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Br J Haematol. 2019 May 24. doi: 10.1111/bjh.15969. [Epub ahead of print]

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

Author information

1
University of Chicago Medical Center, Chicago, IL, USA.
2
Weill Cornell Medical College, New York, NY, USA.
3
Department of Medicine, Division of Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
4
Tisch Cancer Institute/Multiple Myeloma Program, Mount Sinai School of Medicine, New York, NY, USA.
5
Mayo Clinic, Phoenix, AZ, and International Myeloma Foundation, Los Angeles, CA, USA.
6
Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

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).

KEYWORDS:

carfilzomib; dexamethasone; relapsed/refractory multiple myeloma; selinexor

PMID:
31124580
DOI:
10.1111/bjh.15969

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