Farnesyltransferase inhibitors and their role in the treatment of multiple myeloma.

BACKGROUND Ras mutations are among the most common oncogene mutations found in multiple myeloma (MM). Patients with mutated Ras are less likely to respond to chemotherapy and have a shortened median survival. Therefore, targeting Ras farnesylation may be a valuable approach to treatment of MM. R115777 (tipifarnib) is a potent farnesyltransferase inhibitor (FTI) presently undergoing phase II/III clinical trials. METHODS We reviewed the preclinical and clinical experience of FTIs as antineoplastic agents and describe their potential role in the treatment of MM. RESULTS FTIs are a novel group of agents that selectively inhibit farnesyltransferase, an enzyme responsible for the posttranslational modification of several proteins including Ras. Since Ras is among the most commonly mutated oncogenes associated with cancer, this class of drugs has been evaluated in clinical trials in a diversity of tumors. R115777 has been evaluated in a phase II clinical trial in patients with advanced myeloma and found to be well tolerated. It induced disease stabilization in more than 60% of patients with advanced myeloma. CONCLUSIONS The drug selectively targets farnesyltransferase, but this effect did not correlate with disease stabilization, suggesting that these drugs may be targeting a survival pathway independent of Ras processing. Further studies will evaluate the use of FTI in maintenance therapy as well as in combination with other agents in advanced myeloma.