Links to Early Responses in Multiple Myeloma Patients | Doris K Hansen, MD | ASH 2023

My name is Doris Hansen from Moffitt Cancer Center. Today I'll be discussing how pro-inflammatory state and peak cytokines are associated with toxicity in early response in patients receiving endocarpal gene recluse. So IDCell is a CAR T-cell therapy or BCMA that was FDA approved in 2021. And essentially in the study, it was demonstrated that higher P concentrations of inflammatory cytokines were associated with developing higher-grade cytokine release syndrome that no baseline associations were observed. And cytokines are essentially master regulators of the tumor microenvironment as they represent the main communication bridge between cancer cells, tumor stroma, and the immune system. So the purpose of our study was to study the association or the effect of cytokines in a pre-car T bone marrow composition with toxicity in response in patients receiving IDCell at Moffitt Cancer Center. So this was a retrospective analysis. The patients were consented to a biospecimen protocol. We measured a series of cytokines and inflammatory markers. For cytokines, we used the LA amino acid. Our cohort consisted of about 86 patients. One-third of these patients had high least features like they had high miscigenetics, they had a high plasma cell burden, which was defined as having more than 50% plasma cells in the bone marrow biopsy, pre-car T, and also had enterofractory disease. But also I'd like to point out that this population was different than the Karmic clinical trial in the sense that 72% of the patients would have been trial-ineligible. Safety profile is very similar as what we see in trial. We did see that patients who are 65 years or older were more likely to develop any-grade cytokine release syndrome and non-algae toxicity. We did have three deaths related to myeloma complications by day 90. We also looked at the association of serum cytokines with any-grade cytokine release syndrome and identified that higher P concentration of inflammatory cytokines were associated with developing cytokine release syndrome. For grade 2, it was only an association with higher concentration of intraleukin 6. For neurologic toxicity, we found some cytokine associations at baseline. So TNF alpha or TNF alpha is higher at aphoresis, while interleukin 15 and angiocortin 2 to 1 ratio were higher for patients who developed grade 2 or more neurologic toxicity at day 96. And higher P concentrations were observed for interleukin 6 and interleukin 15 and angiocortin 2 to 1 ratio for patients who developed grade 2 or more neurologic toxicity. We also observed that based on ferritin, it's higher for patients who develop neurologic toxicity of any-grade and grade 2 or more and P concentrations of CRP and ferritin were higher for those who developed CRS and neurologic toxicity. We also identified an association with ID cell response. In particular, patients who had higher concentrations of interleukin 2, GMCSF, tumor lacrosse factor alpha, interferon gamma were more likely to achieve a partial response or better with ID cell. This was consistent for best response rate as well as similar for complete response or better. We also found an association with cytokines and tumor burden or systemic inflammation. In particular, so patients who have a high tumor burden were more likely to experience systemic inflammation, as was noted by higher concentration of inflammatory cytokines, as well patients with higher baseline ferritin and peak ferritin. Those patients were more likely to have a high neuroburden or plasma cell burden. In a subset of patients, so 35% or 35 patients were able to perform a bone marrow biopsy pre-car T-terminal cell phenotype T cells, myeloid cells and natural killer cells. And essentially we were able to identify that in patients who have a high plasma cell burden, these patients were more likely to display markers of T cell and natural killer cell exhaustion. In particular, CD39 among CD4 and CD8 T cells and T-stomach lobe line item domain among CD4 T cells and higher expression of CD56 deminatural killer cells, which may lead to impaired activation, proliferation and regulation of inhibitory immune receptors. So in sum, high plasma cell burden is associated with systemic inflammation, which may lead to immune dysregulation, which may impact T cell function, fitness and ultimately car T product. In conclusion, the study demonstrated that cytokines and pre-car T bone marrow composition do appear to be associated with toxicity in response. And hopefully this provides some early insight into potential avenues for toxicity prevention and therapeutic optimization to improve efficacy and reduce redoxes. And certainly larger studies with larger amount of patients are following up on requiring to better understand the relationship between inflammation, immunity, toxicity and response. Thank you very much.