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

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.

Figure 1

Treatment schema. *Once the Maximum Tolerated Dose was established, an expansion cohort of 6–12 patients was enrolled at that dose limited to carfilzomib‐refractory patients. ^†Dose Level 2a and 2b were enrolled simultaneously, alternating patients between the two dose levels. ^‡Carfilzomib initiated at 20 mg/m² on Days 1–2 of Cycle 1 at all dose levels and then at the assigned dose level for the remainder of treatment. C, cycle; CFZ, carfilzomib; dex, dexamethasone; SEL, selinexor.

Figure 2

Depth and duration of response in evaluable patients (n = 20). (A) Change in M‐protein relative to baseline. *Increase >100%. One patient with dose‐limiting toxicity that resulted in treatment discontinuation prior to response evaluation was not included. (B) Duration of response. Three patients had PD at first response assessment and were not included; two patients remained in SD and were not included; one patient with dose‐limiting toxicity that resulted in treatment discontinuation prior to response evaluation was not included. DL, dose level; MR, minimal response; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.

Figure 3

Kaplan–Meier estimated progression‐free survival (A) and overall survival (B) in all patients (N = 21) and by International Myeloma Working Group ‐risk status and dose level. DL, dose level; HR, high risk; mo, months; SR, standard risk.