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Dose Reduction of Selinexor Combo Demonstrates Efficacy in Multiple Myeloma – Cancer Network

© 2022 MJH Life Sciences and Cancer Network. All rights reserved.
© 2022 MJH Life Sciences and Cancer Network. All rights reserved.

Conference | ASH Annual Meeting & Exposition: Multiple Myeloma
A post hoc analysis showed that a dose reduction of selinexor yielded higher safety and efficacy for patients with multiple myeloma.
The phase 3 BOSTON study (NCT03110562) examining the combination of selinexor (Xpovio) plus bortezomib (Velcade) and dexamethasone for patients with multiple myeloma showed efficacy of the treatment, but a post hoc analysis yielded higher efficacy and safety when a dose reduction of selinexor was used, according to a presentation from the 2021 Americacn Society of Hematology Annual Meeting.
In the relapsed or refractory multiple myeloma patient population, dosage for the majority of anti-cancer therapies is either reduced, interrupted, or discontinued. This strategy can optimize the therapeutic window and make treatment more tolerable while maintaining efficacy. This dosing strategy was utilized in the BOSTON study. Although the FDA-recommended dose of the selinexor oral selective inhibitor of XPO1-mediated nuclear export compound is 100 mg once weekly (QW), the median dose of selinexor administered was 80 mg QW.

BOSTON is a phase 3, randomized, open-label, controlled trial of patients with multiple myeloma who had received 1-3 prior therapies. A total of 406 patients were randomized 1:1 to receive XVd or Vd alone with the option to crossover to the XVd arm upon the development of disease progression (PD). Selinexor was initially administered in the experimental arm at 100 mg orally on days 1, 8, 15, 22, and 29 of 35-day cycles. Bortezomib was dosed at 1.3 mg/m2 subcutaneously on days 1, 8, 15, and 22 of 35-day cycles, and dexamethasone was administered orally on days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-cycle. The protocol for XVd required that 40% less bortezomib be administered compared with the amount in the Vd regimen in order to decrease clinic visits by 37% during the first 6 months of treatment.

In the comparator arm, patients were also treated with 1.3 mg/m2 of bortezomib via subcutaneous infusion and oral dexamethasone at 20 mg, but the dosing schedule was different. Bortezomib was administered on days 1, 4, 8, and 11 of every 21-day cycle, and dexamethasone was administered on days 1,2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.

The primary end point of the study was progression-free survival, and the secondary end points were objective response rate (ORR), achievement of a very good partial response (VGPR) or better, grade ≥ 2 peripheral neuropathy, overall survival (OS), duration of response (DOR), time to next treatment (TTNT), and safety.

“We did a post hoc analysis to determine the outcomes of patients who had a dose reduction versus those who did not to understand optimal dosing of selinexor with Velcade,” explained Sundar Jagannath, MD, professor of Medicine, Hematology/Oncology, The Tisch Cancer Institute, during the ASH presentation.

After the 100-mg starting dose, a patient’s' selinexor dose could be reduced to 80 mg QW at first reduction, 60 mg QW at second reduction, and 40 mg QW at third reduction. In total, 195 patients were included in the post hoc analysis and of those patients, 126 had a reduced dose of selinexor while 69 did not.

Baseline characteristics were balanced between the reduced selinexor cohort and the cohort without treatment reduction. Those who received reduced selinexor had a median age of 66 years (range, 44-87), and were 53.2% male and 46.8% female. Some patients received 1 prior line of therapies (50.8%), while others received 2 prior lines (33.3%), or 3 prior lines (15.9%). Prior allogeneic stem cell transplant (ASCT) was performed on 42.1% of patients who received reduced dose selinexor. The median time from diagnosis to enrollment was 4.0 years (range, 0.6-23.0). More than 51% had high-risk cytogenetic abnormalities at baseline. The median dose of selinexor administered in the reduced-dose cohort was 71 mg (range, 29.7-101.4), and the average duration of exposure to the drug was 44.4 weeks (range, 3-120).

In the cohort who did not receive a reduced dose of selinexor, the median age was 66 years (range, 40-84) with 69.6 of patients being male. In terms of prior lines of therapy, 50.7% had 1 prior line, 33.3% had 2 prior lines, and 15.9% had 3 prior lines. Prior ASC was received by 33.3% of the cohort. The median number of years from diagnosis to enrollment in the trial was 3.3 years (range, 0.4-12.9). High-risk cytogenetic abnormalities were identified in 46.4% of the population. Patients in the cohort had a median of 100 mg of selinexor per week, and the median duration of treatment with selinexor was 30.5 weeks (range, 1-118).

Efficacy results showed that the use of XVd was clinically meaningful in terms of PFS, ORR, and OS, with or without selinexor dose reduction. The median PFS observed in the group of patients with selinexor dose reduction was 16.62 months compared with 9.23 months among patients without dose reduction (HR, 0.5678; 95% CI, 0.3614-0.819; P =.0065). The median OS was not reached in either cohort.

The ORR in patients with a selinexor dose reduction was 81.7%, which included a ≥ VGPR of 51.6% of patients. In comparison, patients without a selinexor dose reduction had an ORR of 66.7% with a ≥ VGPR 31.9%.

Safety was assessed in all 195 patients. The most common any-grade treatment-emergent adverse events (TEAEs) in the dose reduction group versus the group without dose reduction were thrombocytopenia (69.8% vs 42.0%), nausea (55.6% vs 40.6%), and fatigue (49.2% vs 29.0%). Treatment discontinuation occurred in 24.6% of the patients with a dose reduction versus 14.5% of patients without a dose reduction. Further, 4.8% of patients in the selinexor dose reduction cohort died compared with 8.7 of those who did not have a dose reduction.

The difference in duration-adjusted incidence of AEs of clinical interest on or before first selinexor dose reeducation versus after first reduction was also evaluated. Among the patients who had an AE or before first reduction versus after, the most common AEs were
nausea (31.6% vs 7.6%), fatigue (28.1% vs 9.9%), and decreased appetite (21.5% vs 6.4%). The most common grade ≥ 3 TEAEs among patients with an event on or before first reduction were anemia (4.7%), fatigue (4.1%), and neutropenia (4.0%). Among patients with an AE after first reduction of selinexor, the most common grade ≥ 3 TEAEs were neutropenia (4.8%), and anemia (3.2%).

“Dose reductions are very effective at managing side effects and lead to better patient outcomes with improved progression-free survival. As patients stay on therapy longer with dose reduction, the responses deepen with time. Dose reduction to a median dose of 80 milligrams once weekly of selinexor was well tolerated when given with weekly Velcade,” Jagannath concluded during the ASH presentation.

Jagannath S, Facon T, Badros A, et al. Clinical outcomes in patients (pts) with dose reduction of selinexor in combination with bortezomib, and dexamethasone (xvd) in previously treated multiple myeloma from the BOSTON study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3793.

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