ASH 2025 | The real-world safety and efficacy of bispecific T-cell engager therapy in systemic AL amyloidosis

I think the basis for this abstract is that we know that obtaining rapid, deep hematologic responses is key to improving organ function and survival outcomes in AL amyloidosis. Although we’ve seen the introduction of anti-CD38 monoclonal antibodies transform newly diagnosed amyloidosis, a significant proportion of patients will respond suboptimally to first-line therapy, that is not obtaining a complete response, and many others will relapse after obtaining an initial response. We’ve seen that bispecific T-cell engagers have produced unprecedented outcomes in relapsed myeloma, and so whether these highly active molecules can be safely applied to AL amyloidosis is a key clinical question. 

Because of this, we undertook a multicenter retrospective study across nine U.S. academic medical centers, which are a part of the U.S. Multiple Myeloma Immunotherapy Consortium. We included all patients with systemic AL amyloidosis who received a bispecific T-cell engager therapy targeting either the B-cell maturation antigen or the GPRC5D antigen. Between 2023 and 2025, we identified 29 patients who had received this therapy, including 19 patients who received teclistamab, 6 who had received elranatamab and 4 who had received talquetamab. 

We saw a predominance of lambda light chain isotype in 60% of individuals and about 30% of individuals had the translocation t(11;14). Our cohort had a high bone marrow plasma cell burden with 74% of cases having a plasma cell burden in excess of 10% at diagnosis of their AL amyloidosis, and 34% of patients having either more than 60% bone marrow plasma cells at diagnosis or a free light chain ratio in excess of 100. Our cohort was extensively treated with a median prior lines of 5, and all patients had seen an anti-CD38 monoclonal antibody. We had two cases who were stage 3A, according to the European modification of the Mayo 2004 prognostic score, and 19% of patients, or five patients, were stage 3B. 66% had cardiac involvement and 59% had renal involvement. 

In terms of tolerability, we saw that the rate of cytokine release syndrome of any grade was 45%; there were no grade 3 events. And we saw the rate of ICANS was 14% and again there were no Grade 3 events. A third of the cohort experienced at least one infection, and 20% of patients experienced a Grade 3 or higher infection. In terms of response rates, the overall response rate was 76% by AL amyloidosis response criteria, and the majority of these were deep responses, with 66% of patients obtaining a complete response, which is very impressive given how much prior treatment they had received. 

We saw that there were six deaths during the study period; three of these occurred while on TCE therapy. There was an episode of ventricular fibrillation arrest, which occurred during step-up dosing, but was not associated with cytokine release syndrome. There was also one death secondary to cardiac failure and one death secondary to an infectious complication. There were three deaths that occurred off therapy, one of unknown etiology, one from progressive disease, one as a complication of an unrelated surgery. In terms of organ responses, we saw that 64% of people with cardiac involvement obtained a cardiac response, and all patients with renal involvement who were available for assessment obtained a response. 

So this is actually the largest real-world cohort of bispecific T-cell engager therapy in AL amyloidosis. It shows that this approach to treatment produces a high rate of rapid and deep hematological responses. Despite a high prevalence of cardiac and renal involvement, actually rates of cytokine release syndrome were modest, and importantly, we did not see any grade 3 events. Nonetheless, infectious complications were frequent, including one death related to infection. I think, although we had a short period of follow-up, these high hematological responses translated to good organ responses, and it is encouraging that this therapy could be more broadly adapted in AL amyloidosis, and of course there’s a number of clinical trials that are exploring this question right now.

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