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

作者：Andrzej Jakubowiak, Jagoda Jasielec, Cara A. Rosenbaum, Craig E. Cole, Ajai Chari, Joseph Mıkhael, Jennifer Nam, Amanda McIver, Erica Severson, Leonor A Stephens, Kathryn M. Tinari, Shaun Rosebeck, Todd M. Zimmerman, Tyler Hycner, Agata Turowski, Theodore Karrison, Jeffrey A. Zonder · 发表于：British Journal of Haematology · 年份：2019 · DOI：10.1111/bjh.15969 · 被引用次数：69 · 研究领域：Multiple Myeloma Research and Treatments、Protein Degradation and Inhibitors、Research on Leishmaniasis Studies

Summary Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 ( XPO 1, also termed CRM 1). Non‐clinical studies support combining selinexor with proteasome inhibitors ( PI s) 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 ( SK d) 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 ( RP 2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP 2D of twice‐weekly SK d was selinexor 60 mg, carfilzomib 20/27 mg/m 2 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. SK d was tolerable and re‐established diseas...