical trials of the Eastern Cooperative Oncology Group will be used to determine allelic frequencies of genetic polymorphisms in genes associated with drug metabolism/transport (cytochrome P450, myeloperoxidase, glutathione S-transferases (M,T,P), multi-drug resistance 1); DNA repair (XRCCC1, ERCC2); and, myeloma related growth factors (lL-6, IL-1b, IL-1RA, IL-10, TNa, Lta, TGFb). Known genetic polymorphisms that alter function of each of these gene products will be correlated with survival, bone disease, toxicity, response, infection, and secondary malignancies. These correlations will provide important genetic markers that will allow better individualized treatment strategies.
