Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma

Abstract

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Trial registration: ClinicalTrials.gov NCT02336815.

Fig 1.

Time on study for patients with a partial response or better. In instances where two responses are given for a patient, the first indicates the first response and the second indicates best response. Arrows indicate that the patient is continuing on study as of the date of data cutoff. X indicates disease progression.

Fig 2.

Depth of response to selinexor and dexamethasone among patients with refractory myeloma. Waterfall plot of best percent change in the primary myeloma marker (serum M-spike, urine M-spike, immunoglobulin, or serum free light chain) from baseline. Thirteen patients with clinical progression but no myeloma markers assessed after treatment are not included in the plot (seven quad-refractory patients and six penta-refractory patients). The dotted lines at −25%, −50%, and −90% indicate reductions that correspond to a minimal response, partial response, and very good partial response, respectively.

Fig 3.

Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS) for (A) all patients and (B) patients achieving at least a minimal response. (C) A landmark analysis comparing OS between patients with and without a minimal response or better who were alive and assessable for response at 1 month. HR, hazard ratio.