ASH 2024 | Pre-treatment biomarkers associated with toxicity and responses in R/R myeloma treated with ide-cel

So yes, this analysis focuses on commercial idecabtagene vicleucel. It involves 108 patients who were treated at our center and consented to a biospecimen protocol. What we really wanted to do is identify factors that predispose to toxicity and durable responses, particularly the immediate toxicity, such as CRS and ICANS, but also to identify what factors associated with a durable response. 

So this was, as I mentioned, a biospecimen protocol. We looked at serum cytokines at different time points. We looked at peak CAR-T expansion and saw how that associated with toxicity and efficacy, as well as we did bone marrow biopsies, pre-unit for the patient, or pre-CAR T-cell therapy, to immune phenotype different immune sub-cells, T-cells, myeloid cells, and natural killer cells. We identified that we had a pretty high-risk population, so about a third of the patients have high plasma cell burden in their pre-CAR-T bone marrow biopsy. About a third of them had penta-refractory disease, and nearly 40% of the patients have high-risk cytogenetics. 

We essentially identified that what predisposed patients to getting grade 2 or more cytokine release syndrome was receiving a higher median CAR-T cell dose. And then, in terms of patients who had a higher risk for neurologic toxicity or any grade ICANS, those patients had more advanced disease, they had a higher plasma cell burden, triple-class refractoriness, and a higher baseline inflammatory state measured by clinical laboratory markers such as ferritin and serologic protein. We also identified cytokine elevations, particularly key elevations that are associated with higher grade toxicities, as well as some baseline elevations in terms of any grade ICANS. 

In terms of the bone marrow analysis, we identified that monocytic myeloid-derived suppressor cells did associate with reduced CAR-T expansion. In terms of durable responders, however, we identified that higher CD4-CD8 ratios and some central memory CD8-positive T-cells did appear to associate with a durable response. And then, as in the past or other studies, in patients with a high plasma cell burden, they do have a high proportion of pretreatment markers of T-cell exhaustion, which ultimately can lead to impaired activation, proliferation, and increased expression of inhibitory immune receptors, favoring to greater immune tolerance. So I think really in summary, we were able to identify some associations with some of these markers like tumor burden, baseline inflammation, cytokines, which are associated with peak expansion, ultimately durable response and an immune subset that’s also associated with CAR-T expansion response durability. And we really hope that the study at least provides some insights and some potential avenues for toxicity mitigation, as well as therapeutic optimization in patients who are deemed to be high risk for ide-cel and hopefully for other novel immunotherapies in the future.

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