[The mechanisms of drug resistance via the interaction of myeloma cells with stromal cells].

Interaction of myeloma cells with bone marrow microenvironment underlies cell adhesion-mediated-drug resistance (CAM-DR). CAM-DR is exerted via not only direct adhesion to stromal cells, fibroblasts, mesenchymal stem cells, or macrophages but also indirect effects of IL-6, IGF-1, and SDF-1 in myeloma cells. Bortezomib overcomes CAM-DR via down-regulation of VLA-4, which is a key adhesion molecule in CAM-DR. Although bortezomib is indispensable for myeloma treatment, it is unclear which is the best drug to be combined. Using isobologram analysis, we show that not cyclophosphamide, adriamycin, and lenalidomide but melphalan exerts additive cytotoxicity under all culture conditions tested (stroma free and in contact with fibronectin or stromal cells). Melphalan is considered the best drug to be combined with bortezomib to overcome CAM-DR.