Efficacy and Safety of Once‐Weekly versus Twice‐Weekly Bortezomib in Patients with Hematologic Malignancies: A Meta‐analysis with Trial Sequential Analysis

Abstract

STUDY OBJECTIVE To compare the efficacy and safety of once-weekly and twice-weekly bortezomib therapy in patients with hematologic malignancies. DESIGN Meta-analysis of 13 clinical or randomized controlled trials, with trial sequential analysis (TSA). PATIENTS A total of 1567 patients with hematologic malignancies who received either once-weekly or twice-weekly bortezomib therapy. MEASUREMENTS AND MAIN RESULTS We conducted a comprehensive literature search of the PubMed, EMBASE, and Cochrane Library databases. A meta-analysis was conducted to calculate the pooled effect size; TSA was performed to assess the reliability of the pooled results. The pooled risk ratio (RR) for the overall response rate (ORR) was 1.00 (95% confidence interval [CI] 0.77-1.29, p=0.99), indicating no significant differences between patients who received once-weekly bortezomib and those who received twice-weekly bortezomib. TSA showed that the cumulative Z-curve of the ORR entered the futility area, implying that reliable evidence was obtained for this pooled result. The pooled RR for any grade of peripheral neuropathy was 0.48 (95% CI 0.26-0.88, p=0.02); however, the TSA plot revealed that there was insufficient evidence for this result. The pooled RR for peripheral neuropathy grade 3 or higher was 0.21 (95% CI 0.13-0.34, p<0.00001), and reliable evidence was obtained according to TSA. Regarding the other toxicities, including anemia, thrombocytopenia, neutropenia, infection, diarrhea, constipation, nausea, vomiting, and fatigue, we did not find any significant differences between patients who received once-weekly bortezomib and those who received twice-weekly bortezomib. CONCLUSION Compared with twice-weekly bortezomib, once-weekly bortezomib had a comparable ORR and a probable lower incidence of peripheral neuropathy. More clinical trials are needed to draw a conclusion regarding the difference in peripheral neuropathy between the two groups because of the insufficient evidence detected by TSA and the inconsistent results among subgroups.

Outcomes with different administration schedules of bortezomib in bortezomib, lenalidomide and dexamethasone (VRd) as first‐line therapy in multiple myeloma

“…We found no difference in the frequency of grade 3 or 4 hematologic toxicities among the three treatment schedules, suggesting that timing of bortezomib administration may have less effect on incidence of hematologic adverse events. These findings are supported in a meta‐analysis of 13 trials by Hu et al which analyzed the efficacy and safety of once weekly vs twice weekly bortezomib among various hematologic malignancies, and found no difference in the emergence of non‐neurologic adverse events 20 . Regarding a contribution of lenalidomide to potentiating neurotoxicity, the median and modal dose for lenalidomide across all three treatment groups was consistent at the standard 25 mg.…”

“…It is difficult to ascertain the reason for increased depth of response among patients receiving treatment once weekly every 21 days, though the faster time to best response among patients receiving twice weekly bortezomib would certainly speak to the specific pharmacokinetics of bortezomib and timing of the reversible proteasome inhibition 22 . Though few other studies have analyzed once weekly vs the standard twice weekly administration of bortezomib, most report similar effectiveness between the two treatment schedules in terms of response rates and PFS 20,21,30,31 . In our study, instead of only analyzing once weekly vs twice weekly treatment schedules, we separately analyzed three different common treatment schedules (twice weekly every 21 days, once weekly every 21 days, and once weekly every 28 days), and therein may lie the differences in treatment responses emerging among the treatment groups.…”

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

“…3 However, the twiceweekly dosing regimen is associated with high rates of sensory, motor and autonomic neuropathy which can be irreversible and often limit prolonged use. [4][5][6] Exportin 1 (XPO1) is overexpressed in most cancer cells including MM and its levels are correlated with poor patient prognosis, resistance and aggressive disease. [7][8] XPO1 is an oncoprotein, 9 mediating the nuclear export and functional inactivation of the majority of tumour suppressor proteins and enhancing the translation of certain oncoproteins including Myc, Bcl-6, and cyclin D1.…”

The Actions and Mechanisms of P2X7R and p38 MAPK Activation in Mediating Bortezomib-Induced Neuropathic Pain

“…Proteasome inhibitors used for treating cancers have been identified to result in a significant higher risk for inducing sensory peripheral neuropathy [1]. Bortezomib (BTZ), a proteasome inhibitor, is a commonly used antitumor drug which has highly effective results on relieving cancer symptoms [2,3]. Bortezomib-induced peripheral neuropathy (BIPN) is a major and debilitating side effect with persistent exacerbation of neuropathic pain during anticancer therapy, which causes drug dose limitation or application discontinuation and worsens cancer prognosis [4].…”