Clinical Pearls & Morning Reports
Published August 21, 2019
Administration of selinexor (80 mg) with dexamethasone (20 mg) according to two dosing schedules had been evaluated among patients with myeloma refractory to either four or five drugs in Part 1 of the phase 2 STORM (Selinexor Treatment of Refractory Myeloma) study. In that heterogeneous population, 21% of patients had a partial response or better. On the basis of those findings, the activity of selinexor at a dose of 80 mg twice weekly was examined in a more uniform population in the STORM Part 2 study. Read the Original Article here.
Q: What is “triple-class refractory myeloma”?
A: Despite the availability of proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for multiple myeloma, most patients will have a relapse and refractory disease will develop. An increasing number of patients have triple-class refractory myeloma, defined as disease refractory to proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, with most patients being treated with all five agents currently in use (carfilzomib, bortezomib, lenalidomide, pomalidomide, and daratumumab; i.e., penta-exposed). Overall survival in patients with myeloma refractory to these classes is short.
Q: What is selinexor?
A: Exportin 1 (XPO1) — the sole known nuclear exporter of tumor suppressor proteins, the glucocorticoid receptor, and oncoprotein messenger RNAs (mRNAs) — is overexpressed in myeloma and correlates with increased bone disease and shorter survival. Selinexor, which was recently approved by the Food and Drug Administration, is a potent, oral, selective inhibitor of nuclear export that binds to Cys528 in the cargo-binding pocket of XPO1, forcing the nuclear localization and functional activation of tumor-suppressor proteins, trapping IĸBα in the nucleus to suppress nuclear factor ĸB activity, and preventing oncoprotein mRNA translation. Selective induction of apoptosis in malignant hematologic and solid tumor cells is a result. Preclinical studies have shown that selinexor with or without dexamethasone induces apoptosis in a number of myeloma cell lines and has antitumor activity in animal models.
A: A partial response or better was observed in 26% of patients (95% confidence interval [CI], 19 to 35), including 2 stringent complete responses (in 2% of the patients), 6 very good partial responses (in 5%), and 24 partial responses (in 20%); because the lower boundary of the confidence interval was more than 10%, the trial met its primary end point. The median time to a partial response or better was 4.1 weeks (range, 1 to 14). A minimal response or better was observed in 39% of patients (95% CI, 31 to 49). The median duration of response was 4.4 months (95% CI, 3.7 to 10.8). Among the patients who had a response, efficacy was consistent across subgroups, including patients with high-risk cytogenetic abnormalities (53% of the patients).
A: The most common adverse events that emerged during treatment were thrombocytopenia (in 73% of the patients), fatigue (in 73%), nausea (in 72%), and anemia (in 67%). The most common grade 3 or 4 adverse events were thrombocytopenia (in 59% of the patients), anemia (in 44%), hyponatremia (in 22%), and neutropenia (in 21%). Thrombocytopenia, which is due in part to inhibition by selinexor of thrombopoietin signaling in early megakaryopoiesis, was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.