The IL-6R/STAT3 pathway has been reported to critically contribute to the pathogenesis of multiple myeloma (MM) and to protect MM cells from apoptosis. However, recently we could demonstrate that MM cells become independent of the IL-6R/STAT3 pathway if they are cocultured with bone marrow stromal cells (BMSCs), suggesting that the BM microenvironment stimulates IL-6-independent pathways that exert a pro-survival effect. It was therfore the aim of this study to analyze the underlying mechanism of this phenomenon. Pathway analysis revealed that BMSCs stimulate STAT3 via the IL-6R, and MAPK in parts via IL-6R-independent mechanisms. Abolition of MEK1, 2 activity with PD98059, or of ERK1,2 through siRNA constructs, was insufficient to induce apoptosis. However, the combined disruption of the IL-6R/STAT3 and MEK1,2/ERK1,2 pathways led to strong induction of apoptosis even in the presence of BMSCs. Thus, disruption of the MEK/ERK pathway restores IL-6/STAT3 dependence of MM cells in the presence of BMSCs indicating that BMSC-mediated induction of the MEK/MAPK pathway is the mechanism by which BMSCs render MM cells IL-6/STAT3 idependent. Consequently, in the presence of cells from the BM microenvironment the combined targeting of different (and independently activated) pathways is required to efficiently induce apoptosis of MM cells. This effect was observed with MM cell lines and with primary MM cells and might have direct implications for the development of future therapeutic strategies for MM.