Selinexor plus dexamethasone active in refractory multiple myeloma

Selinexor and dexamethasone showed antimyeloma activity among patients with quad- or penta-refractory disease, according to data published in Journal of Clinical Oncology.

“Survival of patients with multiple myeloma has improved over the past 15 years as a result of the introduction of several novel therapeutic agents and high-dose chemotherapy with autologous stem-cell transplantation. In particular, five new medications with proven single-agent antimyeloma efficacy have been introduced, including the proteasome inhibitors bortezomib [Velcade, Millennium/Takeda] and carfilzomib [Kyprolis, Amgen], the cereblon-binding drugs lenalidomide [Revlimid, Celgene] and pomalidomide [Pomalyst, Celgene], and the anti-CD38 monoclonal antibody daratumumab [Darzalex, Janssen],” Dan T. Vogl, MD, assistant professor of medicine at Perelman School of Medicine at the University of Pennsylvania, and colleagues wrote. “However, none of these agents are curative, and patients with myeloma eventually develop disease refractory to all available therapies.”

Selinexor (KPT-330, Karyopharm Therapeutics) is a first-in-class, oral, selective exportin 1 inhibitor that induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, and through inhibition of oncoprotein mRNA translation.

Vogl and colleagues evaluated oral, twice weekly selinexor 80 mg and dexamethasone 20 mg for 48 patients with quad-refractory myeloma — or refractory to bortezomib, carfilzomib, lenalidomide and pomalidomide — and 31 patients with penta-refractory disease who also were refractory to an anti-CD38 monoclonal antibody.

Median age of patients was 63 years. Patients had received a median of seven prior regimens (range, 3-17).

Overall response rate served as the study’s primary endpoint.

The ORR was 21% (95% CI; 12-21) overall — which was higher than the prespecified minimally acceptable threshold 15%, although not significantly so — and appeared similar for quad-refractory (21%) and penta-refractory patients (20%). When researchers included an additional 13% of patients with a minimal response, the clinical benefit rate increased to 33% (95% CI, 24-44).

Among the 17 patients with high-risk cytogenetics — including t(4;14), t(14;16) and del(17p) — ORR reached 35%.

Median duration of response was 5 months among at least partial responders; however, 85% of patients who achieved at least a minimal response responded within the first cycle of treatment.

Sixty-five percent of patients were alive at 1 year. Median PFS was 2.3 months, and median OS was 9.3 months. Median OS appeared longer among patients with at least a minimal response than patients with stable or progressive disease (not reached vs. 7.2 months; P = .01).

The most common grade 3 or higher adverse events included thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%) and fatigue (15%).

Dose interruptions for adverse events occurred among 52% of patients; 37% had dose reductions. Researchers discontinued treatment for 18% of patients.

“Selinexor is the first antimyeloma agent to show clear activity in penta-refractory myeloma, a patient population with a high unmet medical need,” the researchers wrote. “Although our observed overall response rate of 21% was not statistically significantly higher than our prespecified threshold of 15%, we believe that this evidence of efficacy is sufficient to warrant further study.” – by Cassie Homer

Disclosures: Vogl reports consultant roles with Amgen, Celgene, Janssen, Karyopharm Therapeutics, Teva and institutional research funding from Acetylon Pharmaceuticals, Calithera Biosciences, Constellation Pharmaceuticals, GlaxoSmithKline and Millennium. Please see the full study for all other authors’ relevant financial disclosures.