The European Medicines Agency has validated a Type II Variation Marketing Authorization Application to Karyopharm Therapeutics Inc. for selinexor in combination with bortezomib and low-dose dexamethasone as a treatment for adult patients with multiple myeloma who have received at least 1 prior therapy.
The European Medicines Agency has validated a Type II Variation Marketing Authorization Application (MAA) to Karyopharm Therapeutics Inc. for selinexor (Nexpovio; Xpovio in US) in combination with bortezomib (Velcade) and low-dose dexamethasone as a treatment for adult patients with multiple myeloma who have received at least 1 prior therapy.1
The application is based on findings of the phase 3 BOSTON trial, which evaluated once-weekly selinexor plus once-weekly bortezomib/low-dose dexamethasone (SVd) vs standard twice-weekly bortezomib/low-dose dexamethasone (Vd) in patients who received 1 to 3 prior lines of therapy.2 Data showed that, overall, the SVd regimen was associated with a 30% reduction in the risk of disease progression or death compared with Vd alone; the median progression-free survival (PFS) was 13.9 months (95% CI, 11.7–not reached) vs 9.5 months (95% CI, 7.6-10.8), respectively (HR 0.70; 95% CI, 0.53-0.93; P = .0075).
Specifically, in patients who received 1 prior line of therapy (n = 198), SVd led to a 36% reduction in the risk of disease progression or death vs Vd.
The BOSTON findings were also the basis for the FDA’s expanded approval of selinexor to include this indication in December 20203 and were also published in The Lancet.2
"The submission of a Type II Variation Marketing Authorization Application based on positive data from the Phase 3 BOSTON study represents an important step towards our goal of further expanding the treatment options available to patients with multiple myeloma in Europe," Sharon Shacham, PhD, MBA, president and chief scientific officer of Karyopharm, the developer of selinexor. "We look forward to the EMA's review of this supplemental data, which further reinforces the broader therapeutic potential of Nexpovio."
Through this validation, the submission of the MAA is now complete and will initiate the EMA’s review process to expand the selinexor regimen to include the indication of patients with myeloma who have received at least 1 prior therapy. The application will be reviewed next by the EMA’s Committee for Medicinal Products for Human Use, which Karyopharm expects to be completed in the fourth quarter of 2021.
The European Commission granted conditional marketing authorization to selinexor in combination with dexamethasone in March 20201 for the treatment of adult patients with multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents, and an anti-CD38 antibody, and who have demonstrated disease progression on their most recent therapy.
The MAA for the indication for the selinexor regimen to be given in adult patients with multiple myeloma after 1 prior therapy will also fulfill the condition marketing authorization given for the initial approval and indication in March 2021.
In BOSTON, investigators randomized 402 adult patients with multiple myeloma who were previously treated with 1 to 3 lines of therapy to receive SVd (n = 195) or Vd (n = 207). With the SVd regimen, patients received 100 mg of selinexor once weekly, 1.3 mg/m2 of bortezomib once weekly, and 20 mg of dexamethasone twice weekly. The Vd regimen comprised 1.3 mg/m2 of bortezomib twice weekly for the first 24 weeks and once weekly thereafter and 20 mg of dexamethasone 4 times weekly for the first 24 weeks and twice per week thereafter.
The primary end point was PFS and the secondary end point was overall response rate (ORR). The median follow-up duration was 13.2 months for SVd and 16.5 months for Vd.
In patients who were aged 65 years or older (n = 241), SVd reduced the risk of disease progression or death by 45% (HR, 0.55; 95% CI, 0.37-0.83). Patients with high-risk cytogenetic abnormalities were broken down into 3 subgroups. The first combined all patients (n = 192) with either deletion (del)17p, translocation (t) 4;14, t(14;16), or 1q21 microdeletions; here, SVd showed an HR of 0.67 (95% CI, 0.45-0.98). In those with (del)17p, there was a 62% reduction in the risk of disease progression with SVd (HR, 0.38).
Overall, SVd elicited an ORR of 76.4% (95% CI, 69.8%-82.2%) vs Vd with 62.3% (95% CI, 55.3%-68.9%; P = .0012). The stringent complete response (sCR) was 10%, the complete response (CR) was 7%, the very good partial response (VGPR) rate was 28%, and partial response (PR) rate was 32% with the selinexor triplet. With Vd arm, these rates were 6%, 4%, 22%, and 30%, respectively.
Regarding safety, peripheral neuropathy of at least grade 2 was lower with SVd at 21% vs 34% of those on Vd (odds ratio, 0.50; 95% CI, 0.32-0.79; P = .0013). The most frequent grade 3/4 adverse events (AEs) were thrombocytopenia (39% with SVd vs 17% with Vd), fatigue (13% vs 1%, respectively), anemia (16% vs 10%), and pneumonia (11% for both SVd and Vd). Twenty-four percent of patients died on the SVd arm vs 30% of those on Vd.
Additionally, treatment discontinuation rates with selinexor due to an were reported in 19% of patients, dose interruptions occurred in 83%, and dose reductions occurred in 64% of patients.