(069) Isatuximab Adverse Event Monitoring: A Safety Meta-Analysis of Randomized Controlled Trials and Refining Signals through Pharmacovigilance Analysis

Background: Isatuximab, an IgG1 monoclonal antibody targeting a distinct CD38 epitope, has garnered approval for treating relapsed/refractory multiple myeloma (RRMM) patients who have undergone at least two prior therapies. Despite its established efficacy, lingering concerns surround the long-term safety profile of isatuximab in broader patient populations, fuelled by sparse data on infrequent and delayed adverse events (AEs)

Objectives: The objective of the study was to enhance the understanding of isatuximab's safety profile in patients with RRMM by amalgamating information from randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS)

Methods: We systematically reviewed RCTs reporting safety outcomes of isatuximab in RRMM patients of any gender, either monotherapy or in combination, applying advanced search on databases like PubMed, EMBASE, and ClinicalTrial.gov. The quality assessment was done using the Cochrane Risk of Bias Tool. We utilized a random effect meta-analysis to calculate risk ratio (RR) with 95% confidence intervals (CI). The Open Vigil 2.1 MedDRAv24 was used to search the FAERS database, with data available until September 2023. Disproportionality was assessed using the proportional reporting ratio and reporting odds ratio. Signal refinement was performed by confining the drug roles to 'primary suspect' status. Furthermore, we stratified the analysis by sex and age categories. The study protocol for meta-analysis was registered with PROSPERO; CRD42022379632.

Results: In the safety meta-analysis, three RCTs with available AEs were examined. Among them, a total of 1135 AEs were linked with the isatuximab group, with 58% classified as grade three or higher. Isatuximab was found to significantly elevate the risk of upper respiratory tract infections (RR = 1.56, 95% CI: 1.18 – 2.07, p = 0.0019), bronchitis (RR = 2.20, 95% CI: 1.47 – 3.29, p-value = 0.0001), thrombocytopenia (RR = 1.07, 95% CI: 1.01 – 1.14, p = 0.0134), thrombocytopenia of grade three or higher (RR = 1.30, 95% CI: 1.03 – 1.64, p = 0.0231), and neutropenia of grade three or higher (RR = 2.13, 95% CI: 1.12 – 4.03, p = 0.0207) compared to the control group. In the FAERS, a total of 1853 patients were reported to have experienced AEs associated with isatuximab. Significant signal scores were identified in hematological, respiratory, and renal disorders. These associations persisted even after refining and stratification.

Conclusions: The findings of the current study represent an important advancement in updating and refining the safety profile of isatuximab during the post-marketing period, assisting in risk evaluation and mitigation for the best possible patient health care.