In vitro studies of ways to overcome resistance to VAMP‐high dose melphalan in the treatment of multiple myeloma

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Abstract
Summary Myeloma colonies (MY‐CFUc) from 7/24 patients undergoing treatment with VAMP (vincristine, adriamycin and methyl prednisolone) and high dose melphalan (HDM) were melphalan‐resistant. It was not possible to conclude that VAMP induced melphalan resistance in MY‐CFUc, but that resistance is endogenous in some myeloma cell populations. In 12/13 of the same patients of whom four had MY‐CFUc which were melphalan resistant, the sensitivity of MY‐CFUc and GM‐CFUc to busulphan was similar. Thus resistance of MY‐CFUc to melphalan did not confer resistance to busulphan.MY‐CFUc from 1/7 of a second group of patients were adriamycin‐resistant. This resistance was removed when the cells were treated with a combination of verapamil (3 μg/ml) and adriamycin. Verapamil also enhanced the toxicity of adriamycin to MY‐CFUc, from two patients where there was no evidence for adriamycin resistance. In these three patients the sensitivity of both MY‐CFUc and GM‐CFUc was similar after treatment with verapamil.Verapamil did not affect the uptake or efflux of 3H‐daunorubicin in sensitive and resistant RPMI‐8226 cells (myeloma) and peripheral blood mononuclear cells from a normal donor; neither did it affect the binding of 3H‐daunorubicin to nucleic acid.It is concluded that verapamil may be a useful adjuvant to VAMP chemotherapy and that busulphan may provide an alternative to melphalan in patients whose myeloma cells are melphalan resistant.

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