PMID- 29203585 OWN - NLM STAT- MEDLINE DCOM- 20190128 LR - 20210202 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 131 IP - 8 DP - 2018 Feb 22 TI - Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. PG - 855-863 LID - 10.1182/blood-2017-08-797886 [doi] AB - 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/m(2)) 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/m(2) 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/m(2) 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/m(2) (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892. CI - (c) 2018 by The American Society of Hematology. FAU - Chen, Christine AU - Chen C AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada. AD - The University of Toronto, Toronto, ON, Canada. FAU - Siegel, David AU - Siegel D AD - Department of Hematology, John Theurer Cancer Center, Hackensack, NJ. FAU - Gutierrez, Martin AU - Gutierrez M AD - Department of Hematology, John Theurer Cancer Center, Hackensack, NJ. FAU - Jacoby, Meagan AU - Jacoby M AD - Siteman Cancer Center, Washington University in Saint Louis, Saint Louis, MO. FAU - Hofmeister, Craig C AU - Hofmeister CC AUID- ORCID: 0000-0003-4816-1607 AD - Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH. FAU - Gabrail, Nashat AU - Gabrail N AD - Gabrail Cancer Institute, Canton, OH. FAU - Baz, Rachid AU - Baz R AUID- ORCID: 0000-0003-4538-4733 AD - Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. FAU - Mau-Sorensen, Morten AU - Mau-Sorensen M AD - Department of Oncology, Rigshospitalet, Copenhagen, Denmark. FAU - Berdeja, Jesus G AU - Berdeja JG AD - Blood Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN. FAU - Savona, Michael AU - Savona M AUID- ORCID: 0000-0003-3763-5504 AD - Division of Hematology & Oncology, Vanderbilt-Ingram Cancer Center/Vanderbilt University Medical Center, Nashville, TN. FAU - Savoie, Lynn AU - Savoie L AD - Tom Baker Cancer Centre Division of Hematology, University of Calgary, Calgary, AB, Canada; and. FAU - Trudel, Suzanne AU - Trudel S AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada. AD - The University of Toronto, Toronto, ON, Canada. FAU - Areethamsirikul, Nuchanan AU - Areethamsirikul N AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada. AD - The University of Toronto, Toronto, ON, Canada. FAU - Unger, T J AU - Unger TJ AD - Karyopharm Therapeutics Inc, Newton, MA. FAU - Rashal, Tami AU - Rashal T AD - Karyopharm Therapeutics Inc, Newton, MA. FAU - Hanke, Tim AU - Hanke T AD - Karyopharm Therapeutics Inc, Newton, MA. FAU - Kauffman, Michael AU - Kauffman M AD - Karyopharm Therapeutics Inc, Newton, MA. FAU - Shacham, Sharon AU - Shacham S AD - Karyopharm Therapeutics Inc, Newton, MA. FAU - Reece, Donna AU - Reece D AD - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada. AD - The University of Toronto, Toronto, ON, Canada. LA - eng SI - ClinicalTrials.gov/NCT01607892 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20171204 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antineoplastic Agents, Hormonal) RN - 0 (Hydrazines) RN - 0 (Triazoles) RN - 31TZ62FO8F (selinexor) RN - 7S5I7G3JQL (Dexamethasone) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents, Hormonal/therapeutic use MH - Dexamethasone/*therapeutic use MH - Drug Therapy, Combination MH - Female MH - Humans MH - Hydrazines/*therapeutic use MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Multiple Myeloma/*drug therapy/pathology MH - Neoplasm Recurrence, Local/*drug therapy/pathology MH - Prognosis MH - Safety MH - Triazoles/*therapeutic use MH - Waldenstrom Macroglobulinemia/*drug therapy/pathology EDAT- 2017/12/06 06:00 MHDA- 2019/01/29 06:00 CRDT- 2017/12/06 06:00 PHST- 2017/08/07 00:00 [received] PHST- 2017/11/22 00:00 [accepted] PHST- 2017/12/06 06:00 [pubmed] PHST- 2019/01/29 06:00 [medline] PHST- 2017/12/06 06:00 [entrez] AID - S0006-4971(20)32449-6 [pii] AID - 10.1182/blood-2017-08-797886 [doi] PST - ppublish SO - Blood. 2018 Feb 22;131(8):855-863. doi: 10.1182/blood-2017-08-797886. Epub 2017 Dec 4.