In the phase IIb STORM Part 2 study reported in The New England Journal of Medicine, Chari et al found that the combination of oral selinexor and dexamethasone produced responses in patients with multiple myeloma refractory to prior treatment with an alkylating agent, immunomodulatory agent, and daratumumab (triple-class refractory).
Selinexor is a nuclear export inhibitor that blocks exportin 1 and induces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation.
“Selinexor/dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies.”— Chari et al
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The study included 123 patients (122 in the modified intent-to-treat primary efficacy analysis) from 60 sites in the U.S. and Europe. Patients were enrolled between May 2015 and March 2018 and treated with selinexor 80 mg and dexamethasone 20 mg twice weekly until disease progression or discontinuation. Patients had to have previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. Patients had a median age of 65 years and had received a median of seven previous regimens, with 53% having high-risk cytogenetic abnormalities.
The primary endpoint was overall response defined as a confirmed partial response or better (≥ 50% reduction in serum level of myeloma protein) as assessed by an independent review committee.
Partial response or better was observed in 32 patients (26%), including stringent complete response in 2 patients. Clinical benefit, defined as confirmed minimal response (≥ 25% to < 50% reduction in serum level of myeloma protein) or better, was observed in 48 patients (39%). Partial response or better was observed in 18% of patients with high-risk cytogenetic abnormalities (minimal response or better in 37%) and in 21% of patients with disease refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (minimal response or better in 37%).
Median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. In patients with a minimal response or better, median overall survival was 15.6 months.
The most common nonhematologic adverse events of any grade were fatigue (73%), nausea (72%), and decreased appetite (56%). The most common grade ≥ 3 nonhematologic adverse events were fatigue (25%), hyponatremia (21%), nausea (10%), and pneumonia (8%). The most common grade ≥ 3 hematologic adverse events were thrombocytopenia (58%), anemia (44%), and neutropenia (21%). Treatment was discontinued due to adverse events in 18% of patients.
Serious adverse events occurred in 63% of patients, with the most common being pneumonia (11%) and sepsis (9%). Adverse events led to death in 12 patients, with death considered related to treatment in 2 (1 due to pneumonia with concurrent disease progression and 1 due to sepsis).
The investigators concluded, “Selinexor/dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies.”
Disclosure: The study was funded by Karyopharm Therapeutics. For full disclosures of the study authors, visit nejm.org.