Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide

Abstract

SummaryEverolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5Á5 months and median overall survival was 29Á5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.

Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study

“…47 Recently, based on in vitro synergism, 48 the combination of everolimus and lenalidomide was explored in a phase I trial and was found to have promising activity and acceptable tolerability in patients with relapsed MM. 49 Interestingly, weekly bortezomib combined with temsirolimus showed promising activity in relapsed MM, with responses in patients who had been refractory to prior bortezomib-containing regimens. 50 Since everolimus as a single agent showed promising activity, with a limited rate of side effects, in relapsed and/or refractory MM patients, efforts should be made to evaluate optimal combination partners to enhance the anti-myeloma activity and to target the PI3K-AKT-mToR signaling network at multiple sites.…”

The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma

“…The results of early phase clinical trials utilizing mTOR inhibitors in MM have been modest thus far 32,33 . Pre-clinical studies have demonstrated improved efficacy using dual TORC1/2 inhibitors and by targeting feedback mechanisms, including the up-regulation of IGF1R phosphorylation and PI3K/AKT activation 34–36 .…”

Kinase inhibitors as potential agents in the treatment of multiple myeloma

“…[122] in a Phase I/II study concluded that temsirolimus in combination with bortezomib may have a role in the treatment of relapsed or refractory MM without the addition of steroids. A Phase I study of everolimus in combination with lenalidomide drew a similar conclusion [123]. Recently, Li et al [124] extensively reviewed mTOR signaling as a therapeutic target in MM.…”