February 4, 2021 — The Israeli Ministry of Health has approved selinexor for the treatment of patients with multiple myeloma or diffuse large B-cell lymphoma.
The Israeli Ministry of Health has approved selinexor (Xpovio) for the treatment of patients with multiple myeloma or diffuse large B-cell lymphoma (DLBCL), according to an announcement from Karyopharm Therapeutics, Inc.1
Specifically, selinexor was indicated for use in combination with dexamethasone in adult patients with relapsed/refractory multiple myeloma who had received at least 3 previous therapies and whose disease is refractory to at least 1 proteasome inhibitor (PI), 1 immunomodulatory agent (IMiD), and 1 anti-CD39 monoclonal antibody.
The agent was also approved for use in adult patients with relapsed/refractory DLBCL not otherwise specified, including disease that arises from follicular lymphoma, or at least 2 lines of systemic treatment.
The registration license that permits commercial and marketing authorization for the agent in Israel is expected during the second quarter of 2021.
“The approval of [selinexor] in Israel represents its first regulatory approval outside the United States and is a tremendous milestone for both Karyopharm and the patients we hope to serve in the future,” Sharon Shacham, PhD, MBA, founder, president, and chief scientific officer of Karyopharm, stated in a press release. “The approval of [selinexor] in Israel further demonstrates our commitment to expand [selinexor’s] reach to cancer patients across the globe who are in need of novel therapies.”
The decision follows a recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use to grant a conditional approval for the use of selinexor in combination with dexamethasone in the treatment of patients with multiple myeloma who have previously received at least 4 therapies and whose disease is refractory to at least 2 PIs, 2 IMiDs, and an anti-CD38 monoclonal antibody, and who have progressed on their last treatment.2
The positive opinion was based on data reported from the phase 2b STORM trial (NCT02336815), in which the selinexor regimen was found to induce a partial response (PR) or better in 26% (95% CI, 19%-35%) of patients with multiple myeloma who were refractory to all available options.3 Here, 2 stringent complete responses, 6 very good partial responses, and 24 PRs were observed.
Thirteen percent of patients (n = 16) experienced minimal response with the doublet in accordance with International Myeloma Working Group (IMWG) criteria. A minimal response or better was observed in 39% (95% CI, 31%-49%) of patients. Thirty-nine percent (n = 48) of patients achieved disease stability. Moreover, 21% (n = 26) of patients progressed or had disease determined to be unevaluable. Investigators reported a median time to a PR or better of 4.1 weeks.
The multicenter, open-label, phase 2b STORM trial enrolled patients with measurable myeloma per IMWG criteria between May 2015 and March 2018 at 60 sites across the United States and Europe. Patients had received prior bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), daratumumab (Darzalex), glucocorticoids, and an alkylating agent. Participants had disease that was refractory to at least 1 IMiD, 1 P1, daratumumab, glucocorticoids, and their most recently received treatment.
To be eligible for enrollment, patients had to have an ECOG performance status of 0-2 and acceptable hepatic, renal, and hematopoietic function. If patients had systemic light-chain amyloidosis, active central nervous system involvement, peripheral neuropathy that was grade 3 or higher in severity, or painful neuropathy that was grade 2 or higher, they were excluded.
The primary end point of the trial was overall response, while key secondary end points comprised duration of response (DOR), clinical benefit, progression-free survival, and overall survival.
A total of 122 patients comprised the intent-to-treat population. Patients received oral selinexor at a dose of 80 mg plus 20 mg of dexamethasone on days 1 and 3, weekly, in 4-week treatment cycles until either progressive disease, death, or discontinuation. To manage toxicities, investigators utilized a dose-modification protocol. All participants received ondansetron at 8 mg prior to their first dose of the agent; they received ondansetron 2 or 3 times per day, as required.
The median age of study participants was 65.2 years and about half, or 53%, had high-risk cytogenetic abnormalities. At the time of enrollment, all patients had progressive disease, with most patients experiencing rapid progression. The median number of prior lines of treatment was 7 (range, 3-18), with 70% of patients having received prior daratumumab in combination with other drugs. Moreover, 84% had previously undergone stem cell transplantation and 2% had prior CAR T-cell therapy.
Additional results revealed that the median DOR with selinexor was 4.4 months (95% CI, 3.7-10.8). Moreover, the median PFS was 3.7 months (95% CI, 3.0-5.3), while the median OS was 8.6 months (95% CI, 6.2-11.3). In the subset of patients who achieved a minimal response or better, the median OS was longer, at 15.6 months.
Regarding safety, the most common toxicities reported in those given selinexor included thrombocytopenia (73%), fatigue (73%), nausea (72%), and anemia (67%). Grade 3 or 4 adverse effects included thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).
Eighteen percent of patients discontinued treatment due to toxicity determined to be related to either selinexor or dexamethasone. Eighty percent of patients required dose modifications.
Previously, in July 2019, selinexor was granted accelerated approval from the FDA for use in combination with dexamethasone in the treatment of patients with relapsed/refractory myeloma who had received 4 or more previous therapies and whose disease is refractory to 2 or more PIs, at least 2 IMiDs, and a CD38-targeted monoclonal antibody. The decision was based on data yielded in the STORM trial.