Early Phase Study of Selinexor With and Without Dexamethasone for Patients With Myeloma and Waldenström Macroglobulinemia

According to results of a phase I study published in Blood, treatment with the XPO1 inhibitor selinexor and dexamethasone led to half of patients with heavily pretreated myeloma responding and 46 percent of patients showing a reduction in myeloma markers from baseline. However, the results with selinexor alone were more modest, with just 4 percent of patients responding to treatment.

The small study, led by Christine Chen, MEd, MD, from the Princess Margaret Cancer Centre in Toronto, Ontario, assessed the safety, efficacy, and recommended maximum tolerated dose (MTD) of selinexor with or without dexamethasone in adult patients with relapsed/refractory myeloma (n=81) or Waldenström macroglobulinemia (WM; n=3). This was conducted as part of a larger, multicenter, dose-escalation, phase I study assessing selinexor in patients with advanced hematologic malignancies (n=285) who were enrolled between July 2012 and September 2015.

Patients were included if they had confirmed progressive disease; an Eastern Cooperative Oncology Group performance status score of ≤1; and adequate hepatic, renal, hematopoietic, and cardiac function. Exclusion criteria included receiving any anti-cancer therapies within two weeks of starting the study drug or having grade ≥2 peripheral neuropathy.

Participants (median age = 62 years; range = 43-85 years) had received a median of six prior therapies (range = 1=16 therapies); 23 (27%) had received lenalidomide, bortezomib, carfilzomib, and pomalidomide prior to enrollment.

Fifty-seven patients received selinexor as a single agent, including 25 patients in the dose-escalation phase and 32 in the dose-expansion phase. Selinexor was administered at 12 doses, ranging from 3 mg/m2 to 60 mg/m2 in eight or 10 doses per 28-day cycle. The other 27 patients received selinexor 45 mg/m2 (n=12) or 60 mg/m2 (n=15) plus dexamethasone 20 mg.

The median duration of treatment for all patients was 45 days (range = 2-774 days). Some patients discontinued treatment because of progressive disease (n=49), adverse events (AEs; n=26), or withdrawal of consent (n=9).

All 84 patients received at least one dose of selinexor; however, 14 were considered non-evaluable based on early consent withdrawal (n=6), protocol violation because of concurrent anti-myeloma treatment (n=4), or septic death during the first treatment cycle that was deemed unrelated to selinexor (n=2).

Among all enrolled patients, the most common non-hematologic AEs were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%). The most common grade 3 or 4 hematologic AEs were thrombocytopenia (45%), neutropenia (23%), and anemia (23%).

One dose-limiting toxicity (grade 4 thrombocytopenia) was reported in a patient receiving selinexor 16.8 mg/m2. Twenty-three serious AEs were reported as “possibly related to study treatment,” with 14 (61%) occurring in patients receiving single-agent selinexor and nine (39%) in those treated with both agents. Among those experiencing serious AEs in the selinexor-only cohort, the events occurred at doses ranging from 16.8 mg/m2 to 60 mg/m2, “with no apparent relation to dose schedule,” the authors wrote.

The MTD was not identified, but, the authors noted, “patients dosed at selinexor 45 mg/m2 plus dexamethasone 20 mg required fewer dose reductions and drug ‘holidays’ and received more of their target dose over the first cycle [compared with patients who received selinexor 60 mg/m2 plus dexamethasone 20 mg].”

Patients receiving selinexor 45 mg/m2 and dexamethasone 20 mg also remained on study longer (median = 118 days; range = 14-391 days), compared with those receiving selinexor 60 mg/m2 (median = 29 days; range = 2-108 days), suggesting an improved tolerability at the lower dose (p=0.04).

In the entire cohort, the overall response rate was 10 percent (95% CI 0.05-0.18), including one complete response (CR) and seven partial responses (PRs). Minimal response (MR) was observed in 13 patients (15%), for a clinical benefit rate (defined as CR, very good PR, PR, and MR) of 25 percent. See TABLE for all responses.

The median time to first response was 1 month (range = 1-3 months). The median duration of response was five months (range = 2-11 months). Five of the 13 patients with MR remained on study for longer than 10 months (range = 10-14 months), and one patient with stable disease remained on study for more than two years.

Nearly half of patients (n=39; 46%) had a quantifiable reduction in M-spike values from baseline.

Among the 27 patients who received selinexor plus dexamethasone, the overall response rate (ORR) was 22 percent, compared with 4 percent in the selinexor-alone group. All responses were observed in the 45 mg/m2 group, the authors reported, for an ORR of 50 percent. “From both a safety and efficacy perspective, we identified selinexor 45 mg/m2 … in combination with dexamethasone 20 mg twice-weekly as a promising, and better tolerated, regimen for subsequent trials,” the authors wrote.

The study is limited by its small patient population and lack of a comparator arm. The researchers noted that the selinexor and dexamethasone combination is being evaluated in several phase II trials, at a recommended dose of selinexor 45 mg/m2 and dexamethasone 20 mg.

Karyopharm Therapeutics sponsored the study.

The corresponding authors report no financial conflicts. 


Reference

Chen C, Siegel D, Gutierrez M, et al. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom’s macroglobulinemia. Blood. 2017 December 4. [Epub ahead of print]

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