In phase I trials, the first-in-class selective inhibitor of XPO1 selinexor (with or without low-dose dexamethasone) showed clinical activity against several types of hematologic malignancies, including multiple myeloma (MM). Based on these results, Dan T. Vogl, MD, of the Perelman School of Medicine at the University of Pennsylvania, and researchers evaluated the selinexor combination in a phase II study of heavily pretreated patients with MM.
About one-fifth of participants responded to treatment, suggesting that “selinexor plus dexamethasone has significant potential to be a new treatment option for patients with refractory MM,” the authors wrote of their findings, which were published in The Journal of Clinical Oncology.
The multicenter, open-label study included 79 patients (median age = 63 years; range = 34-78 years). Eligible participants were previously treated with at least three anti-myeloma agents (including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, and pomalidomide) and had disease that was refractory to the most recent regimen (defined as ≤25% response to therapy or progression during or within 60 days of completion of therapy).
Patients received a median of seven prior regimens (range = 3-17 regimens), and many (77%) had undergone autologous hematopoietic cell transplantation.
More than half of participants (n=48) had disease that was quad-refractory (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and 31 had disease that was penta-refractory (refractory to the previously listed agents, as well as an anti-CD38 antibody).
Among the patients with penta-refractory disease, 25 (81%) received single-agent daratumumab (n=15) or isatuximab (n=10), while six (19%) received an anti-CD38 antibody combination including lenalidomide or pomalidomide. “The relatively short median time since diagnosis of the patients [median = 4 years; range = <1-35 years], coupled with their quad- and penta-refractory status, suggests that this population had particularly aggressive MM,” the researchers commented.
- oral selinexor 80 mg twice-weekly on days 1, 3, 8, 10, 15, and 17 of each 28-day cycle
- oral dexamethasone 20 mg at time of selinexor administration
Once 23 patients were enrolled, the protocol was amended to allow for continuous dosing of twice-weekly selinexor and dexamethasone on days one, three, eight, 10, 15, 17, 22, and 24 of each 28-day cycle (8 cycles vs. 6 cycles). Patients with stable disease who tolerated selinexor could increase to a 100 mg dose.
Sixteen patients responded to treatment, for an overall response rate (ORR; primary endpoint; defined as a partial response [PR] or better) of 21 percent; the ORR was 21 percent (n=10) in those with quad-refractory disease and 20 percent (n=6) in those with penta-refractory disease. The ORR “was numerically higher than the prespecified minimally acceptable threshold of 15 percent, although the difference was not statistically significant (p=0.17),” the authors wrote.
See TABLE for ORR according to refractory status and cytogenetic risk.
Responses were “rapid,” the authors noted, with 85 percent of patients who achieved a minimal response or better (n=22/26) responding within the first treatment cycle. The median duration of response for those with a PR or better was five months (range not reported), with at least one response lasting 8.4 months.
Median progression-free and overall survival (OS) were 2.3 months and 9.3 months, respectively (ranges not reported). Patients who achieved at least a minimal response after one cycle had significantly better OS than those with stable or progressive disease (median = not reached vs. 7.2 months, respectively; p=0.01) among 60 patients who were alive and evaluable at last follow-up.
Although the observed ORR was not statistically significantly higher than the prespecified study threshold, “we believe that this evidence of efficacy is sufficient to warrant further study,” the authors noted.
The most common any-grade adverse events (AEs) were nausea (n=58; 73%), thrombocytopenia (n=58; 73%), fatigue (n=50; 63%), anemia (n=39; 49%), decreased appetite (n=39; 49%), and vomiting (n=35; 44%). The most common grade 3 AEs were anemia (n=21; 27%), thrombocytopenia (n=20; 25%), and hyponatremia (n=17; 22%).
More than half of patients required dose interruptions (n=41; 52%) or reductions (n=29; 37%) because of AEs, and 14 (18%) discontinued treatment. Dose reductions and interruptions appeared to occur more frequently among patients treated with the amended eight-dose protocol than with the six-dose protocol (71% vs. 43%; p value not reported). The selinexor 100 mg dose was also associated with increased AEs.
Twenty-two serious AEs reported in 19 patients were deemed “at least possibly related to study treatment,” the authors wrote. One patient had fatal intracranial bleeding that was attributed to MM, prior myelotoxic therapy, and possibly selinexor, according to the report.
“Selinexor is the first anti-myeloma agent to show clear activity in penta-refractory MM,” the researchers wrote. “Combining selinexor with dexamethasone has a mechanistic rationale and is associated with higher response rates than single-agent selinexor.”
The study is limited by its lack of a comparator arm and small patient population.
Karyopharm Therapeutics provided support for the study.
The corresponding authors report financial support from Celgene, Amgen, Karyopharm Therapeutics, Teva, Janssen, Millennium, Acetylon, GlaxoSmithKline, Calithera Biosciences, Constellation Pharmaceuticals, and Takeda.
Vogl DT, Dingli D, Cornell RF, et al. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018 January 30. [Epub ahead of print]