The European Commission has granted conditional marketing authorization for selinexor for use in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have previously received at least 4 therapies and whose disease is refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody, and have experienced progressive disease on their last therapy.
The European Commission has granted conditional marketing authorization for selinexor (Nexpovio) for use in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have previously received at least 4 therapies and whose disease is refractory to at least 2 proteasome inhibitors (PIs), 2 immunomodulatory agents (IMiDs), and an anti-CD38 monoclonal antibody, and have experienced progressive disease on their last therapy.1
The regulatory decision was based on data from the phase 2b STORM trial, where treatment with the combination resulted in a partial response (PR) or better in 26% of patients (95% confidence interval [CI], 19-35); this included 2 stringent complete responses, 6 very good partial responses, and 24 partial responses.2 Because the lower boundary of the CI was more than 10, the trial met its primary end point.
“[Selinexor] represents the first and only nuclear export inhibitor authorized in Europe and we are delighted to bring this new treatment option to eligible adult patients with heavily pretreated multiple myeloma,” Sharon Shacham, PhD, MBA, founder, president, and chief scientific officer of Karyopharm, stated in a press release. “Despite advancements in the treatment of multiple myeloma, most adult patients will eventually relapse and develop disease that is refractory to all authorized therapies, further highlighting the urgent need for new therapies with novel mechanism of actions like [selinexor].”
In the phase 2b, multicenter, open-label trial, patients were enrolled from May 2015 to March 2018 at 60 sites across the United States and Europe. To be eligible for enrollment, patients had to have measurable myeloma per International Myeloma Working Group (IMWG) criteria; have previously received bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), daratumumab (Darzalex), glucocorticoids, and an alkylating agent; and have disease that was refractory to at least 1 IMiD, 1 PI, daratumumab, glucocorticoids, and their most recent regimen. Additionally, patients had to have an ECOG performance status of 0 to 2, and acceptable hepatic, renal, and hematopoietic function, to participate.
If patients had systemic light-chain amyloidosis, active central nervous system involvement, peripheral neuropathy that is grade 3 or higher in severity, or painful neuropathy that is grade 2 or higher, they were excluded.
Study participants were given oral selinexor at a dose of 80 mg plus dexamethasone at a dose of 20 mg on days 1 and 3 on a weekly basis in 4-week treatment cycles. Treatment was given until either progressive disease, death, or discontinuation. All participants needed to receive 8 mg of ondansetron prior to their first dose of study treatment and 2 or 3 times daily, as required. Notably, olanzapine and neurokinin-1 receptor antagonists were allowed for those who experienced intolerable toxicities with ondansetron or who had persistent nausea.
The primary end point of the trial was overall response rate, while key secondary end points included duration of response (DOR), clinical benefit, progression-free survival (PFS), and overall survival (OS). Investigators also evaluated quality of life, as well as safety in those who received the regimen.
A total of 123 patients were enrolled to the trial and all were included in the safety population. Because 1 patient did not meet the eligibility criteria, 122 patients comprised the modified intent-to-treat (ITT) population.
The median age among study participants was 65.2 years, the median duration of myeloma was 6.6 years, and 53% had high-risk cytogenetic abnormalities. All participants had progressive disease at the time of enrollment, and most were experiencing rapid progression. Specifically, 88% of patients experienced a median increase in disease burden of 22%. Additionally, 32% of patients had creatinine clearance of less than 60 mL/min, while 11% had clearance of less than 40 mL/min.
Moreover, the median number of previous therapies received was 7 (range, 3-18). Seventy percent of patients had prior daratumumab plus other agents, 84% had prior stem cell transplant, and 2% had previously received CAR T-cell therapy.
Among those in the modified ITT population, all had penta-exposed myeloma that was refractory to at least 1 PI, 1 IMiD, and daratumumab. Sixty-eight percent of patients had penta-refractory disease and the overwhelming majority, or 96%, were refractory to the most potent agent of each class: carfilzomib, pomalidomide, and daratumumab.
Additional results indicated that minimal response per IMWG criteria was reported in 13% of patients and 39% achieved disease stability. Twenty-one percent of patients experienced disease progression or had disease that could not be assessed for response. The median time to PR or better was 4.1 weeks. A minimal response or better was reported in 39% of patients (95% CI, 31-49).
Additionally, the median DOR with the investigational regimen was 4.4 months (95% CI, 3.7-10.8), the median PFS was 3.7 months (95% CI, 3.0-5.3), and the median OS was 8.6 months (95% CI, 6.2-11.3). Notably, in those who achieved a PR or better or a minimal response or better to treatment, the median OS was higher, at 15.6 months.
Regarding safety, the most frequently experienced toxicities included thrombocytopenia (73%), fatigue (73%), nausea (72%), and anemia (67%). The most common effects that were grade 3 or 4 in severity were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).
Eighteen percent of participants discontinued treatment because of a toxicity that was determined to be associated with selinexor or dexamethasone. Eighty percent of patients, however, experienced adverse effects (AEs) that resulted in dose modifications or interruptions; most of these toxicities were experienced within the first 2 cycles of treatment. The most common AEs that led to reductions or interruptions included thrombocytopenia (43%), fatigue (16%), and neutropenia (11%). Sixty-three percent of patients experienced serious AEs, the most common of which included pneumonia (11%) and sepsis (9%).
Twenty-eight patients died during the study; 16 were because of progressive disease and 12 were from toxicities. Of the 12 who died due to AEs, 2 were determined to be related to treatment.
“Today’s authorization is an important step forward in the international expansion of selinexor, now with marketing authorization for use in Europe, Israel, and the United States,” Michael G. Kaufman, MD, PhD, chief medical officer of Karyopharm, added in the release. “We are committed to making [selinexor] available in Europe initially through a Named Patient Program and are on track to submit a second European regulatory filing in April based on the positive data from the phase 3 BOSTON study to potentially further expand [selinexor] to eligible adult patients in need of new treatment options.”