The U.S. Food and Drug Administration (FDA) has approved a triple combination of Xpovio (selinexor) plus Velcade (bortezomib) and low-dose dexamethasone for the treatment of people with multiple myeloma who received at least one line of therapy.
The approval, which comes three months ahead of deadline, was based on promising data from the BOSTON Phase 3 trial (NCT03110562), in which the triple combo significantly extended patients’ lives without disease worsening, increased response rates, and prolonged survival compared with standard Velcade plus dexamethasone.
“Today’s U.S. approval broadens the existing label for Xpovio and allows Karyopharm to offer a new, highly active, treatment option to a significantly expanded patient population,” Sharon Shacham, PhD, founder, president, and chief scientific officer of Karyopharm, said in a press release.
Xpovio is a first-in-class oral inhibitor of the XPO1 protein, a nuclear transporter that is produced in greater amounts by cancer cells to escape the action of tumor suppressor proteins. By preventing the exit of tumor suppressors from the cell nucleus, Xpovio leads to cancer cell’s death.
Xpovio is conditionally approved for adults with relapsed or refractory multiple myeloma who have tried at least four prior therapies, and have failed to respond to at least two proteasome inhibitors, two immunomodulatory agents, and one CD38 inhibitor.
The new approval now makes Xpovio available as soon as an individual first relapses, significantly expanding the patient population that might benefit from this therapy. Karyopharm Therapeutics, the developer of Xpovio, has plans to make the treatment available as soon as possible for this indication.
“We plan to immediately launch Xpovio in this earlier-line indication by leveraging our established commercial infrastructure and growing account base of academic institutions and community-based oncology practices,” said Michael G. Kauffman, MD, PhD, CEO of Karyopharm.
BOSTON included a total of 402 adults, previously treated with one to three prior lines of therapy. All were randomly assigned to the triple combination or to standard Velcade plus dexamethasone, which served as the control regimen.
For those in the Xpovio arm, the therapy and Velcade both were given once a week, along with 40 mg of dexamethasone weekly. Standard treatment patients were given Velcade twice weekly plus 80 mg of dexamethasone each week.
Karyopharm announced in early 2020 that BOSTON met its primary goal of progression-free survival, meaning that patients receiving the triple combination lived significantly longer — a median of 13.9 months, or a little more than a year — without signs of disease progression than did those on standard treatment, who lived for 9.5 months with no signs of their cancer worsening.
This 4.4-month extension represented a 30% reduction in the risk of disease worsening or death, an improvement that was consistent among different patient subgroups.
Additional data published in The Lancet demonstrated that the triple combination also increased the rate of responses (76.4% vs. 62.3%), including those defined as at least very good partial response (44.6% vs. 32.4%), and significantly extended the duration of responses — from 12.9 months to 20.3 months.
The rate of complete responses also was higher in Xpovio-treated patients (17% vs. 10%).
Notably, patients given the triple combo required about 35% fewer clinic visits, and received 40% less Velcade and 25% less dexamethasone compared with the controls in the first 24 weeks (nearly six months), according to Paul Richardson, MD, co-senior author of the study.
“This once-weekly dosing feature helps makes the [triple combo] regimen attractively simple,” said Richardson, also the clinical program leader and director of clinical research at the multiple myeloma center at the Dana-Farber Cancer Institute, in Boston.
“As the only approved nuclear export inhibitor that has demonstrated a strong synergistic effect with a proteasome inhibitor such as bortezomib, selinexor has, in my opinion, the potential to meet a current treatment gap for our multiple myeloma patients in need of new therapeutic options,” Richardson said.
Xpovio also was linked to improvements in overall survival and to lower rates (21.0% vs. 34.3%) of severe peripheral neuropathy, or damage to the nerves controlling sensation and movement.
The most common treatment-related adverse events observed in patients on the triple therapy were low blood counts and gastrointestinal symptoms.
“Adverse events with [the Xpovio combination] were important but generally self-limiting, reversible, and proved manageable with dose modifications and aggressive supportive care, as well as generating significantly lower rates of peripheral neuropathy compared to the control group,” Richardson added.
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