As reported in The Lancet by Sebastian Grosicki, MD, of the Medical University of Silesia, Katowice, Poland, and colleagues, the phase III BOSTON trial has shown significantly prolonged progression-free survival with once-weekly selinexor plus bortezomib/dexamethasone vs twice-weekly bortezomib/dexamethasone in previously treated multiple myeloma.¹

Study Details

In the open-label trial, 402 patients from sites in 21 countries who had previously received one to three lines of therapy were randomly assigned between June 2017 and February 2019 to receive oral selinexor at 100 mg once per week, subcutaneous bortezomib at 1.3 mg/m² once per week, and oral dexamethasone at 20 mg twice per week (selinexor group; n = 195) or bortezomib at 1.3 mg/m² twice per week for the first 24 weeks and once per week thereafter and dexamethasone at 20 mg four times per week for the first 24 weeks and twice per week thereafter (control group; n = 207).

Sebastian Grosicki, MD

Randomization was stratified by previous proteasome inhibitor therapy, lines of treatment, and disease stage. All patients received antinausea treatment with 5-hydroxytryptamine (8 mg or equivalent) before the first dose of the study drug and two to three times daily on days 1 and 2 of each cycle, as needed. Patients with systemic light-chain amyloidosis, central nervous system involvement, or grade 2 painful or grade ≥ 2 peripheral neuropathy were excluded from the trial. Crossover to selinexor plus bortezomib/dexamethasone was permitted upon disease progression in the control group. The primary endpoint was progression-free survival as determined by an independent review committee in the intention-to-treat population.

For the selinexor vs control groups, median patient age was 66 vs 67 years (17% vs 23% ≥ 75 years) and 59% vs 56% were male. Eastern Cooperative Oncology Group performance status was 0 or 1 in 89% vs 92% and 2 in 10% vs 8%. Overall, 50% vs 46% had cytogenetic abnormalities consisting of del(17p), t(14;16), t(4;14), or 1q21 amplification. Revised International Staging System disease stage was I or II in 89% vs 86% and III in 6% vs 8%.

Progression-Free Survival

Median follow-up for progression-free survival was 13.2 months in the selinexor group and 16.5 months in the control group. Median progression-free survival was 13.93 months (95% confidence interval [CI] = 11.73 months to not evaluable) in the selinexor group vs 9.46 months (95% CI = 8.11–10.78 months) in the control group (hazard ratio [HR] = 0.70, 95% CI = 0.53–0.93, P = .0075).

Hazard ratios favored the selinexor group in the majority of subgroups evaluated. For stratification factors, hazard ratios were 0.81 (95% CI = 0.59–1.10) among patients with previous bortezomib treatment and 0.62 (95% CI = 0.24–1.60) among those with previous carfilzomib treatment; 0.63 (95% CI = 0.41–0.96), 0.65 (95% CI = 0.40–1.07), and 0.82 (95% CI = 0.45–1.48) among those with one, two, and three previous lines of treatment and 0.69 (95% CI = 0.48–1.01) among those with at least two lines; and 0.57 (95% CI = 0.42–0.77), 0.41 (95% CI = 0.22–0.75), 0.67 (95% CI = 0.47–0.95), and 1.28 (95% CI = 0.51–3.24) for disease stage I–II, I, II, and III at baseline.

In total, 69 patients in the selinexor group and 42 in the control group (excluding those who crossed over to receive selinexor plus bortezomib/dexamethasone) received subsequent treatment. Median progression-free survival after the first subsequent therapy was 6.60 months (95% CI = 5.39–9.43 months) vs 8.84 months (95% CI = 5.78 months to not evaluable).

Objective response was observed in 76.4% vs 62.3% of patients (odds ratio [OR] = 1.96, 95% CI = 1.3–3.1, P = .0012), with a very good partial response or better occurring in 44.6% vs 32.4% (OR = 1.66, P = .0082). The median duration of response was 20.3 months (95% CI = 12.5 months to not evaluable) vs 12.9 months (95% CI = 9.3–15.8 months; HR = 0.81, P = .1364).

Overall, 63 patients in the control group (30%) crossed over to selinexor plus bortezomib/dexamethasone treatment at disease progression. At the time of data cutoff, after median follow-up for overall survival of 17.3 months vs 17.5 months, death had occurred in 47 patients (24%) in the selinexor group vs 62 patients (30%) in the control group. Estimated median overall survival was not reached in the selinexor group vs 25 months (95% CI = 23.5 months to not evaluable) in the control group (HR = 0.84, 95% CI = 0.57–1.23, P = .1852).

Among the 63 patients who crossed over to selinexor plus bortezomib/dexamethasone, the objective response rate was 19.0%, with 3 patients (4.8%) having a very good partial response and 9 (14.3%) having a partial response. Median progression-free survival was 3.91 months (95% CI = 3.48–6.93 months). Among 31 patients who received subsequent therapy, median progression-free survival after the first subsequent therapy was 3.88 months (95% CI = 2.79 months to not evaluable).

Adverse Events

The most common grade 3 or 4 adverse events in the selinexor group were thrombocytopenia (39% vs 17% in the control group), anemia (16% vs 10%), fatigue (13% vs 1%), pneumonia (11% vs 11%), cataract (9% vs 1%), neutropenia (9% vs 3%), asthenia (8% vs 4%), and nausea (8% vs 0%). Peripheral neuropathy of grade ≥ 2 occurred in 21% vs 34% of patients (OR = 0.50, P = .0013). Serious adverse events occurred in 52% vs 38% of patients, with the most common in the selinexor group being pneumonia (12% vs 12%), diarrhea (4% vs 2%), and vomiting (4% vs 2%). Adverse events led to treatment discontinuation in 21% vs 16% of patients, with the most common causes in the selinexor group being peripheral neuropathy (5%), fatigue (4%), and nausea (3%). Death due to adverse events occurred in 12 patients (6%) in the selinexor group, with the most common causes being pneumonia in 3 (2%) and sepsis in 3 (2%), and in 11 patients (5%) in the control group; death in 4 patients in the selinexor group and 1 patient in the control group was considered related to treatment.

The investigators concluded: “A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy.” 

DISCLOSURE: The study was funded by Karyopharm Therapeutics. Dr. Grosicki reported no conflicts of interest.

REFERENCE

1. Grosicki S, Simonova M, Spicka I, et al: Once-per-week selinexor, bortezomib, and dexamethasone vs twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): A randomised, open-label, phase III trial. Lancet 396:1563-1573, 2020.