Dose adjustment of selinesol improves survival, response rate and QOL in MM

The BOSTON trial (NCT03110562) evaluated the use of selinexor in patients with multiple myeloma (MM) and found that adjusting the starting dose based on initial adverse effects (AEs) produced promising results, including improved efficacy, reduced incidence of AEs, and improved quality of life. Appropriate dose reductions in the 100 mg selinesol starting dose in the BOSTON trial were associated with potentially longer progression-free survival, duration of response, time to next antimyeloma treatment, reduced incidence of adverse events, and improved quality of life.

In the BOSTON study, 126 patients (65%) had their dose of selinesol reduced (median dose, 71.4 mg/week), and the median progression-free survival (PFS) was 16.6 months, compared with 9.2 months for patients who did not reduce their dose. The overall response rates (ORR) of the dose reduction group and the non-reduction group were 81.7% and 66.7%, respectively, and the partial response rates were 51.6% and 31.9%.

In addition, the median duration of response (DOR) was not reached in patients who received a reduced dose compared with 12.0 months in patients who received a reduced dose, and the time to next treatment (TTNT) was 22.6 months compared with 10.5 months in patients who received a reduced dose. Begin with a weekly dose of 100 mg selinesol and may adjust the dose based on adverse events to improve tolerability. The initial dose is 100 mg once weekly, followed by reduction to 80 mg once weekly, 60 mg once weekly, and 40 mg once weekly. The most common adverse events at any grade were thrombocytopenia, nausea, and fatigue. Dose reduction rates for selinesol were lower compared with those for thrombocytopenia, nausea, fatigue, decreased appetite, anemia, and diarrhea.

Based on the findings of the STORM study (NCT02336815) and the Phase 3 BOSTON study, selinesol has received 2 approvals from the U.S. Food and Drug Administration (FDA) . BOSTON is a randomized phase 3 study comparing the efficacy and safety of once-weekly oral selinesol (at a dose of 100 mg) with once-weekly subcutaneous injections of bortezomib (Velcade) and low-dose dexamethasone (XVd) versus twice-weekly standard bortezomib and low-dose dexamethasone (Vd). The study evaluated the efficacy, safety and quality of life of the combination in 195 patients with relapsed/refractory multiple myeloma and compared patients who had a reduced dose with those who did not. The primary endpoint is PFS, and secondary endpoints include ORR, OS, DOR and TTNT.

Of the 195 patients who participated in the BOSTON study and received XVd, 126 (65%) had their selinesol dose reduced. The mean age of the two groups was66.0 years, and the age ranges of the two groups were similar. Among patients who had selinesol dose reduction and those who did not, respectively, 67 (53.2%) and 48 (69.6%) were male, 74 (58.7%) and 43 (62.3%) had an International Staging System score of II at baseline, and 93 (73.8%) and 55 (79.7%) had previously received proteasome inhibitor therapy. Patients in both groups received a median of 1 prior therapy.

During treatment, the median dose intensity of selinesol was 71.4 mg weekly in the dose-reduced group compared with 100 mg weekly in the non-reduced dose group. The median duration of dose reduction was 68 days. The median duration of study treatment was 34.5 weeks for patients whose dose was reduced compared with 20.0 weeks for patients who did not reduce their dose.

Other study results showed that compared with baseline, the mean optimal change in the EORTC QLQ-C30 global health status/quality of life scale was 10.0 ± 20.5 in the selinesol dose reduction group and 4.0 ± 20.9 in the no dose reduction group. Fifty-four of 121 patients (44.6%) in the dose reduction group had an increase of 10 points or more from baseline, compared with 20 of 61 patients (32.8%). Dose adjustments should be guided by adverse effects such as thrombocytopenia, nausea, fatigue, loss of appetite, anemia, and diarrhea. By adjusting the dose, responding patients will be able to use the drug for longer without losing control of their disease.

In terms of safety, the most commonly reported treatment-emergent AEs of any grade in the reduced dose group versus the non-reduced dose group included thrombocytopenia, nausea, fatigue, decreased appetite, diarrhea, peripheral neuropathy, and anemia. The investigators also observed a lower incidence of duration-adjusted AEs after selinesol dose reduction. These include thrombocytopenia, nausea, fatigue, decreased appetite, anemia, and diarrhea.

Selinisol can be easily combined with other drugs to treat relapsed and/or refractory myeloma. Therefore, its continued use and further investigation in combination with T cell redirection therapy and CelMoDS is warranted.