We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficiency (SCID) mouse using both the drug-sensitive 8226/S human myeboma cell line and the P-glycoproteinexpressing multidrug-resistant 8226/C1N subline. As demonstrated previously, the SCID mouse is well suited as a model for myeloma because: (a) human SCID xenografts are readily attained; (b) human myeloma xenografts are readily detected by their immunoglobulin secretion; and (c) differential therapy effects in drug-sensitive versus drug-resistant cell lines are readily demonstrable by monitoring mouse urinary human immunoglobulin output. In the current study, we have utilized this model to evaluate the in vivo efficacy of chemomodulators of P-glycoprotein-related mubtidrug resistance. In our initial experiments, doxorubicin alone was effective in treating the 8226/S human myeloma xenografts but had no effect on the drug-resistant 8226/C iN xenografts, in the absence of the chemosensitizing agent verapamil. In subsequent experiments, the combination of verapamil and doxorubicin resulted in both a decrease in human X light chain urinary excretion and an increase in survival of those animals bearing the 8226/C1N tumor. The median survival time of animals injected with 8226/C1N cells and subsequently treated with doxorubicin was 48.6 ± 7 days, which compared to a survival of 89.6 ± 18 days in animals receiving the 8226/S cell line and treated with doxorubicin alone (P < 0.001). When verapamil was added to the treatment regimen of those animals bearing the 8226/C1N xenografts, there was a 179% increase in their life span (P < 0.001), which corresponded with the observed decreased light chain in the urine. In animals receiving multiple courses of chemotherapy, an attenuated response to veraReceived 5/2/95: revised 7/10/95: accepted 8/2/95. I This work was supported in part by National Cancer Institute Grants CA57228. CA17094. CA43043. ES06694. and CA23074. 2 To whom requests for reprints should be addressed. at Department of Pathology, College of Medicine, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724. Phone: (520) 626-6032: Fax: (520) 626-1027. pamil and doxorubicin was observed, in a manner analogous to the clinical setting of human drug-resistant myeloma escape from chemosensitivity. The SCID human myeloma xenograft model thus offers a means of evaluating the in vivo efficacy and potential toxicities of new therapeutic approaches directed against P-glycoprotein in multidrug-resistant human myeloma.