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Selinexor in combination with twice-weekly dexamethasone led to a median overall survival of 15.6 months in patients with heavily pretreated multiple myeloma who had a minimal response or better to the novel agent compared with 1.7 months in those whose disease progressed or had unevaluable responses.
Sundar Jagannath, MD
Selinexor (Xpovio) in combination with twice-weekly dexamethasone led to a median overall survival (OS) of 15.6 months in patients with heavily pretreated multiple myeloma who had a minimal response or better to the novel agent compared with 1.7 months in those whose disease progressed or had unevaluable responses, according to data from the phase IIb STORM trial that were published in the New England Journal of Medicine.1,2
The published findings follow the FDA’s accelerated approval in July 2019 of selinexor 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 (PIs), ≥2 immunomodulatory agents (IMiDs), and a CD38-targeted monoclonal antibody.
“The data from the STORM study demonstrate that oral selinexor, a first-in-class XPO1 inhibitor, combined with dexamethasone twice weekly, resulted in a response rate of 26% in heavily pretreated patients,” principal investigator and co-lead author Sundar Jagannath, MD, director of the Multiple Myeloma Program, professor of medicine (hematology and medical oncology), of the Tisch Cancer Institute at Mount Sinai School of Medicine, stated in a press release.
“The characteristics of the patients in the STORM study, including being heavily pretreated, yet still experiencing rapidly progressing disease, are consistent with the growing population of patients who have exhausted available myeloma therapies, but still desire to continue therapy. Of particular significance, for the 39% of patients who had a minimal response or better, OS was 15.6 months, compared to 1.7 months in patients whose disease progressed or where response was not evaluable.”
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. The agent 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.
Selinexor’s approval was based on data from a prespecified subgroup analysis of 83 patients of Part 2 of the multicenter, single-arm, open-label, phase II STORM trial. In this subpopulation, patients’ disease was refractory to bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab (Darzalex), and the benefit-risk ratio appeared to be greater in this more heavily pretreated subgroup than in the overall population with an ORR of 25.3%. Thirty-seven percent (n = 31) of patients had a minimal response or better to selinexor.
Overall, the study enrolled 122 patients with relapsed/refractory multiple myeloma who had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent, and also whose disease was refractory to ≥1 PI, 1 IMiD, and daratumumab. Patients with smoldering multiple myeloma, plasma cell leukemia, systemic amyloid light chain amyloidosis, and central nervous system myeloma were excluded.
Patients were treated with 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly until disease progression. The median age was 65 years (range, 40-85), and the median number of prior therapies was 7. Fifty-three percent of patients had high-risk cytogenetic abnormalities.
The primary endpoint was ORR; secondary endpoints included duration of response (DOR) and clinical benefit rate, or minimal response or better.
Of the 122 patients included in the analysis, results showed that the ORR, which included a partial response (PR) or better, was 26% (95% CI, 19-35) as assessed by an Independent Review Committee, based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. This comprised 2 (2%) stringent complete responses (sCRs), 6 (5%) very good partial responses, and 24 (20%) PRs. Both patients who previously received CAR T-cell therapy and relapsed achieved PRs.
The clinical benefit rate was 39% (n = 48). Minimal response per IMWG criteria was observed in 16 (13%) patients and 48 patients (39%) had stable disease, and the median time to PR or better was 4.1 weeks.
The median DOR was 4.4 months (95% CI, 3.7-10.8), the median progression-free survival was 3.7 months (95% CI, 3.0-5.3), and the median OS was 8.6 months (95% CI, 6.2-11.3).
Regarding safety, the most common treatment-emergent adverse events (TEAEs) included thrombocytopenia (73%), nausea (72%), anemia (67%), and fatigue (73%). The most common grade 3/4 TEAEs were thrombocytopenia (59%), anemia (44%), neutropenia (21%), and hyponatremia (22%). Most nonhematologic AEs were of grade 1/2; 10% of patients experienced grade 3 nausea and 3% experienced grade 3 emesis.
Serious AEs occurred in 63% of patients; the most common included pneumonia (11%) and sepsis (9%). There were 28 deaths on study due to disease progression (n = 16) or an AE (n = 12). In the AE-related deaths, two were determined by the investigator to be related to treatment—1 caused by pneumonia and 1 caused by sepsis.
The treatment discontinuation rate believed to be due to a treatment-related AE was 18%, and AEs leading to dose modifications or holds occurred in 80% of patients. The majority of modifications or holds occurred in the first 2 cycles. The most common AEs that led to reductions or interruptions were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%). Supportive care approaches generally reduced the intensity and/or duration of such AEs, and were comprised of strategies such as G-CSF, thrombopoietin receptor agonists, optimization of fluid and caloric intake, appetite stimulants, psychostimulants and/or additional antinausea therapies.
“We are pleased to have the STORM study results published in such a highly esteemed, peer-reviewed journal and this publication further supports the potential utility of oral Xpovio in patients with highly refractory multiple myeloma,” said Sharon Shacham, PhD, MBA, president and chief scientific officer of Karyopharm, the developer of selinexor, in the press release. “With the recent accelerated approval of oral Xpovio, patients with heavily pretreated myeloma now have a new therapeutic option to treat their disease.”
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.
The FDA 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.
Moreover, the European Medicines Agency is currently reviewing a Marketing Authorization Application for conditional approval of selinexor in this setting. Karyopharm stated that it expects to receive a decision on the application by the end of 2019 or early 2020.