January 29, 2021 - The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for selinexor for use in combination with dexamethasone in the treatment of select adult patients with refractory multiple myeloma.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for selinexor (Nexpovio) for use in combination with dexamethasone in 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 who have progressed on their last therapy.1
The recommendation is supported by findings from the phase 2b STORM trial (NCT02336815), which showed that the doublet elicited objective responses in patients with multiple myeloma whose disease was refractory to all available therapies. A partial response (PR) or better was reported in 26% of patients (95% CI, 19-35); this included 2 stringent complete responses, 6 very good partial responses, and 24 PRs.2
Moreover, minimal response per International Myeloma Working Group criteria was noted in 13% of patients (n = 16) and 39% achieved stable disease with the doublet (n = 48). Twenty-one percent of patients (n = 26) experienced disease progression or had disease that was not response evaluable. The median time to a PR or better was 4.1 weeks, and a minimal response or better was reported in 39% of patients (95% CI, 31-49).
“We are delighted that the CHMP has adopted a positive opinion for [selinexor], which could lead to Karyopharm’s first regulatory approval in Europe,” Sharon Shacham, PhD, MBA, founder, president, and chief scientific officer of Karyopharm, stated in a press release.
“This positive opinion highlights the CHMP’s recognition of the positive clinical benefit-risk profile for oral [selinexor] and takes Karyopharm one step closer to bringing this important medicine to European patients in need of novel multiple myeloma treatment options,” Shacham added. “We look forward to the European Commission’s final decision on the [selinexor] marketing authorization application, which is expected by April 2021.”
The second portion of the international, multicenter, single-arm, open-label, phase 3 trial enrolled a total of 122 patients with heavily pretreated, triple-class refractory multiple myeloma. The median age of participants who were enrolled to STORM was 65.2 years and 53% had high-risk cytogenetic abnormalities. Notably, patients had received a median of 7 prior treatments, including a median of 10 unique antimyeloma drugs. Seventy percent (n = 86) had received prior daratumumab (Darzalex) plus other drugs, 84% (n = 102) had previously received stem cell transplantation, and 2% (n = 2) had prior CAR T-cell therapy.
Patients on the trial received oral selinexor at a dose of 80 mg plus dexamethasone at a dose of 20 mg on days 1 and 3, weekly. Treatment was administered in 4-week cycles until either progressive disease, death, or discontinuation. All participants were given ondansetron at a dose of 8 mg prior to the first dose of study treatment and 2 or 3 times daily, as required.
The primary end point of the trial was overall response, defined as confirmed PR or better with response adjudicated by the independent review committee. Key secondary end points comprised duration of response (DOR), clinical benefit, progression-free survival (PFS) and overall survival (OS).
Additional results showed that the median DOR with the doublet 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). The median OS in participants who achieved a PR or better or a minimal response or better was 15.6 months.
Regarding safety, the most frequently reported toxicities included thrombocytopenia (73%), fatigue (73%), nausea (72%), and anemia (67%). The most commonly experienced grade 3 or 4 effects comprised thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).
Eighteen percent of participants discontinued treatment because of an adverse effect (AE) associated with either selinexor or dexamethasone. Eighty percent of patients experienced dose modifications or interruptions; most of these effects happened within the first 2 treatment cycles. Thrombocytopenia (43%), fatigue (16%), and neutropenia (11%) were the most common toxicities to result in dose reduction or interruption. Serious AEs were reported in 63% of participants and pneumonia and sepsis were the most frequent, occurring in 11% and 9% of patients, respectively.
In July 2019, the FDA granted an accelerated approval to selinexor for use in combination with dexamethasone in patients with relapsed/refractory disease who had received 4 or more prior therapies and whose disease is refractory to 2 or more proteasome inhibitors, at least 2 immunomodulatory agents, and a CD38-targeted monoclonal antibody.
Karyopharm Therapeutics, Inc. announced that they will be submitting a second regulatory filing to the European Medicines Agency, a type II variation, by April 2021, based on findings from the confirmatory phase 3 BOSTON trial (NCT03110562). Here, the addition of selinexor to bortezomib (Velcade) and dexamethasone resulted in improved PFS and overall response rate (ORR), as well as a reduction in the incidence of peripheral neuropathy.3
The triplet resulted in a median PFS of 13.93 months versus 9.46 months with bortezomib/dexamethasone alone (HR, 0.70; P = .0075); this benefit was observed across all subgroups analyzed, including those with 17p deletions and those who previously received lenalidomide (Revlimid).
The triplet also resulted in a higher ORR over the doublet, at 76.4% versus 62.3%, respectively (P = .0012); this also proved to be true across all subgroups. The median OS had not yet been reached in those who received the selinexor regimen versus 25.0 months in those who received the control (HR, 0.84; 95% CI, 0.57-12.3; P =.19).
Additionally, using the European Organisation for Research and Treatment of Cancer’s questionnaire QLQ-CIPN20, investigators found that peripheral neuropathy rates that were grade 2 or higher were significantly lower with the triplet versus the doublet, at 21.0% versus 34.3% (P = .0013).