Once Weekly Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma: High-Risk Cytogenetic Risk Planned Subgroup Analyses from the Phase 3 Boston Study

Introduction: Despite recent advances, there remains an unmet need for novel therapies to improve outcomes and abrogate the adverse effects of high-risk cytogenetics in patients with multiple myeloma (MM). In patients with triple class refractory MM in the Phase 2b STORM study, the clinical benefit of selinexor plus low dose dexamethasone (sel-dex) was preserved across high-risk cytogenetic subgroups, supporting further evaluation of selinexor combined with other anti-MM therapies (Nooka et al. ASH 2019). The phase 3 BOSTON study evaluated the combination of weekly sel-dex with the proteasome inhibitor (PI) bortezomib (SVd) against standard twice weekly bortezomib-dex (Vd) in patients with MM who had received 1-3 prior therapies. SVd significantly improved progression free survival (PFS), time to next therapy (TTNT), overall response rate (ORR) and depth of response (≥VGPR), while inducing less overall and grade ≥2 peripheral neuropathy (PN) compared with Vd. Here, we present the results of prespecified subgroup analyses from the BOSTON study according to cytogenetic risk status.

Methods: In the BOSTON study, patients were randomly assigned (1:1) to once weekly oral sel (100 mg) plus once weekly subcutaneous (SC) bortezomib (1.3 mg/m²) and dex (20 mg BIW) in the SVd arm or twice weekly SC bortezomib (1.3 mg/m²) and dex (20 mg QIW) in the Vd arm. Treatment was administered in both arms until disease progression. The primary endpoint was PFS, as assessed by an Independent Review Committee (IRC). Central FISH analyses were performed on CD138⁺ sorted cells from bone marrow aspirates collected at screening. The high-risk group consisted of patients with at least 1 of the following abnormalities: del(17p), t(4;14), t(14;16), and amplification of 1q21 in ≥10% of screened plasma cells with amp (1q21) requiring ≥3 copies. The standard-risk group consisted of all other patients with available and known baseline cytogenetics.

Results: Of the 402 enrolled patients, 192 (48%) had high-risk (SVd=97, Vd=95) and 210 (52%) had standard-risk (SVd=98, Vd=112) cytogenetics. Baseline patient and disease characteristics were well balanced across treatment arms. SVd significantly improved PFS relative to Vd in the high-risk (12.9 vs 8.1 months; HR, 0.67; 95% CI, 0.45-0.98; P=0.0192) and standard-risk (16.6 vs 9.7 months; HR, 0.63; 95% CI, 0.42-0.95; P=0.0131) groups. Time to next treatment was significantly increased with SVd in the high-risk (14.6 vs 8.7 months; P=0.0049) and standard risk groups (NR vs 13.1 months; P=0.0158). The ORR was significantly improved with SVd in the high-risk group (77.3% vs 55.8%; P=0.0008) and numerically improved in the standard-risk group (75.5% vs 67.9%; P=0.11) with comparable rates between the high-risk and standard-risk groups in the SVd arm. Very good partial response or better was achieved in 42.3% patients on SVd versus 24.2% on Vd (P=0.0041) and 46.9% on SVd versus 39.3% on Vd (P=0.13) in the high-risk and standard-risk groups, respectively. Overall survival was 23.5 months in the high-risk group in the Vd arm and was not reached in the other groups. Efficacy by specific cytogenetics abnormalities in the high-risk subgroup is shown in the table below. PFS and ORR were improved with SVd compared with Vd across all subgroups except t(14;16) which was the smallest subgroup (N=18, 4% of the study population). There were 61 deaths in the high-risk group (SVd=27 and Vd=34) versus 48 in the standard-risk group (SVd=20 and Vd=28). The safety profiles of SVd and Vd in the high-risk and standard-risk groups were consistent with the overall population. Rate of grade ≥2 peripheral neuropathy was lower with SVd compared with Vd in both the high-risk (26.8% vs 32.3%; P=0.18) and standard-risk groups (15.3% vs 36.0%; P=0.0003).

Conclusions: These prespecified subgroup analyses from the BOSTON study demonstrate that despite utilizing 40% less bortezomib and 25% less dexamethasone during the first 24-weeks of treatment, SVd is superior to Vd in patients with MM including high-risk patients. The PFS benefit was particularly notable in patients with del(17p), t(4;14) and amp(1q21) abnormalities. The ORR was comparable between the high-risk and standard-risk groups in the SVd arm. These data support the use of selinexor, with its novel mechanism of action, in the treatment of patients with early relapsed MM, including those with high risk cytogenetic abnormalities.