Selinexor (SEL) is a novel, first-in-class, oral selective inhibitor of nuclear export. SEL blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, subsequently causing apoptosis in cancer cells. The hypothesis of this study was that the addition of once-weekly SEL to pomalidomide (POM) + dexamethasone (dex; SPd) would demonstrate improved activity and acceptable tolerability when compared with POM + dex alone.
STOMP is a multicenter, open-label phase 1b/2, dose-escalation study with an expansion phase. Patients were eligible if they had relapsed/refractory multiple myeloma (RRMM) and had received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor in either separate or the same regimens. SEL was evaluated in 28-day cycles, using 2 different dosing schedules (once-weekly 60, 80, or 100 mg or twice-weekly 60 or 80 mg), with escalating doses of POM 2 mg, 3 mg, or 4 mg (days 1-21), and dex 20 mg twice weekly or 40 mg once weekly. This study had 2 primary objectives. The first was to determine the maximum tolerated dose and the recommended phase 2 dose. The second was to assess the safety, tolerability, overall response rate (ORR), and progression-free survival (PFS) of SPd in patients with RRMM.
A total of 65 patients were enrolled. The median age was 64 years (range, 37-85 years). Patients received a median of 3 (range, 1-10) prior therapies, including 47 (72.3%) with autologous stem-cell transplantation. During the escalation phase, 6 dose-limiting toxicities were noted. Common hematologic treatment-related adverse events (TRAEs) included (all grades; grade ≥3) neutropenia (60.3%; 54.0%), anemia (54%; 33.3%), thrombocytopenia (54%; 31.7%), and leukopenia (23.8%; 12.7%). Common nonhematologic TRAEs (all grades; grade ≥3) included nausea (60.3%; 1.6%), fatigue (50.8%; 9.5%), decreased appetite (44.4%; 1.6%), weight loss (38.1%; 0%), diarrhea (28.6%; 0%), and vomiting (20.6%; 1.6%). Following a review of all the safety data, the recommended phase 2 dose was SEL 60 mg once weekly, POM 4 mg (days 1-21), and dex 40 mg once weekly.
Sixty of the 65 patients were evaluable for response. Among POM-naïve patients (n = 46), the ORR was 54.3% (1 complete response, 9 very good partial responses [VGPRs], and 15 partial responses [PRs]). For this group, the median PFS was 12.3 months and the median overall survival was 19.0 months. The ORR for patients who previously received POM was 35.7% (1 VGPR and 4 PRs). The mean PFS for all patients was 12.2 months, and the duration of response was 11.3 months.
In conclusion, the recommended phase 3 dose is SEL 60 mg once weekly, POM 4 mg once daily, and dex 40 mg once weekly. All TRAEs were expected and manageable with appropriate supportive care (eg, administration of granulocyte colony-stimulating factor for neutropenia) and/or dose modifications. The combination of SPd appears to offer relatively high ORRs, with good durability and encouraging PFS in heavily pretreated patients with multiple myeloma.
Abstract 726. ASH 2020. December 7, 2020. Selinexor in Combination with Pomalidomide and Dexamethasone (SPd) for Treatment of Patients with Relapsed Refractory Multiple Myeloma (RRMM).