Farnesyl transferase inhibitors (FTIs) are anticancer agents designed to target ras processing and ras-dependent signal pathways. Because oncogenic ras mutations are found in up to 50% of multiple myeloma (MM) specimens, these agents may be effective in this disease. However, some preclinical studies suggest that FTI antitumor responses are unrelated to effects on ras. To address this issue in myeloma, we used the ANBL-6 myeloma cell line where interleukin (IL)-6-dependent cells are stably transfected with mutated N-ras or K-ras genes. Because expression of mutated ras allows for IL-6-independent growth, this is a good model to test whether FTIs specifically target growth-promoting ras-activated pathways in myeloma. Although they had little effect in 10% serum, two separate FTIs induced apoptosis of myeloma cells when cultured in low serum, and mutated ras-expressing cells were more sensitive than wild-type (WT) ras-expressing cells. However, induction of apoptosis did not correlate with inhibition of ras processing. Although they had no effect on AKT activity, under low serum conditions FTIs inhibited constitutive activation of the p70S6kinase and nuclear factor kappaB signal proteins in both mutated ras-expressing MM lines and extracellular signal-regulated kinase (ERK) activity in mutated N-ras-expressing cells. However, in studies where p70, nuclear factor kappaB, and ERK were comparably inhibited by other inhibitors or by gene transfer, we could not identify effects on these pathways as participating in the apoptotic response. FTIs were also able to abrogate the IL-6 proliferative response of WT ras-expressing MM cells, and this was associated with inhibition of IL-6-induced activation of ERK, AKT, and p70. The induction of apoptosis and prevention of the IL-6 response in MM cells containing mutated or WT ras provide support for the therapeutic potential of FTIs in this disease.