Weekly Selinexor, Bortizomib and Dexamethasone (SVd) Versus Twice Weekly Bortizomib and Dexamethasone (Vd) in Chinese Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Primary Analysis of Phase 3 Bench Study

Introduction:

Selinexor (ATG-010) is a first-in-class, orally bioavailable XPO1 inhibitor which binds to exportin 1, inhibiting nuclear export of tumor suppressor proteins. It synergizes with proteasome inhibitors (PIs) in preclinical studies and produces high response rates in patients (pts) with PI refractory and non-refractory MM. In the global phase 3 BOSTON study (NCT03110562), SVd significantly improved progression free survival (PFS), compared to twice weekly Vd [harzard ratio (HR) 0.70)]. The China registrational bridging study, BENCH (NCT04939142) aimed to demonstrate the consistency of efficacy and safety outcomes between these 2 studies.

Methods:

This phase 3, randomized, open label, study was conducted at 33 sites in China. The adult pts with RRMM, who had previously been treated with 1 to 3 lines of therapy, were randomly allocated (2:1) to receive SVd: selinexor (100 mg once per week), bortezomib (1.3mg/m2 once per week) and dexamethasone (20 mg twice per week), or Vd: bortezomib (1.3mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Pts receiving Vd could cross over to either SVd or Sd treatment after confirmation of progression. The primary endpoint was PFS in the intention-to-treat (ITT) population. The key secondary endpoints included ORR (≥PR), response rate of ≥VGPR and the incidence of Grade ≥2 peripheral neuropathy (PN). Efficacy was assessed by independent review committee per IMWG 2016. The PFS HR should reach less than 0.85 to show consistency (at least 50% efficacy with BOSTON study).

Results:

As of 9^th May 2024, a total of 154 Chinese RRMM pts were randomized to SVd group (n=101) or Vd group (n=53) and 152 pts received at least one dose of study drug (safety population). The baseline demographic and clinical characteristics were approximately balanced across the two treatment groups. The median age was 62 (range: 33-78). 87 pts (56.5%) were male and 67 pts (43.5%) were female. R-ISS stage III and high-risk cytogenetic abnormalities (including del(17p), t(14;16), t(4;14), 1q21) were present in 18 (11.7%) and 105 (68.2%) pts, respectively. However, SVd group included more pts with extramedullary disease than Vd group [24 (23.8%) vs 4 (7.5%)].

At a median follow-up time of 20.6 months (range:10.2-33.4), the median PFS was 8.1 months with SVd group and 6.3 months with Vd group. The HR reached 0.74 (95% CI 0.48-1.15; P=0.180). A similar reduction in the risk of progression was observed for SVd group between BENCH and BOSTON study. The ORR was higher in SVd group than in Vd group (72.3% vs 62.3%, P=0.173). SVd group had a significantly higher proportion of pts with response of VGPR or better (45.5% vs 22.6%, P=0.005). Among pts with response of CR or better, 59% (13/22) vs 25% (1/4) (SVd vs Vd) achieved MRD negativity (<1x10^-5). The median time to response and the median duration of response were 0.8 vs 1.4 months and 9.7 vs 7.2 months (SVd vs Vd) respectively. The median overall survival was not reached in both groups.

The most frequent Grade 3-4 adverse events (AEs) for SVd and Vd (≥10%) were thrombocytopenia (55.0% vs 28.8%), lymphocytopenia (37.0% vs 17.3%), anemia (25% vs 17.3%), neutropenia (17.0% vs 3.8%), pneumonia (14.0% vs 13.5%), cataract (13.0% vs 0%), diarrhea (6.0% vs 15.4%) and hypokalemia (8.0% vs 11.5%). The incidence of Grade≥2 PN was significantly lower in SVd than in Vd group (8% vs 32.7%, P=0.001).

Conclusion:

SVd regimen decreased the risk of progression and obtained much more profound responses compared to standard Vd regimen in Chinese pts with RRMM. The incidence of Grade ≥2 PN were significantly reduced. The results of BENCH study were consistent with the BOSTON study despite differences in patient populations and the primary end point achieved.

Fu:Takeda (China) International Trading Co., Ltd: Consultancy, Honoraria, Research Funding. Yu:Antengene Therapeutics Ltd.: Current Employment. Guo:Antengene Therapeutics Ltd.: Current Employment. Zhao:Antengene Therapeutics Ltd.: Current Employment.