FDA Approves Selinexor Combo for Previously Treated Multiple Myeloma

The FDA has approved the first-in-class oral selective inhibitor of nuclear export (SINE) medicine, selinexor (Xpovio), in combination with bortezomib (Velcade) and dexamethasone for the treatment of adults with multiple myeloma who have received at least 1 prior therapy, according to Karyopharm Therapeutics, the agent’s developer.¹

“New treatments for multiple myeloma remain a critical need for both patients and their treating physicians,” co-senior author of the BOSTON study Paul Richardson, MD, who is also clinical program leader and director of Clinical Research in the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, said in a press release. “Selinexor with once weekly bortezomib-dexamethasone demonstrated encouraging and highly significant results in the Phase 3 BOSTON study, including a 47% improvement in progression-free survival versus standard twice weekly bortezomib-dexamethasone.”

The approval of this expanded indication for selinexor is supported by the results of the multi-center, randomized, phase 3 BOSTON study (NCT03110562), which evaluated 402 adult patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy at over 120 clinical sites internationally.² The BOSTON study was designed to compare the efficacy, safety, and certain health-related quality-of-life parameters of once-weekly selinexor in combination with once-weekly bortezomib plus low-dose dexamethasone (SVd) versus twice-weekly bortezomib plus dexamethasone (Vd).

The study’s primary end point was progression-free survival (PFS) and key secondary end points included overall response rate (ORR) and rate of peripheral neuropathy, among others. Importantly, the BOSTON study allowed for patients on the Vd control arm to cross over to the SVd arm following objective (quantitative) progression of disease verified by an Independent Review Committee (IRC).

Compared with other bortezomib-based studies in previously treated multiple myeloma, the BOSTON study had one of the highest proportions of patients with high-risk cytogenetics (48%); however, the median PFS in the SVd arm was 13.9 months compared with 9.5 months in the Vd arm, representing a 4.4 month (47%) increase in median PFS (HR, 0.70; 95% CI, 0.53-0.93 P = .0075). In addition, the SVd arm also showed a significantly greater ORR at 76.4% compared with 62.3% in the Vd arm (OR, 1.96; 95% CI, 1.3-3.1; P = .0012). Importantly, SVd therapy compared to Vd therapy demonstrated consistent PFS benefit and higher ORR across several important subgroups, including those 65 years of age or older, with high-risk cytogenetics, and with previous lenalidomide (Revlimid) therapy.

Regarding safety, the most common adverse events (AEs) observed were cytopenias, along with gastrointestinal and constitutional symptoms and were consistent with those previously reported from other selinexor studies. However, most AEs were found to be manageable with dose modifications and/or standard supportive care.

The most common non-hematologic AEs were fatigue (59%), nausea (50%), decreased appetite (35%), and diarrhea (32%) and were mostly grade 1/2 in severity. The most common grade 3/4 AEs were thrombocytopenia (43%), lymphopenia (38%), fatigue (28%), and anemia (17%).

“Patients receiving SVd had approximately 35% fewer clinic visits compared to those receiving the standard, twice-weekly Vd regimen, thus receiving 40% less bortezomib and 25% less dexamethasone as compared with the control arm in the first 24 weeks of therapy,” Richardson added. “This once-weekly dosing feature helps makes the SVd regimen attractively simple. Importantly, patients achieved a significantly higher overall response of 76% with once-weekly SVd compared with the standard control arm therapy, and higher response rates were observed regardless of prior therapies received, the presence of high-risk cytogenetics, renal impairment, or advanced age.”

“Finally, adverse events with SVd 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. 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 [patients with] multiple myeloma in need of new therapeutic options."

Of note, selinexor was previously approved under the FDA’s Accelerated Approval Program for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody, based on results from the phase 2 STORM trial (NCT02336815).³

“We plan to immediately launch [selinexor] in this earlier-line indication by leveraging our established commercial infrastructure and growing account base of academic institutions and community-based oncology practices,” Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm, said in the release. “In parallel to our commercial initiatives in the [United States], we continue to collaborate with the European Medicines Agency [EMA] on the Marketing Authorization Application [MAA] of [selinexor] with the goal of further growing the global reach of [selinexor] to more patients in need.”

References:

1. Karyopharm Announces FDA Approval of XPOVIO® (Selinexor) as a Treatment for Patients with Multiple Myeloma After At Least One Prior Therapy [news release]. Newton, Mass. Published December 18, 2020. Accessed December 18, 2020. https://www.prnewswire.com/news-releases/karyopharm-announces-fda-approval-of-xpovio-selinexor-as-a-treatment-for-patients-with-multiple-myeloma-after-at-least-one-prior-therapy-301196120.html

2. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. doi: 10.1016/S0140-6736(20)32292-3

3. FDA grants accelerated approval to selinexor for multiple myeloma [news release]. Published July 3, 2019. Accessed December 18, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selinexor-multiple-myeloma