ASH 2025 | Evaluating the real-world safety and efficacy of BCMA-directed CAR-T in systemic AL amyloidosis

So, again, it’s paramount in AL amyloidosis to obtain a deep hematological response. This is the only way we presently have to permit organ recovery and improve mortality in this condition. While daratumumab has really transformed the management of newly diagnosed disease, it isn’t a complete cure for all patients, and a number of patients will either respond suboptimally or later relapse after treatment with this agent. We know that chimeric antigen receptor T-cell therapy, or CAR-T, is a highly active modality in multiple myeloma where it produces very deep and durable remissions, and so whether this strategy can be safely and effectively adopted in AL amyloidosis, a population where patients will often have concomitant organ dysfunction, is an important unanswered question. 

So to address this, we undertook a retrospective study of eight US academic medical centers who were a part of the US Multiple Myeloma Immunotherapy Consortium. We included patients who had a diagnosis of systemic AL amyloidosis who received BCMA-targeted CAR-T therapy. All of these patients, importantly, had a concurrent diagnosis of multiple myeloma. Between 2021 and 2025, we identified 33 patients who were treated with CAR-T. Nine patients received ide-cel, 24 patients received cilta-cel. 

The median age of our patients was 69 years. There was a predominance of the kappa light chain isotype, which I think reflects the fact that there was a myeloma flavor to a number of the patients involved. We also saw that all patients had a high plasma cell burden at diagnosis, 88% of individuals having more than 20% bone marrow plasma cells at their initial diagnosis. This cohort was extensively treated; the median number of prior lines was six, and all patients had had prior CD38 exposure. In terms of organ involvement, we saw 30% of patients had cardiac involvement, or again 30% had renal involvement, a quarter had gastrointestinal involvement, and around 12% had some form of nervous system involvement. Prior to CAR-T therapy, we had incomplete staging information, but we importantly did not have any known cases of stage 3b disease. 

In terms of cytokine release syndrome and safety, the rate of CRS of any grade was 64%. We saw only two cases of grade 3 CRS, no cases of grade 4 CRS. In terms of ICANS, the overall rate of any grade was 15% and there were only two cases of grade 3 ICANS. The rates of CRS were slightly higher with cilta-cel compared to ide-cel, as one might expect, at 67% versus 56%. The median time to CRS also differed between the two agents, at one day for ide-cel, but six days for cilta-cel. We did not see any cases of non-ICANS neurotoxicity, and we saw about 30% of individuals had an infection of any grade, but less than 10% of patients had a severe infection grade 3 or higher. 

The overall response rate according to AL amyloidosis criteria was 91 percent. The vast majority of these were either very good or complete responses – there were 24 complete responses. Again, these were comparable between the two agents although slightly higher cilta-cel, where the overall response rate was 96%, compared to ide-cel, where the overall response rate was 78%. In terms of deaths, there were five deaths, three which were related to the underlying disease, one related to an infection associated with IECHS, and one which was unrelated. In terms of organ response, we had seven patients who were eligible for cardiac organ assessment. Three of them obtained a cardiac response, and three patients were eligible for renal organ assessment; of those two obtained a response. 

So I think this study shows that commercial BCMA-targeted CAR-T therapy induces deep, rapid hematological responses in heavily pretreated patients with AL amyloidosis and concurrent multiple myeloma. This form of therapy was feasible to administer, the rates of CRS were acceptable, and there were only isolated severe cases of CRS and ICANS. Nearly all of our patients obtained a deep hematological response, and in the patients who were assessable for organ response, this appeared to translate into organ improvement.

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