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Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom's 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 and Donna Reece

Key points

  • Selinexor is an oral, XPO1 inhibitor with anti-myeloma activity.

  • The RP2D is 45 mg/m2 (80mg) selinexor plus 20mg dexamethasone given twice-weekly.

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's 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 60mg flat dose) without corticosteroids in 21 day cycles. The most common non-hematologic 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 (CBR) of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥PR occurring in the 45 mg/m2 selinexor plus 20mg dexamethasone twice weekly cohort (ORR=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 (80mg) plus 20mg dexamethasone given twice-weekly.

  • Submitted August 7, 2017.
  • Accepted November 22, 2017.