Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia

Christine Chen, David Siegel, Martin Gutierrez, Meagan Jacoby, Craig C. Hofmeister, Nashat Gabrail, Rachid Baz, Morten Mau-Sorensen, Jesus G. Berdeja, Michael Savona, Lynn Savoie, Suzanne Trudel, Nuchanan Areethamsirikul, T. J. Unger, Tami Rashal, Tim Hanke, Michael Kauffman, Sharon Shacham, Donna Reece

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43 Scopus citations

Abstract

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ‡partial response occurring in the 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR 5 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2 (80 mg) plus 20 mg dexamethasone given twice weekly.

Original languageEnglish
Pages (from-to)855-863
Number of pages9
JournalBlood
Volume131
Issue number8
DOIs
StatePublished - Feb 22 2018

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    Chen, C., Siegel, D., Gutierrez, M., Jacoby, M., Hofmeister, C. C., Gabrail, N., Baz, R., Mau-Sorensen, M., Berdeja, J. G., Savona, M., Savoie, L., Trudel, S., Areethamsirikul, N., Unger, T. J., Rashal, T., Hanke, T., Kauffman, M., Shacham, S., & Reece, D. (2018). Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood, 131(8), 855-863. https://doi.org/10.1182/blood-2017-08-797886