Based on interim results from the STOMP study in patients with relapsed/refractory multiple myeloma (RRMM) who are heavily pretreated, the combination of selinexor, pomalidomide, and dexamethasone appears to offer relatively high overall response rates (ORRs) and encouraging progression-free survival (PFS).
Selinexor (SEL) is a novel, first-in-class, oral selective inhibitor of nuclear export. SEL blocks XPO1, which forces the nuclear retention and activation of tumor suppressor proteins and subsequently causes apoptosis in cancer cells. The study hypothesis was that the addition of once-weekly SEL to pomalidomide (POM) plus dexamethasone (S+Pd or SPd) would show improved activity and acceptable tolerability when compared with Pd alone.
STOMP is a multicenter, open-label, phase 1b/2, dose-escalation study with an expansion phase. If patients had RRMM and had received ≥2 prior therapies, including lenalidomide (LEN) and a proteasome inhibitor in either separate or the same regimens, they were eligible for the study. With 2 different dosing schedules, SEL was evaluated in 28-day cycles (once weekly 60, 80, or 100 mg or twice weekly 60 or 80 mg), with escalating doses of POM 2, 3, or 4 mg (days 1-21) and dexamethasone 20 mg twice weekly or 40 mg once weekly. There were 2 primary objectives to this study. The first objective was to determine the maximum tolerated dose and the recommended phase 2 dose. The second objective was to assess the safety, tolerability, ORR, and progression-free survival (PFS) of SPd in patients with RRMM.
As of June 1, 2020, there were 52 patients enrolled in the study. Median age was 64 years (range, 43-85 years). Patients received a median of 3 (1-10) prior therapies, including 44 (84.6%) with autologous stem-cell transplantation. During the escalation phase, 8 dose-limiting toxicities were noted: 1 patient in the SEL 60 mg twice weekly/POM 4 mg once daily (grade 3 fatigue), 1 in SEL 60 mg twice weekly/POM 3 mg once daily (grade 3 febrile neutropenia), 2 in SEL 80 mg once weekly/POM 4 mg once daily (grade 3 febrile neutropenia and grade 4 neutropenia), 2 in SEL 80 mg once weekly/POM 3 mg once daily (POM dose reduction for grade 2 neutropenia/grade 3 thrombocytopenia and grade 3 febrile neutropenia), 1 in 80 mg once weekly/POM 2 mg once daily (grade 3 febrile neutropenia), and 1 in SEL 60 mg once weekly/POM 4 mg once daily (SEL dose holds for grade 3 anemia and grade 4 thrombocytopenia). Common hematologic treatment-related adverse events (TRAEs) included (all grades; grade ≥3) neutropenia (62%; 56%), anemia (60%; 37%), and thrombocytopenia (56%; 35%). Common nonhematologic TRAEs (all grades; grade ≥3) included nausea (62%; 2%), fatigue (56%; 12%), decreased appetite (48%; 2%), weight loss (42%; 0%), diarrhea (35%; 0%), and vomiting (23%; 2%). Rates of grade ≥3 hematologic TRAEs were lower in SEL once-weekly than SEL twice-weekly schedules (thrombocytopenia [29% vs 44%] and anemia [32% vs 44%]). After a review of the safety data, the recommended phase 2 dose was SEL 60 mg once weekly, POM 4 mg (days 1-21), and dexamethasone 40 mg once weekly.
Forty-seven of the 52 patients were evaluable for response. Previously treated/refractory rates were lenalidomide (LEN; 100%/96%), bortezomib (94%/45%), carfilzomib (38%/34%), POM (30%/30%), and daratumumab (21%/21%). Among patients who are POM-naïve (N = 33), all (100%) received prior LEN therapy and 31 (94%) had documented LEN-refractory multiple myeloma. For POM-naïve patients, the ORR was 58% (1 complete response, 5 very good partial responses, and 13 partial responses). For this group, median PFS was 12.3 months, and median overall survival was 19.0 months. For patients who previously received POM, the ORR was 36% (1 very good partial response and 4 partial responses). For this group, median PFS and median overall survival rates were 8.8 months and 8.0 months, respectively.
In conclusion, the recommended phase 3 dose is SEL 60 mg once weekly, POM 4 mg once daily, and dexamethasone 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. In patients with multiple myeloma who are heavily pretreated, the combination of SPd appears to offer relatively high ORRs with good durability and encouraging PFS.
Abstract 728. ASH 2020. December 7, 2020. Selinexor in combination with pomalidomide and dexamethasone (SPd) for treatment of patients with relapsed refractory multiple myeloma (RRMM).