Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma

Abstract

This phase 1/2 trial evaluated the maximum tolerated doses, safety, and efficacy of pomalidomide, bortezomib, and dexamethasone (PVD) combination in patients with relapsed lenalidomide-refractory multiple myeloma (MM). In phase 1, dose level 1 consisted of pomalidomide (4 mg by mouth on days 1 to 21), IV or subcutaneous bortezomib (1.0 mg/m2 on days 1, 8, 15, and 22), and dexamethasone (40 mg by mouth on days 1, 8, 15, and 22) given every 28 days. Bortezomib was increased to 1.3 mg/m2 for dose level 2 and adopted in the phase 2 expansion cohort. We describe the results of 50 patients. Objective response rate was 86% (95% confidence interval [CI], 73-94) among all evaluable patients (stringent complete response, 12%; complete response, 10%; very good partial response, 28%; and partial response, 36%) and 100% among high-risk patients. Within a median follow-up of 42 months, 20% remain progression free, 66% are alive, and 4% remain on treatment. Median progression-free survival was 13.7 months (95% CI, 9.6-17.7). The most common toxicities were neutropenia (96%), leukopenia (84%), thrombocytopenia (82%), anemia (74%), and fatigue (72%); however, the majority of these were grade 1 or 2. The most common grade ≥3 toxicities included neutropenia (70%), leukopenia (36%), and lymphopenia (20%). Deep vein thrombosis occurred in 5 patients. In conclusion, PVD is a highly effective combination in lenalidomide-refractory MM patients. Weekly administration of bortezomib enhanced tolerability and convenience. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy. This trial was registered at www.clinicaltrials.gov as #NCT01212952.

Conflict of interest statement

Conflict-of-interest disclosure: S.K. has received honoraria from Skyline Diagnostics. Research support from Abbvie, Celgene, Novartis, Amgen, Takeda, Sanofi, and Janssen has been provided to the Mayo Clinic for conduct of clinical trials on which S.K. serves as a principal investigator. M.A.G. has received research support from Ionis Pharmaceuticals and Prothena and honoraria from Celgene, Millennium Pharmaceuticals, and Novartis. A.D. has received research support from Celgene, Millenium, Pfizer, Jannsen, and Alnylam. P.K. has received research funding from Takeda (Mayo Clinic), Onyx (Mayo Clinic), and Celgene (Mayo Clinic) and consulting fees from Celgene and Sanofi (Mayo Clinic). D.D. has received research funding from Takeda, Karyopharm, and Amgen. Y.L. receives research funding from Janssen. P.L.B. has served as a consultant for Amgen and Jannsen. S.A. has served as a consultant for Novartis Pharmaceuticals, Amgen Pharmaceuticals, Pharmacyclics, Inc., and Takeda and has received research funding from Pharmacyclics, Inc. C.B.R. has received research support from Celgene, Novartis, and Millennium. M.Q.L. receives research funding from Celgene. The remaining authors declare no competing financial interests.

© 2017 by The American Society of Hematology.

Figures

Figure 1.

Best response to PVD. Waterfall plot for all patients treated with PVD.

Figure 2.

OS and PFS curves. (A) PFS and OS for all patients treated with PVD. NE, not evaluated. (B) PFS by mSMART risk groups.

Figure 3.

Peripheral sensory neuropathy by grade and cycle. Grade ≥1 peripheral sensory neuropathy at least possibly related to the intervention by cycle of treatment.