Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma

J Clin Oncol. 2018 Mar 20;36(9):859-866. doi: 10.1200/JCO.2017.75.5207. Epub 2018 Jan 30.

Abstract

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Trial registration: ClinicalTrials.gov NCT02336815.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Dexamethasone / administration & dosage
  • Dexamethasone / adverse effects
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Hydrazines / administration & dosage
  • Hydrazines / adverse effects
  • Karyopherins / antagonists & inhibitors*
  • Karyopherins / metabolism
  • Male
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Progression-Free Survival
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Triazoles / administration & dosage
  • Triazoles / adverse effects

Substances

  • Hydrazines
  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear
  • Triazoles
  • exportin 1 protein
  • selinexor
  • Dexamethasone

Associated data

  • ClinicalTrials.gov/NCT02336815