Major finding: Lenalidomide is a substrate of P-glycoprotein.
Approach: Phase I clinical trial evaluated lenalidomide and CCI-779 in patients with relapsed MM.
Future direction: Development of regimens including lenalidomide should consider that it is a P-gp substrate.
Multiple myeloma (MM) is an incurable hematologic malignancy of plasma cells in the bone marrow. Lenalidomide, an effective immunomodulatory and tumoricidal agent, is a derivative of thalidomide and a standard treatment for initial and relapsed MM. Preclinical models have demonstrated that the PI3K/Akt/mTOR pathway plays a role in MM pathogenesis, suggesting that inhibition of this pathway in combination with lenalidomide may provide additional therapeutic benefit. CCI-779 (temsirolimus), which targets mTOR, showed single agent efficacy in a phase II study of MM, and CCI-779 combined with lenalidomide demonstrated synergy in vitro. These observations prompted Hofmeister and colleagues to conduct a phase I clinical trial of lenalidomide in combination with CCI-779 in patients with relapsed MM. Although the study established the maximum-tolerated dose of the combination, adverse events were more frequent than expected and pharmacokinetic analysis suggested a drug-drug interaction. CCI-779 is a substrate of P-glycoprotein (P-gp), an ATP-dependent drug efflux pump encoded by the ABCB1 gene. The authors therefore hypothesized that an interaction was occurring during drug transport. In vitro studies confirmed that lenalidomide is also a P-gp substrate and its efflux from cells is inhibited by CCI-779. Taken together, the findings are an example of how clinical observations can reciprocally drive basic science research. The molecular mechanism underlying the drug interaction may explain both the increased systemic concentrations of lenalidomide and related toxicities seen in the trial and informs the future development of therapeutic regimens that include lenalidomide.
Hofmeister CC, Yang X, Pichiorri F, Chen P, Rozewski DM, Johnson AJ, et al. Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. J Clin Oncol. 2011 Aug 8. [Epub ahead of print]
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.