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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; 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.
Afiliación
  • Jakubowiak AJ; University of Chicago Medical Center, Chicago, IL, USA.
  • Jasielec JK; University of Chicago Medical Center, Chicago, IL, USA.
  • Rosenbaum CA; Weill Cornell Medical College, New York, NY, USA.
  • Cole CE; Department of Medicine, Division of Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
  • Chari A; Tisch Cancer Institute/Multiple Myeloma Program, Mount Sinai School of Medicine, New York, NY, USA.
  • Mikhael J; Mayo Clinic, Phoenix, AZ, and International Myeloma Foundation, Los Angeles, CA, USA.
  • Nam J; University of Chicago Medical Center, Chicago, IL, USA.
  • McIver A; University of Chicago Medical Center, Chicago, IL, USA.
  • Severson E; University of Chicago Medical Center, Chicago, IL, USA.
  • Stephens LA; University of Chicago Medical Center, Chicago, IL, USA.
  • Tinari K; University of Chicago Medical Center, Chicago, IL, USA.
  • Rosebeck S; University of Chicago Medical Center, Chicago, IL, USA.
  • Zimmerman TM; University of Chicago Medical Center, Chicago, IL, USA.
  • Hycner T; University of Chicago Medical Center, Chicago, IL, USA.
  • Turowski A; University of Chicago Medical Center, Chicago, IL, USA.
  • Karrison T; University of Chicago Medical Center, Chicago, IL, USA.
  • Zonder JA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
Br J Haematol ; 186(4): 549-560, 2019 08.
Article en En | MEDLINE | ID: mdl-31124580
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).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Mieloma Múltiple Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Br J Haematol Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Mieloma Múltiple Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Br J Haematol Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido