Selinexor Plus Vd Combo Shows Potential as a Treatment Option for High-Risk Multiple Myeloma

Weekly selinexor combined with bortezomib and dexamethasone appears to be a promising option in patients with high-risk multiple myeloma.

Treatment with weekly selinexor (Xpovio) plus bortezomib (Velcade) and dexamethasone (XVd) in patients with high-risk multiple myeloma appears to be a potential treatment option regardless of cytogenetic profile, according to findings from 2 phase 2 trials presented at the 2021 American Society of Hematology Annual Meeting and Exposition.

Results from a post-hoc analysis of the phase 1b/2 STOMP study (NCT02343042) and the phase 3 BOSTON study (NCT03110562) were presented in a poster by Nizar J. Bahlis, MD during the American Society of Hematologic Oncology Annual Meeting & Exposition 2021. Results were favorable for patients with high-risk cytogenetics and standard-risk cytogenetics, and the safety profile of the combination was manageable.

Selinexor is an oral, selective inhibitor of exportin 1 (XPO1)-mediated nuclear export. The agent is designed to reactivate several tumor suppressor proteins (TSPs) and repress oncoprotein translation.

“XP01 has been shown to overexpress in multiple myeloma and it does result in the inactivation of variable tumor suppressor proteins such as p53 and IκB, as well as enhancement of the oncoproteins such as c-Myc, Bcl-xL, and cyclin translation,” explained Bahlis during the ASH presentation.

The high-risk cytogenetic abnormalities common in multiple myeloma include del(17p), t(4;14), t(14;16), and gain 1q21 (≥ 3 copies). These features are associated with shorter PFS and overall survival (OS) compared with standard-risk cytogenetic features. Therefore, an unmet medical need exists for treatment regimens that can address the high-risk cytogenetic abnormalities in patients with multiple myeloma.

The post hoc analysis was carried out to determine the impact high-risk cytogenetics may have on treatment outcomes. Patients in the BOSTON trial arm received XVd weekly in 35-day cycles, which was administered as selinexor 100 mg once weekly with bortezomib 1.3 mg/m2 once weekly, dexamethasone 20 mg twice weekly until disease progression (PD) or unacceptable toxicity. The primary end points of the study were ORR by the independent review committee, achievement of a very good partial response (VGPR) or higher, and grade ≥ 2 peripheral neuropathy.

In the STOMP arm, XVd weekly consisted of selinexor 80/100 mg once weekly or 60/80 mg twice weekly combined with bortezomib 1.3 mg/m2 once weekly, and dexamethasone 20 mg twice weekly or 40 mg once weekly until PD or unacceptable toxicity. The study assessed the coprimary end points of ORR and duration of response.

Patients with high-risk cytogenetics in both trials were defined as those with at least 3 features found in 10% of screened plasma including del(17p), t(4;14), t(14;16), and gain 1q21 (≥ 3 copies). Overall, 106 patients with high-risk cytogenetics were included in the post hoc analysis and compared with 131 patients who had standard-risk cytogenetics.

In the high-risk abnormality group, the median age was 67 years (range, 42-84). The group was 52.8% male and 47.3% females. Most patients with high-risk cytogenetics had 1 prior line of therapy (49.1%), and 32.1% has 2 prior lines of therapy, 16.0% had 3, and only 2.8% had 4 or more prior lines of therapy. Eighty-five patients (80.2%) were previously treated with a proton inhibitor, and 40.6% previously underwent an allogeneic stem cell transplant. The median number of years since diagnosis to enrollment in the study was 3.5 years, (range, 0.8-23.0). The most common high-risk cytogenetic feature was gain 1q21 (≥ 3 copies). Del (17p) or p53 was found in 23.5% of patients, t (4:14) was found in 23.5% of patients, and t (14;16) was identified in 9.4% of patients.

In the standard-risk group, patients had a median age of 65 years (range, 38-84). The group was 62.6% male and 37.4% female. Forty-two percent of the population had 1 prior line of therapy, 31.3% had 2, 13.7% had 3, and the remaining 13.0% had 4 or more prior lines of therapy. Overall, 77.1% of patients were previously treated with PI, and 49.6% had prior ASCT. The median years since diagnosis to study enrollment was 4.3 years (range, 0.4-21.5).

The median PFS among patients with only 1 high-risk cytogenetic feature was 13.14 months. Patients with 2 or more high-feature abnormalities and a median PFS of 12.91 months, and those with standard-risk cytogenetics had a median PFS of 16.62 months. In terms of responses, the ORR for patients with any high-risk abnormality was 76.4% compared with 69.5% in the standard-risk population.

“The median overall survival was not reached in both groups and the overall response rate was comparable in both groups. Now, specifically, when we look at [cytogenetic features] individually, you will know that the median progression-free survival was comparable among these subgroups ranging from 12.2 to 13.9 months, said Bahlis during the presentation.

The median PFS, median OS, and ORR were also assessed according to high-risk cytogenetic type. Among the subgroup of 25 patients with del(17p), the median PFS was 12.22 months, the median OS was not reached, and the ORR was 72.0%. Those with t(4;14) have a median PFS of 13.24 months, a 20.44-month median OS, and an ORR of 88.0%.

In the subgroup of patients with t(14;16) multiple myeloma, the median PFS was only 5.29 months, with a median OS of 16.43 months, and an ORR of 90.0%. Finally, patients with gain 1q21 (≥ 3 copies) achieved a 13.93-month median PFS. The median OS was not reached in this subgroup, but the ORR was 73.8%.

The safety profile of XVd was similar in the high-risk and standard0risk multiple myeloma subgroups. In the high-risk population versus the standard-risk group, the most common treatment-emergent adverse events (TEAEs) were thrombocytopenia (65.1% vs 54/2%), nausea (53.8% vs 53.4%), fatigue (47.2% vs 45.0%), and decreased appetite (37.7% vs 42.0%). The most common grade ≥ 3 TEAEs in the high-risk population compared with the standard-risk population were thrombocytopenia (50.9% vs 32.1%), anemia (17.9% vs 19.1%), and fatigue 12.3% vs. 14.5%).

“Once weekly XVd was shown to be a safe and active regimen in patients with multiple myeloma, including those with high-risk features. The regimen could represent an important treatment option for this patient population,” according to Bahlis.

Reference

Bahlis N, Richard S, White D, et al. Effects of cytogenetic risk on outcomes in multiple myeloma treated with selinexor, bortezomib, and dexamethasone (XVd). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 1634.