Validation of prototype biomarkers to identify risk factors of inflammatory adverse events (iAEs) following idecabtagene vicleucel (ide-cel) infusion in patients with relapsed and refractory multiple myeloma (RRMM) in KarMMa-3

• Published in: Journal of clinical oncology Vol. 42; no. 16_suppl; p. 7529
• Main Authors: Sengupta, Sanhita, Takhar, Mandeep, Lin, Yi, Manier, Salomon, Baz, Rachid C., Juluri, Krishna Rangadhamarao, Kaeding, Allison, Mashadi-Hossein, Afshin, Piasecki, Julia, Campbell, Timothy Brandon, Kaiser, Shari, Rytlewski, Julie, Shamsuzzaman, Md, Martin, Nathan
• Format: Journal Article
• Language: English
• Published: American Society of Clinical Oncology 01.06.2024
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2024.42.16_suppl.7529

7529Background: iAEs, such as cytokine release syndrome (CRS) and macrophage activation syndrome (MAS), can occur after infusion of chimeric antigen receptor T cell therapies such as ide-cel, but are typically low-grade and manageable with tocilizumab and corticosteroids. Although high-grade iAEs are rare with ide-cel, identification of patients at increased risk may improve management and remains an unmet need. Three composite biomarkers (multivariate models) of iAE risk were previously developed in a discovery cohort from the KarMMa and KarMMa-2 studies of ide-cel in RRMM (Mashadi-Hossein A, et al. J Clin Oncol 2023;41(16_suppl):e20005). Here, we validate these 3 prototype models for risk of developing high-grade iAEs after ide-cel infusion. Methods: Two models used pretreatment patient and routine clinical laboratory parameters; the third model also included change in 6 exploratory cytokines from baseline to 1 day following ide-cel infusion. To validate, each model was retrospectively applied to KarMMa-3 (NCT03651128) data in a blinded fashion, and sensitivity and specificity to identify grade ≥3 CRS and any-grade MAS were determined. Model performance thresholds used for sensitivity and specificity were 90% and 50%, respectively. Performance for identifying grade 2 CRS was also analyzed post hoc. Results: The first and simplest model comprised a manual algorithm with 7 features; it identified patients with grade ≥3 CRS or MAS with 85% sensitivity and 60% specificity. The second model comprised 19 routinely measured pretreatment features; it identified grade ≥3 CRS with 91% sensitivity and 59% specificity, and any-grade MAS with 60% sensitivity and 88% specificity. The third and most complex model comprised 7 pretreatment clinical features and 6 exploratory cytokines; it identified grade ≥3 CRS with 100% sensitivity and 51% specificity, and any-grade MAS with 100% sensitivity and 81% specificity. None of the models identified grade ≥2 CRS with passable sensitivity or specificity. Clustering analyses across all features showed that only a subset of grade 2 CRS cases was within the previously identified high-risk iAE cluster while the remaining grade 2 CRS cases were spread across other clusters. Conclusions: Two of the 3 composite biomarkers met validation criteria for grade ≥3 CRS risk. Criteria were not met for grade 2 CRS, suggesting these models are specific to higher-grade events and that grade 2 CRS represents a more heterogeneous group of patients. While high-grade iAEs are rare with ide-cel, these models may further optimize the robust benefit-risk profile that ide-cel has demonstrated by helping identify, prior to or shortly after infusion, patients most at risk for severe events. Clinical trial information: NCT03651128.