Comprehensive safety evaluation of isatuximab in multiple myeloma using disproportionality analysis of FAERS and meta-analysis of randomized controlled trials

Abstract

Isatuximab, an anti-CD38 monoclonal antibody, has been shown to induce apoptosis in multiple myeloma (MM) cells and is effective in both relapsed/refractory and newly diagnosed MM cases. This study aims to compare the safety profile of isatuximab by examining a broader range of adverse events (AEs) using data from the FDA Adverse Event Reporting System (FAERS) and a meta-analysis of randomized controlled trials (RCTs). The study analyzed FAERS data up to March 2024, identifying suspected AEs using Preferred Terms. Data extraction from FAERS was conducted using OpenVigil-2.1-MedDRA-v24. Disproportionality analysis was performed by calculating the proportional reporting ratio (PRR) with Chi-square value, and the reporting odds ratio (ROR) with a 95% confidence interval (CI). For the meta-analysis, safety outcomes of isatuximab in adult patients were reviewed from RCTs sourced from databases such as PubMed, EMBASE, and ClinicalTrials.gov, employing a random-effects meta-analysis to determine the risk ratio (RR) with 95% CI. The meta-analysis protocol was registered with PROSPERO (CRD42022379632). Based on the FAERS quarterly reports, a total of 2,325 AE reports were identified, with a higher incidence in men (n = 1156, 49.7%) compared to women (n = 960, 41.3%). AEs commonly observed with isatuximab therapy included neutropenia, pneumonia, infusion-related reactions, thrombocytopenia, acute kidney injury, and anemia. In our meta-analysis of three RCTs involving 1,258 patients, 659 (52.4%) in the isatuximab treatment group experienced 1,135 AEs, with 58% classified as grade three or higher. In comparison, 599 (47.6%) patients in the control group reported 906 AEs, with 59% categorized as grade three or higher. Notably, the isatuximab group showed a statistically significant increased risk of grade three or higher neutropenia (RR = 2.13, 95% CI: 1.12-4.03, p = 0.0207) and a 30% increased risk of grade 3 or higher thrombocytopenia (RR = 1.30, 95% CI: 1.03-1.64, p = 0.0244). Isatuximab therapy was generally well-tolerated and exhibited a manageable safety profile. Considering these findings, future research might benefit from longer follow-up periods to capture delayed and less frequent AEs.

Keywords: Adverse events; Disproportionality; Isatuximab; Meta-analysis; Multiple myeloma; Safety.

Fig. 1

PRISMA flowchart for the selection of studies in the meta-analysis.

Fig. 2

(a) The risk of neutropenia of all grades in the isatuximab group compared to the control group. (b) The risk of neutropenia of grades three or higher in the isatuximab group compared to the control group.

Fig. 3

(a) The risk of thrombocytopenia of all grades in the isatuximab group compared to the control group. (b) The risk of thrombocytopenia of grades three or higher in the isatuximab group compared to the control group.