BMSC-mediated resistance to apoptosis via IL-6R blockade is abolished through concomitant blockade of the MAPK pathway in primary myeloma cells. (A) Survival of primary myeloma cells kept in medium supplemented with 2 ng/mL IL-6 and exposed to combinations of the MEK1,2 inhibitor PD98059 (50 μM) and the IL-6R antagonist Sant7 (50 μg/mL). Treatment with Sant7 reduced viability by about 50%, and the combination of both inhibitors produced a further marked increase in cell death. (B) Survival of primary myeloma cells cocultured with primary BMSCs and exposed to combinations of PD98059 (50 μM) and Sant7 (50 μg/mL). Coculturing had no effect on the slight decrease in myeloma cell viability recorded with PD98059, but it protected the cells from apoptosis induced by Sant7. Combined application of both pathway inhibitors was required to achieve a profound loss of viability in this setting. Myeloma cell preparations from 11 patients were used, and shown are the individual values for the percentage of viable cells after treatment with the respective inhibitor(s). The horizontal lines indicate the median of each treatment cohort. The numerical data are provided in Table 1. Statistical analysis revealed significant (^*) or very significant differences (^**) as indicated.