Bendamustine and melphalan kill myeloma cells similarly through reactive oxygen species production and activation of the p53 pathway and do not overcome resistance to each other

Because the old alkylating drug bendamustine (BDM) is currently under evaluation in patients with multiple myeloma, we compared its efficacy to that of melphalan in 29 human myeloma cell lines (HMCLs). The concentrations of BDM and melphalan that killed 50% of cells (LD50) in HMCLs were linearly correlated (p < 0.001), and reactive oxygen (ROS) scavengers similarly inhibited cell death induced by both drugs. Sensitivity of HMCLs to both drugs was correlated to p53: the BDM and melphalan median LD50 values of TP53(wild-type) HMCLs were more than two-fold lower than those of TP53(abnormal) HMCLs (p < 0.001), and p53 silencing in TP53(wt) NCI-H929 cells inhibited BDM- and melphalan-induced cell death. Both drugs induced expression of p53 targets, p21, Puma and DR5, only in TP53wt HMCLs. In primary cells, both drugs induced an increase in DR5 expression in cells without del(17p). Finally, we demonstrated that the combined effect of BDM and melphalan was additive, and that BDM did not overcome melphalan resistance and vice versa.