The real-world safety profile and potential mechanism of isatuximab: Integration of pharmacovigilance and...

Isatuximab, approved for the treatment of relapsed/refractory multiple myeloma in 2020, lacks sufficient long-term safety profile in real-world clinical practice. Leveraging the FDA adverse event reporting system over a 5-year period, this study conducted a comprehensive pharmacovigilance study integrating 4 disproportionality analyses to identify isatuximab-related adverse events. Data extraction and standardization from FAERS were conducted using R and MedDRA. Concurrently, transcriptomic profiling via single-sample Gene Set Enrichment Analysis (ssGSEA) of 50 hallmark gene sets elucidated potential immunological mechanisms. Among 1884 AE reports attributing isatuximab as the primary suspect, significant signals emerged across 25 system organ classes and 129 preferred terms, with high disproportionality for neutropenia, pneumonia, and kidney injury. Tumor lysis syndrome and hypoproteinemia were newly detected and unlisted on the drug label, while females demonstrated elevated urinary tract infection risk. Transcriptomically, the CD38-high group exhibited marked upregulation of immune activation such as interferon gamma response and metabolic stress pathways including fatty acid metabolism and apoptosis, suggesting a dual phenotype of immunosuppression and hyperinflammation that may predispose to infections and renal toxicity. By synergizing real-world pharmacovigilance with transcriptomic data, this study delineates novel clinical AE signals and mechanistic insights linking CD38-driven immunometabolic dysregulation to isatuximab toxicity. These findings underscore the imperative for vigilant monitoring and tailored therapeutic strategies to mitigate risks of immune dysfunction, informing both clinical practice and future biomarker-driven interventions.