Think of it as a biological nuclear export ban: A combination of the nuclear export protein inhibitor selinexor and dexamethasone was associated with relatively good objective response rates and clinical benefit rates among some patients with relapsed or refractory multiple myeloma (MM).

In the dose-expansion portion of a phase 1 dose-finding trial, the objective response rate (ORR) among 12 patients treated with selinexor 45 mg/m2 and 20 mg dexamethasone twice weekly was 50%, and the clinical benefit rate – a composite of complete responses, very good partial responses, partial responses and minimal responses – was 58%, reported Christine Chen, MD, of Princess Margaret Cancer Centre in Toronto, and her colleagues.

“Selinexor is an oral agent with a completely novel mechanism of action and anti-MM activity in combination with dexamethasone that could provide a new option for patients suffering from this incurable disease,” wrote Dr. Chen and her colleagues. The report was published in Blood .

Selinexor is a selective oral inhibitor of the cellular nuclear export protein exportin 1 (XPO1). Inhibition of this protein causes tumor suppressor proteins to accumulate in the nuclei of malignant cells, leading to programmed cell death (apoptosis) of malignant cells, but with minimal effects on normal cells.

The study, performed in centers in Canada, the United States, and Denmark, was designed primarily to identify the recommended dose of oral selinexor for phase 2 trials, with or without corticosteroids.

A total of 84 patients were enrolled, including 22 with MM and 3 with Waldenstrom macroglobulinemia in the dose-escalation phase, and 59 with MM in the dose expansion phase.

In the dose-expansion phase, patients were treated with one of two dosing schemes: either selinexor at a dose of 45 or 60 mg/m2 plus dexamethasone 20 mg twice weekly in 28-day cycles, or selinexor in a 40 mg or 60 mg flat dose without corticosteroids in 21-day cycles.

As a single agent, selinexor showed minimal activity, with an ORR of 4%, and clinical benefit rate of 21% in 57 patients.

Among 12 patients assigned to the 45 mg/m2 selinexor dose plus dexamethasone, the ORR was 50%, consisting of one complete response and five partial responses. In addition, one patient at this dose level had a minimal response, three had stable disease, one had disease progression, and one was withdrawn from the study before disease assessment, with no evidence of progression.

There were no objective responses in the 60-mg/m2 selinexor dose group.

Among all 84 patients enrolled, the ORR with selinexor alone or in combination was 10%, and the clinical benefit rate was 25%. Of the patients with Waldenstrom macroglobulinemia, one had a partial response and one had a minimal response.

In the safety analysis, which included all patients who received at least one dose of selinexor, the most common grade 3 or 4 adverse events included thrombocytopenia in 45% of patients, hyponatremia in 26% of patients, and anemia and neutropenia in 23% each.

The most common nonhematologic adverse events – primarily grade 1 or 2 – included nausea, fatigue, anorexia, vomiting, and weight loss and diarrhea.

The combination of selinexor and dexamethasone is currently being investigated in the phase 2 Selinexor Treatment of Refractory Myeloma study, in combination with standard multiple myeloma therapies in the STOMP trial (Selinexor and Backbone Treatments of Multiple Myeloma Patients), and with bortezomib in the BOSTON trial (Bortezomib, Selinexor and Dexamethasone in Patients with Multiple Myeloma).

Dr. Chen reported no conflicts of interest. Her coauthors reported financial ties to Karyopharm Therapeutics, which funded the study.

SOURCE: Chen C et al. Blood. 2018;131(8):855-63 .