There is a strong correlation between ex vivo sensitivity of primary multiple myeloma (MM) cells to T-cell engaging bispecific antibodies teclistamab and talquetamab, indicating that these bispecific antibodies have shared response and resistance mechanisms, according to data presented at the European Hematology Association (EHA) 2024 Congress.
“T-cell redirecting therapies are changing the treatment landscape for MM agents,” said study presenter Christie Verkleij, a PhD student and hematologist in training at Amsterdam UMC in The Netherlands.
“Bispecific antibodies have shown deep and durable responses in patients with MM already heavily pretreated, but unfortunately we don’t know much about primary resistance and relapse after initial response,” Ms. Verkleij said. “Teclistamab and talquetamab share a similar structure and are similar in targeting the CD3 biding domain but differ in the tumor association antigen binding domain. Up until now it is unclear whether bispecifics targeting different tumor antigens have shared determinants of response.”
In this study, Ms. Verkleij and colleagues evaluated the sensitivity of MM cells to teclistamab and talquetamab in bone marrow samples from 41 patients with MM.
The bone marrow samples from bispecific antibody-naïve patients contained tumor cells but also effector cells and immune effector cells. Bispecific antibody activity was markedly heterogeneous among patient samples, Ms. Verkleij noted. However, there was strong correlation between teclistamab-induced cell lysis and talquetamab-induced cell lysis.
In patients with poor ex vivo response to bispecific antibodies, patients’ LDH levels were significantly higher, as was the proportion of regulatory T cells. T cell-to-MM cell ratio — or effector-to-target ratio — was significantly higher in samples from patients who responded very well to both bispecific antibodies.
The study also evaluated the phenotype and functional characteristics of T cells in serial peripheral blood and bone marrow samples from 25 patients with MM before and after receipt of bispecific antibody therapy.
The researchers first looked at the effect of T-cell characteristics at baseline on response in these 25 patients treated with teclistmab or talquetamab in clinical studies.
“We found that the proportion of PD-1+ CD4+, CTLA4+ CD4+, CD38+ CD4+ T cells was significantly lower in responding patients, but we did not see this difference in the CD8 subset,” Ms. Verkleij said.
There was no significant difference at baseline in T-cell differentiation subsets. Although not statistically significant, poor responders had higher proportions of regulatory T cells compared with responders, which has also been shown in clinical trials.
Ex vivo experiments showed that increasing T cell-to-MM cell ratios by adding autologous T cells, or healthy-donor derived T cells, to bone marrow samples from poor responders enhanced sensitivity to bispecific antibodies. This indicated that when it comes to primary resistance, the T cell-to-MM cell ratio was an important driver of response, Ms. Verkleij said.
The researchers also conducted experiments to examine acquired resistance and found that T-cell dysfunction due to continuous T-cell activation plays a role. This finding could have implications for dosing schedules — less frequent administration of bispecific antibodies, for example — but also for possible combination therapies with checkpoint inhibitors or immunomodulatory drugs.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Verkleij C, O’Neill C, Broekmans M, et al. Impact of T-cell characteristics on response and resistance to T-cell redirecting bispecific antibodies in multiple myeloma. Abstract S192. Presented at the European Hematology Association (EHA) 2024 Congress; June 15, 2024; Madrid, Spain.
