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Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma
Author(s) -
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.
Publication year - 2019
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.15969
Subject(s) - carfilzomib , medicine , pomalidomide , refractory (planetary science) , lenalidomide , adverse effect , dexamethasone , neutropenia , multiple myeloma , oncology , population , gastroenterology , pharmacology , toxicity , physics , environmental health , astrobiology
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 disease control in RRMM patients, including carfilzomib‐refractory patients. Registered at ClinicalTrials.gov (NCT02199665)