Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial.

BACKGROUND: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. METHODS: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/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). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. FINDINGS: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. INTERPRETATION: 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. FUNDING: Karyopharm Therapeutics.

Racial differences in long-term outcomes after percutaneous coronary intervention with paclitaxel-eluting coronary stents.

OBJECTIVES: To assess the influence of race on long-term outcomes following percutaneous coronary intervention (PCI) with paclitaxel-eluting stents (PES). BACKGROUND: Data on the influence of race on long-term outcomes following PCI with drug-eluting stents are limited because of severe underrepresentation of minority populations in randomized trials. METHODS: We compared 5-year outcomes of 2,301 whites, 127 blacks, and 169 Asians treated with PES in the TAXUS IV, V, and ATLAS trials. Outcomes were adjusted using a propensity score logistic regression model with 1:4 matching. RESULTS: Blacks were more likely than whites to be female, have a history of hypertension, diabetes mellitus, congestive heart failure, and stroke, but were less likely to have prior coronary artery disease. Compared with whites, Asians were younger, more likely to be male, have stable angina, and left anterior descending disease, and less likely to have silent ischemia, previous coronary artery bypass surgery, prior coronary artery disease, diabetes mellitus, peripheral vascular disease, and to receive glycoprotein IIb/IIIa inhibitors. Despite higher antiplatelet compliance, the adjusted 5-year rates of myocardial infarction (15.4% vs. 5.4%, P < 0.001) and stent thrombosis (5.6% vs. 1.1%, P = 0.002) were higher in blacks than whites. Despite lower antiplatelet compliance, Asians had no differences in myocardial infarction and stent thrombosis compared with whites. Mortality and revascularization rates were similar between the three groups. CONCLUSIONS: The long-term risk of major thrombotic events after PCI with PES was higher in blacks, but not Asians, compared with whites. The mechanisms underlying these racial differences warrant further investigation.

Primary endpoint results of the EVOLVE trial: a randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent.

OBJECTIVES: This study sought to compare the safety and efficacy of 2 dose formulations of SYNERGY, a novel bioabsorbable polymer everolimus-eluting stent (EES) (Boston Scientific Corp., Natick, Massachusetts) compared with the durable polymer PROMUS Element EES (Boston Scientific Corp.). BACKGROUND: Durable polymer coatings on drug-eluting stents have been associated with chronic inflammation and impaired healing. Bioabsorbable polymer-coated drug-delivery systems may reduce the risk of late adverse events, including stent thrombosis, and thus the need for prolonged dual-antiplatelet therapy. METHODS: A total of 291 patients with a de novo lesion ≤28 mm in length, in a coronary artery of ≥2.25 to ≤3.5 mm diameter, were enrolled in the EVOLVE study, a prospective, randomized, single-blind, noninferiority trial. Patients were randomly assigned in a 1:1:1 ratio to PROMUS Element, SYNERGY, or SYNERGY half dose. The primary clinical endpoint was the 30-day rate of target lesion failure, defined as cardiac death or myocardial infarction related to the target vessel, or target lesion revascularization. The primary angiographic endpoint was 6-month in-stent late loss measured by quantitative coronary angiography. RESULTS: The 30-day primary clinical endpoint of target lesion failure occurred in 0%, 1.1%, and 3.1% of patients in the PROMUS Element, SYNERGY, and SYNERGY half dose groups, respectively. The 6-month in-stent late loss was 0.15 ± 0.34 mm for PROMUS Element, 0.10 ± 0.25 mm for SYNERGY, and 0.13 ± 0.26 mm for SYNERGY half dose (SYNERGY, difference -0.06, upper 95.2% confidence limit: 0.02, p for noninferiority <0.001; SYNERGY half dose, difference -0.03, upper 95.2% confidence limit: 0.05, p for noninferiority <0.001). Clinical event rates remained low and comparable between groups, with no stent thromboses in any group at 6 months. CONCLUSIONS: The EVOLVE trial confirms the effective delivery of everolimus by a unique directional bioabsorbable polymer system utilizing the SYNERGY stent. (A Prospective Randomized Multicenter Single-Blind Noninferiority Trial to Assess the Safety and Performance of the Evolution Everolimus-Eluting Monorail Coronary Stent System [Evolution Stent System] for the Treatment of a De Novo Atherosclerotic Lesion [EVOLVE]; NCT01135225).

Everolimus-eluting stents: update on current clinical studies.

Everolimus-eluting stents (EES) have become the most commonly implanted coronary stents worldwide. This review describes and analyzes the clinical data supporting the use of EES, focusing primarily on published, randomized, controlled trials. Everolimus-eluting stents have been shown to have less restenosis, stent thrombosis, and periprocedural myocardial infarction compared with earlier generation paclitaxel-eluting stents (PES). Lower rates of adverse events for EES compared with PES were generally seen in all subgroups, with the notable exception of patients with diabetes mellitus. There have been fewer, randomized, clinical trials comparing EES with either sirolimus-eluting stents or zotarolimus-eluting stents, although very good results with EES have been observed in the trials that have been performed. Recent clinical trial data suggest that this excellent safety and efficacy profile is maintained in a next-generation EES designed to have improved mechanical properties and radiopacity.

Influence of sex on long-term outcomes after percutaneous coronary intervention with the paclitaxel-eluting coronary stent: results of the "TAXUS Woman" analysis.

OBJECTIVES: We conducted the "TAXUS Woman" analysis to assess the influence of sex on long-term outcomes after percutaneous coronary intervention using paclitaxel-eluting stents (PES) in a broad spectrum of patients. BACKGROUND: Previous studies indicate that the sex gap suggesting worse outcomes in women has narrowed. However, limited data are available on long-term sex-based outcomes with drug-eluting stents despite their extensive use in current practice. METHODS: We analyzed 2,271 PES-treated patients (women = 665), from 5 randomized trials and 7,492 PES-treated patients (women = 2,449) from 2 "real-world" registries. The trial and registry datasets were stratified by sex to compare long-term outcomes. Additionally, the outcomes in PES-treated women were compared with bare-metal stent-treated women (n = 395) in the randomized trials. RESULTS: In the randomized trials, PES-treated women had a lower target lesion revascularization (TLR) rate (11.5% vs. 22.6%, p < 0.001) than bare-metal stent-treated women, with no significant sex-based differences in death, myocardial infarction, stent thrombosis, or TLR through 5 years. In both the trials and the registries, although women had more adverse baseline characteristics including advanced age, hypertension, and diabetes, they had similar outcomes to men. In expanded-use patients, however, women showed significantly higher rates of death and TLR, although only the higher TLR rate was confirmed by multivariate analysis. CONCLUSIONS: This study of nearly 10,000 patients including more than 3,000 women demonstrates that despite their higher-risk profile, women have comparable benefits to men from percutaneous coronary intervention with PES except for a slightly higher revascularization rate in the high-risk cohort.

Long-term paclitaxel-eluting stent outcomes in elderly patients.

BACKGROUND: Although drug-eluting stents have become a mainstay of percutaneous coronary intervention, information about drug-eluting stents outcomes in elderly patients is limited. Data from the paclitaxel-eluting stent (PES) trials and registries were pooled to assess PES benefits relative to advancing patient age, including comparison with bare-metal stents. METHODS AND RESULTS: Data from 5 randomized trials (2271 patients with PES, 1397 patients with bare-metal stents) and from 2 postmarket registries (7492 patients with PES) were pooled separately. Each dataset was stratified into age groups: <60, 60 to 70, and >70 years. At baseline, patients aged >70 years in both datasets had significantly more adverse characteristics than younger patients. Through 5 years, trial data showed that patients aged >70 years had higher death rates, but comparable rates of myocardial infarction, stent thrombosis, and target lesion revascularization with younger patients. Compared with patients with bare-metal stents, patients with PES aged >70 years had comparable rates of death, myocardial infarction, and stent thrombosis but a significantly lower target lesion revascularization rate (22.2 versus 10.2, P<0.001). These findings were echoed in the registry data through 2 years that showed that PES patients aged >70 years had significantly higher death rates, but lower myocardial infarction, stent thrombosis, and target lesion revascularization rates, compared with younger patients. Although the mortality rates of patients aged >70 years were higher than those of younger patients, they were comparable with those of age- and gender-matched norms in the general population. CONCLUSIONS: This analysis of almost 10 000 patients demonstrated that percutaneous coronary intervention with PES is a safe and an effective treatment option that should not be withheld based on age.