Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

Andrzej J. Jakubowiak, Jagoda K. Jasielec, Cara A. Rosenbaum, Craig E. Cole, Ajai Chari, Joseph Mikhael, Jennifer Nam, Amanda McIver, Erica Severson, Leonor A. Stephens, Kathryn Tinari, Shaun Rosebeck, Todd M. Zimmerman, Tyler Hycner, Agata Turowski, Theodore Karrison, Jeffrey A. Zonder

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665).

Original languageEnglish (US)
Pages (from-to)549-560
Number of pages12
JournalBritish journal of haematology
Volume186
Issue number4
DOIs
StatePublished - Jan 1 2019

Keywords

  • carfilzomib
  • dexamethasone
  • relapsed/refractory multiple myeloma
  • selinexor

ASJC Scopus subject areas

  • Hematology

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    Jakubowiak, A. J., Jasielec, J. K., Rosenbaum, C. A., Cole, C. E., Chari, A., Mikhael, J., Nam, J., McIver, A., Severson, E., Stephens, L. A., Tinari, K., Rosebeck, S., Zimmerman, T. M., Hycner, T., Turowski, A., Karrison, T., & Zonder, J. A. (2019). Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. British journal of haematology, 186(4), 549-560. https://doi.org/10.1111/bjh.15969