Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma

Abstract

Purpose: Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM.

Patients and methods: Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m(2) on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination.

Results: Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m(2). Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months.

Conclusion: Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM.

Fig 1.

Putative mechanistic basis for the use of the lenalidomide-bortezomib-dexamethasone combination. Lenalidomide and dexamethasone have been shown to trigger myeloma cell apoptosis via caspase-8 and caspase-9, respectively. Bortezomib can activate both of these pathways and also can counteract the inhibitory effect of nuclear factor–κB (NF-κB) on the antimyeloma activity of dexamethasone (Dex). These molecular events potentiate the induction of a dual caspase-8 and caspase-9–mediated apoptotic cascade with poly(ADP-ribose) polymerase (PARP) cleavage, leading to enhanced antimyeloma activity.

Fig 2.

Kaplan-Meier estimates (in months) and 95% CIs of (A) time to progression, (B) progression-free survival, and (C) overall survival in 36 patients.