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 R 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

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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)
JournalBritish journal of haematology
DOIs
StatePublished - Jan 1 2019

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Multiple Myeloma
Dexamethasone
Proteasome Inhibitors
Therapeutics
Lymphopenia
Maximum Tolerated Dose
Cell Nucleus Active Transport
Neutropenia
Thrombocytopenia
Disease-Free Survival
KPT-330
carfilzomib
Anemia
Adrenal Cortex Hormones
Heart Failure
Survival
Infection
Pharmaceutical Preparations
Population

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Jakubowiak, A. J., Jasielec, J. K., Rosenbaum, C. A., Cole, C. E., Chari, A., Mikhael, J. R., ... 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. https://doi.org/10.1111/bjh.15969

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. / Jakubowiak, Andrzej J.; Jasielec, Jagoda K.; Rosenbaum, Cara A.; Cole, Craig E.; Chari, Ajai; Mikhael, Joseph R; Nam, Jennifer; McIver, Amanda; Severson, Erica; Stephens, Leonor A.; Tinari, Kathryn; Rosebeck, Shaun; Zimmerman, Todd M.; Hycner, Tyler; Turowski, Agata; Karrison, Theodore; Zonder, Jeffrey A.

In: British journal of haematology, 01.01.2019.

Research output: Contribution to journalArticle

Jakubowiak, AJ, Jasielec, JK, Rosenbaum, CA, Cole, CE, Chari, A, Mikhael, JR, Nam, J, McIver, A, Severson, E, Stephens, LA, Tinari, K, Rosebeck, S, Zimmerman, TM, Hycner, T, Turowski, A, Karrison, T & Zonder, JA 2019, 'Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma', British journal of haematology. https://doi.org/10.1111/bjh.15969
Jakubowiak, Andrzej J. ; Jasielec, Jagoda K. ; Rosenbaum, Cara A. ; Cole, Craig E. ; Chari, Ajai ; Mikhael, Joseph R ; Nam, Jennifer ; McIver, Amanda ; Severson, Erica ; Stephens, Leonor A. ; Tinari, Kathryn ; Rosebeck, Shaun ; Zimmerman, Todd M. ; Hycner, Tyler ; Turowski, Agata ; Karrison, Theodore ; Zonder, Jeffrey A. / Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. In: British journal of haematology. 2019.
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AU - Rosenbaum, Cara A.

AU - Cole, Craig E.

AU - Chari, Ajai

AU - Mikhael, Joseph R

AU - Nam, Jennifer

AU - McIver, Amanda

AU - Severson, Erica

AU - Stephens, Leonor A.

AU - Tinari, Kathryn

AU - Rosebeck, Shaun

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