The FDA has granted an accelerated approval to selinexor in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody.
The FDA has granted an accelerated approval to selinexor (Xpovio) for use in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody.1,2
The approval is based on findings from a prespecified subgroup analysis of Part 2 of the multicenter, single-arm, open-label, phase II STORM trial, in which the overall response rate (ORR) was 25.3% (95% CI, 16.4-36.0) as assessed by an Independent Review Committee, based on the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma, in 83 patients whose disease was refractory to bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab (Darzalex). Moreover, the stringent complete response rate was 1%, the very good partial response rate was 5%, and the partial response rate was 19%.
The recommended starting dosage of selinexor is 80 mg orally on days 1 and 3 weekly until disease progression or unacceptable toxicity, and the dexamethasone dosage is at 20 mg orally on days 1 and 3 weekly. Karyopharm, the drug's manufacturer, anticipates selinexor becoming commercially available on or before July 10, 2019. Additionally, the European Medicines Agency is also reviewing a Marketing Authorization Application for selinexor for this indication.
The approval is contingent on the results of a confirmatory trial, which is the phase III BOSTON study that is evaluating the addition of selinexor to bortezomib and low-dose dexamethasone versus bortezomib/low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who have received 1 to 3 prior regimens.
The decision follows a February 2018 FDA Oncologic Drugs Advisory Committee (ODAC) hearing, in which the committee voted 8 to 5 against accelerated approval of the new drug application (NDA) for selinexor, as it recommended the agency to delay a decision on the drug until the BOSTON data became available.3 Following the ODAC meeting, the FDA added 3 months to the review period for the application, making the new action date July 6, 2019, and requested further information from Karyopharm as an amendment to the NDA. The original date was set for April 6, 2019.
During the February meeting, ODAC panel members expressed several concerns about the NDA. First, STORM was a single-arm combination trial and a prior phase I trial did not demonstrate strong single-agent activity with selinexor. Therefore, it is difficult to isolate the specific impact of selinexor. Additionally, there was significant safety concerns with selinexor in the STORM study, including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and TEAEs that resulted in patient deaths.
The STORM trial enrolled 122 patients with relapsed/refractory multiple myeloma who had previously received ≥3 anti-myeloma treatment regimens, including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and a CD38-directed monoclonal antibody, and whose disease was refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, a CD38-directed monoclonal antibody, and to their last line of therapy. A total of 83 patients were refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. Patients with smoldering multiple myeloma, plasma cell leukemia, systemic amyloid light chain amyloidosis, and central nervous system myeloma were excluded.
The median age was 65 years (range, 40-85), and patients were treated with 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly until disease progression. The primary endpoint was ORR; secondary endpoints included duration of response (DOR) and clinical benefit rate.
Additional data showed that the median time to first response was 4 weeks (range, 1-10 weeks), and the median DOR was 3.8 months (95% CI, 2.3—not estimable).
Safety findings of the 202 total patients enrolled in Parts 1 and 2 who received the combination of selinexor/dexamethasone showed that the most common (≥20%) adverse events (AEs) were thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infections. Twenty-seven percent of patients discontinued due to AEs, and 53% of patients experienced dose reductions; 65.3% had selinexor dose interruptions, The most frequent AEs requiring permanent discontinuation in ≥4% of patients who received selinexor included fatigue, nausea, and thrombocytopenia. Fatal AEs occurred in 8.9% of patients.
"Despite recent advances in the treatment of multiple myeloma, almost all our patients will develop disease that is resistant to the five most commonly used anti-myeloma drugs we currently have available, and the prognosis for this patient population is particularly poor. The accelerated approval of oral Xpovio marks an important advance in the treatment paradigm for patients with relapsed refractory multiple myeloma, and in my view, is an important addition to our therapeutic armamentarium," Paul Richardson, MD, clinical program leader and director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, stated in the press release.
Selinexor is a first-in-class SINE (Selective Inhibitor of Nuclear Export) compound. The drug inhibits chromosomal maintenance protein exportin-1 (XPO1), a nuclear export protein that mediates the transport of more than 200 cargo proteins, including most tumor-suppressor proteins. Selinexor works to block the export process by binding to other proteins within the nucleus of the cell and shuttling them through the nuclear pores into the cytoplasm in the rest of the cell.
"The 25.3% response rate seen in the subgroup of 83 patients in the pivotal phase IIb STORM study that served as the basis for Xpovio's accelerated approval is clinically meaningful and a validated surrogate marker for clinical benefit in our patients with advanced refractory disease," Sundar Jagannath, MD, director of the Multiple Myeloma Program, professor of medicine (hematology and medical oncology) at Tisch Cancer Institute at Mount Sinai School of Medicine, and principal investigator of the STORM study, stated in a press release.