Multiple myeloma is an incurable disease with standard dose chemotherapy, having a median survival with treatment of about three years. In an effort to improve the outcome for patients with multiple myeloma, high-dose chemotherapy regimens with autologous stem cell rescue have been undertaken and have demonstrated complete response rates of 40-50%. However, the lack of a plateau in progression free survival after high-dose chemotherapy suggests that more effective drug combinations involving new antitumor agents are needed. A major hypothesis of this application is that the sequencing and timing of the antitumor agents is important in the killing of myeloma cells in vivo. The preclinical data suggest that a high-dose chemotherapy sequence of alkylating agent followed by topoisomerase II inhibitor followed by topoisomerase II inhibitor is a reasonable approach and may demonstrate synergistic activity. The major reason that patients fail to respond to antineoplastic agents is because of intrinsic or acquired drug resistance. It is likely that the drug resistance of myeloma cells in vivo is due to the concurrent expression of multiple mechanisms of resistance, perhaps including perturbations in DNA topoisomerases. The second major hypothesis of this application is that alterations in topoisomerase I and II (content, location and activity) are involved in the drug resistance of myeloma cells in vivo.
Four specific aims are proposed to address these two hypotheses. 1. To establish the toxicity and potential efficacy of a high-dose regimen sequenced as melphalan followed by topotecan followed by VP-16 phosphate (MTV) followed by peripheral blood stem cell rescue in the treatment of multiple myeloma. 2. To evaluate the pharmacokinetic profiles of intensive-dose topotecan, melphalan and VP-16 phosphate and to investigate the pharamcodynamic relationships with respect to the efficacy and toxicity of this regimen. 3. To examine the hypothesis generated in vitro that the specific sequence of administration of antineoplastic agents as alkylator followed by topoisomerase I inhibitor followed by topoisomerase II inhibitor has a biochemical justification in vivo in the treatment of multiple myeloma. 4. To determine the role(s) of quantitative, qualitative, and distributive alterations in DNA topoisomerase I, II-alpha and II-beta in the clinical drug resistance of multiple myeloma in patients who have been treated with the high-dose MTV regimen.
