Administration of T-cell-engaging bispecific antibodies as bridging therapy before chimeric antigen receptor (CAR) T-cell therapy achieved excellent responses in patients with relapsed or refractory multiple myeloma (R/R MM), according to results of a study presented at the European Hematology Association 2024 Congress.
Patients who received bridging therapy with bispecific antibodies had the highest overall response rate (ORR) compared with the other evaluated bridging therapies, the study showed.
“Bridging therapy before CAR T-cell therapy is not standard in the clinic or in prospective studies,” said presenter David Fandrei of University Hospital Leipzig in Germany. “Our data warrant further investigation into whether it should be more standardized.”
In the last few years, several new immunotherapy options for patients with R/R MM have been developed, including two approved CAR T-cell therapies — ciltacabtagene autoleucel and idecabtagene vicleucel — and bispecific antibodies such as teclistamab, elaranatamab, and talquetamab.
“There are a lack of data justifying which of those options — CAR T-cell therapy or bispecific antibodies — should be used in earlier lines of therapy,” Mr. Fandrei told ASH Clinical News. “Our approach to this question was to evaluate bispecific antibodies as bridging therapy.”
Mr. Fandrei and colleagues retrospectively evaluated 52 patients with R/R MM treated with anti-B-cell maturation antigen (BCMA) CAR T-cell therapies and looked at response after bridging therapy and on day 30 after CAR T-cell re-infusion. Bridging therapies included teclistamab (n=5), talquetamab (n=5), chemotherapy (n=15), anti-CD38-based antibody (n=19), or anti-SLAMF7 based antibody (n=8).
The ORR to bridging therapy with bispecific antibodies was 100%, which was significantly higher than ORR with other regimens. Progression-free survival (PFS) was not significantly different between bridging regimens, which Mr. Fandrei said was likely the result of short follow-up and different risk profiles between patient groups.
“Use of bispecific antibodies was predominantly in patients with the highest-risk categories,” Mr. Fandrei said. “Nine out of 10 had high-risk cytogenetics.”
Immunophenotyping showed differential CAR-T expansion dynamics among patients who received bridging therapy with bispecific antibodies. There was a trend toward earlier expansion of CD4 CAR T cells and delayed expansion of CD8 CAR T cells.
The researchers also examined the role of bispecific antibodies on T-cell exhaustion and found that at leukapheresis there was a higher proportion of PD-1-positive cells in patients receiving bispecific antibodies. However, upon CAR T-cell infusion, there was a significant increase in PD-1 expression only in those who received conventional bridging therapies and not in those who received bispecific antibodies.
“We conclude that the short duration of bispecific antibodies as bridging therapy might mitigate the long-term effect of increased exhaustion that is seen in patients who receive it over a longer course of time,” Mr. Fandrei said.
One limitation of the study, Mr. Fandrei said, was the lack of difference in PFS between bridging therapies, which is likely because patients who bridged with bispecific antibodies were a higher-risk group.
One interesting research question for the future is whether it is favorable to switch the target antigen between bridging therapy and CAR T-cell therapy. For example, is it better to use the GPRC5D-targeting talquetamab or BCMA-targeting taclistamab before BCMA-directed CAR T-cell therapy?
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Fandrei D, Seiffert S, Rade M, et al. Sequential administration of bispecific antibodies and anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma is associated with expansion of CD8 effector clones and high response rates. Abstract S194. Presented at the European Hematology Association (EHA) 2024 Congress; June 13, 2024; Madrid, Spain.