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Blood. 2018 Feb 22;131(8):855-863. doi: 10.1182/blood-2017-08-797886. Epub 2017 Dec 4.

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

Author information

1
Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
2
The University of Toronto, Toronto, ON, Canada.
3
Department of Hematology, John Theurer Cancer Center, Hackensack, NJ.
4
Siteman Cancer Center, Washington University in Saint Louis, Saint Louis, MO.
5
Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH.
6
Gabrail Cancer Institute, Canton, OH.
7
Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
8
Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
9
Blood Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN.
10
Division of Hematology & Oncology, Vanderbilt-Ingram Cancer Center/Vanderbilt University Medical Center, Nashville, TN.
11
Tom Baker Cancer Centre Division of Hematology, University of Calgary, Calgary, AB, Canada; and.
12
Karyopharm Therapeutics Inc, Newton, MA.

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 ‚Č•partial response occurring in the 45 mg/m2 selinexor plus 20 mg 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 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892.

PMID:
29203585
DOI:
10.1182/blood-2017-08-797886
[Indexed for MEDLINE]
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