TO THE EDITOR:
There is no current established standard-of-care for patients with relapsed/refractory light chain (AL) amyloidosis. Although the introduction of daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone 1 as frontline therapy has significantly improved outcomes, a subset of patients fail to achieve adequate responses or relapse, posing a therapeutic challenge.
Given the demonstrated efficacy of chimeric antigen receptor T-cell (CAR-T) therapy, particularly in multiple myeloma (MM), 2 , 3 their potential application in AL amyloidosis is under active investigation. However, organ dysfunction, especially cardiac and renal, frequently precludes trial eligibility, limiting available data.
In this real-world study, we describe the clinical course of patients with systemic AL amyloidosis who underwent CAR-T therapy. The primary objective was to evaluate the safety and efficacy of this approach in a high-risk patient population.
We retrospectively identified 9 patients with histologically confirmed systemic AL amyloidosis who underwent commercial B-cell maturation antigen (BCMA)–directed CAR-T therapy at Mayo Clinic between 1 March 2021 and 31 March 2025. We included 2 patients previously reported by Das et al 4 with updated follow-up and 1 who underwent CAR-T therapy externally. The study was approved by the institutional review board. AL amyloidosis was confirmed via tissue biopsy with Congo red staining and amyloid typing using mass spectrometry. Four additional patients with amyloid limited to the bone marrow and/or fat pad were excluded.
Cardiac 5 and renal involvement 6 were staged according to established criteria. Hematologic 7 and organ responses 8 were evaluated using consensus definitions for AL amyloidosis.
All patients received lymphodepleting (LD) chemotherapy with cyclophosphamide and fludarabine; fludarabine dosing was attenuated for patients with impaired renal function as per institutional practice. Bridging therapy, when used, was discontinued at least 14 days before LD. Three patients (33%) received idecabtagene vicleucel, and 6 (67%) received ciltacabtagene autoleucel. Adverse events were graded according to common terminology criteria for adverse events (CTCAE) version 5.0. 9 Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome were graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria. 10
Patient characteristics are summarized in Table 1 . The median age at CAR-T infusion was 70 years. Concurrent MM, defined by the presence of hypercalcemia, renal dysfunction, anemia, bone disease (CRAB) criteria, was present in 5 patients (56%). Table 1. Baseline characteristics of patients with AL amyloidosis receiving BCMA-directed CAR-T therapy Variables All (N = 9) Ide-cel (n = 3) Cilta-cel (n = 6) Sex , n (%) Male 4 (44) 1 (33) 3 (50) Female 5 (56) 2 (67) 3 (50) Age ∗ , median (range), y 70 (33-78) 72 (61-78) 67 (33-71) ECOG ∗ , n (%) 0 2 (22) 0 2 (33) 1 6 (67) 3 (100) 3 (50) 2 1 (11) 0 1 (17) dFLC ∗ , median (range), mg/L 120 (59-787) 329 (9-457) 60 (0-1170) Involved organs at diagnosis, n (%) Heart 8 (89) 3 (100) 5 (83) Kidney 5 (56) 1 (33) 4 (67) Gastrointestinal tract 2 (22) 0 2 (33) Peripheral nervous system 2 (22) 1 (33) 1 (17) Autonomic nervous system 1 (11) 0 1 (17) Musculoskeletal 1 (11) 0 1 (17) Mayo 2004 (European mod) stage ∗ , n (%) 1 1 (11) 1 (33) 0 2 3 (33) 2 (67) 1 (17) 3a 4 (44) 0 4 (67) 3b 0 0 0 Renal Stage ∗ , n (%) 1 1 (11) 0 1 (17) 2 3 (33) 1 (33) 2 (33) 3 1 (11) 0 1 (17) eGFR ∗ before CAR-T, median (range), mL/min per 1.72 m 2 54 (15-90) 52 (15-90) 55 (32-77) Concomitant MM, n (%) MM by PC only 0 0 0 MM by CRAB criteria 5 (56) 1 (33) 4 (67) Bone marrow plasma cells ∗ , median (range), % 7 (0-90) 10 (10) 3 (0-90) t(11;14), n (%) 1 (11) 0 1 (11) Number of prior lines of therapy, median (range) 5 (3-11) 8 (4-11) 5 (4-7) Triple class, n (%) Exposed 1 (11) 0 1 (17) Refractory 7 (78) 3 (100) 4 (67) Penta drug, n (%) Exposed 1 (11) 1 (33) 0 Refractory 2 (22) 1 (33) 1 (17) Time from diagnosis to CAR-T, median (range), y 7 (3-11) 9 (8-11) 6 (3-7) Bridging therapy, n (%) 7 (78) 1 (33) 6 (100) Data are represented for the entire cohort (N = 9) and stratified by CAR-T product (ide-cel, n = 3; cilta-cel, n = 6). cilta-cel, ciltacabtagene autoleucel; CRAB, hypercalcemia, renal dysfunction, anemia, bone disease; ECOG, Eastern Cooperative Oncology Group; dFLC, difference between involved and noninvolved free ALs; eGFR, estimated glomerular filtration rate; ide-cel, idecabtagene vicleucel; MM, multiple myeloma; PC, plasma cells. ∗ Before CAR-T therapy.
Table 1.
Baseline characteristics of patients with AL amyloidosis receiving BCMA-directed CAR-T therapy
Data are represented for the entire cohort (N = 9) and stratified by CAR-T product (ide-cel, n = 3; cilta-cel, n = 6). cilta-cel, ciltacabtagene autoleucel; CRAB, hypercalcemia, renal dysfunction, anemia, bone disease; ECOG, Eastern Cooperative Oncology Group; dFLC, difference between involved and noninvolved free ALs; eGFR, estimated glomerular filtration rate; ide-cel, idecabtagene vicleucel; MM, multiple myeloma; PC, plasma cells.
∗ Before CAR-T therapy.
| Variables | All (N = 9) | Ide-cel (n = 3) | Cilta-cel (n = 6) |
| Sex , n (%) | |||
| Male | 4 (44) | 1 (33) | 3 (50) |
| Female | 5 (56) | 2 (67) | 3 (50) |
| Age ∗ , median (range), y | 70 (33-78) | 72 (61-78) | 67 (33-71) |
| ECOG ∗ , n (%) | |||
| 0 | 2 (22) | 0 | 2 (33) |
| 1 | 6 (67) | 3 (100) | 3 (50) |
| 2 | 1 (11) | 0 | 1 (17) |
| dFLC ∗ , median (range), mg/L | 120 (59-787) | 329 (9-457) | 60 (0-1170) |
| Involved organs at diagnosis, n (%) | |||
| Heart | 8 (89) | 3 (100) | 5 (83) |
| Kidney | 5 (56) | 1 (33) | 4 (67) |
| Gastrointestinal tract | 2 (22) | 0 | 2 (33) |
| Peripheral nervous system | 2 (22) | 1 (33) | 1 (17) |
| Autonomic nervous system | 1 (11) | 0 | 1 (17) |
| Musculoskeletal | 1 (11) | 0 | 1 (17) |
| Mayo 2004 (European mod) stage ∗ , n (%) | |||
| 1 | 1 (11) | 1 (33) | 0 |
| 2 | 3 (33) | 2 (67) | 1 (17) |
| 3a | 4 (44) | 0 | 4 (67) |
| 3b | 0 | 0 | 0 |
| Renal Stage ∗ , n (%) | |||
| 1 | 1 (11) | 0 | 1 (17) |
| 2 | 3 (33) | 1 (33) | 2 (33) |
| 3 | 1 (11) | 0 | 1 (17) |
| eGFR ∗ before CAR-T, median (range), mL/min per 1.72 m 2 | 54 (15-90) | 52 (15-90) | 55 (32-77) |
| Concomitant MM, n (%) | |||
| MM by PC only | 0 | 0 | 0 |
| MM by CRAB criteria | 5 (56) | 1 (33) | 4 (67) |
| Bone marrow plasma cells ∗ , median (range), % | 7 (0-90) | 10 (10) | 3 (0-90) |
| t(11;14), n (%) | 1 (11) | 0 | 1 (11) |
| Number of prior lines of therapy, median (range) | 5 (3-11) | 8 (4-11) | 5 (4-7) |
| Triple class, n (%) | |||
| Exposed | 1 (11) | 0 | 1 (17) |
| Refractory | 7 (78) | 3 (100) | 4 (67) |
| Penta drug, n (%) | |||
| Exposed | 1 (11) | 1 (33) | 0 |
| Refractory | 2 (22) | 1 (33) | 1 (17) |
| Time from diagnosis to CAR-T, median (range), y | 7 (3-11) | 9 (8-11) | 6 (3-7) |
| Bridging therapy, n (%) | 7 (78) | 1 (33) | 6 (100) |
Cardiac involvement was present in 8 patients (89%) at diagnosis. Seven patients (78%) had cardiac involvement at the time of CAR-T underwent, with Mayo 2004 (European modification) cardiac staging as follows: stage 1 (n = 1), stage 2 (n = 3), and stage 3a (n = 4). At the time of CAR-T, the median troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were 0.034 μg/L (range, 0.021-0.530) and 2008 pg/mL (range, 389-8831), respectively.
Renal involvement was present in 5 patients (56%) at diagnosis (median 24-hour urine protein, 1690 mg [range, 396-3799]) and 4 patients (44%) at the time of CAR-T. At CAR-T infusion, renal staging was as follows: stage 1 (n = 1), stage 2 (n = 3), and stage 3 (n = 1). The median estimated glomerular filtration rate was 39 mL/min per 1.73 m 2 (range, 15-77), and the median 24-hour urine protein was 400 mg (range, 107-887) before CAR-T.
Patients received a median of 5 prior lines of therapy (range, 3-11); 7 patients (78%) were triple-class refractory, 2 (22%) were penta-drug refractory, and 7 had previous autologous stem cell transplant. None had received prior T-cell–redirecting agents or BCMA-targeted therapies. Bridging therapy was administered to 7 patients (78%).
Infections were observed in 3 patients between days –4 and +14 of CAR-T infusion ( Figure 1 ). Two developed bacteremia, including patient 1 who also developed immune effector cell–associated hemophagocytic syndrome (IEC-HS). Patient 7, who tested positive for coronavirus disease 2019 on day –4, experienced supraventricular tachycardia on days –1 and +7, likely related to underlying cardiac amyloidosis and triggered by the concurrent viral infection. This was managed conservatively with beta-blockers. Figure 1. Swimmer plot depicting hematologic and organ responses, adverse events, and follow-up after CAR-T infusion. Each horizontal bar represents an individual patient, with time (days) from CAR-T infusion shown on the x-axis. At a median follow-up of 19 months (range, 0-28), no relapses or deaths have occurred.
Early immune effector cell–associated hematotoxicity was observed in 6 patients (grade 1, n = 5; grade 2, n = 1) and late immune effector cell–associated hematotoxicity in 4 (grade 1, n = 2; grade 2, n = 1; and grade 3, n = 1). Grade ≥3 anemia and thrombocytopenia were observed in 6 (67%) and 5 patients (56%), respectively. The median duration of grade 4 neutropenia (absolute neutrophil count <500/μL) within the first 30 days was 4 days (range, 0-9). Two patients received filgrastim for neutropenia, including patient 1, who also received romiplostim for prolonged thrombocytopenia ( supplemental Table 1 ).
CRS occurred in 8 patients (89%; grade 3, n = 2) and IEC-HS in 1. All cases of CRS and IEC-HS resolved with supportive care. Six patients received tocilizumab, 5 received corticosteroids, and patient 1 required combination therapy with tocilizumab, dexamethasone, anakinra, siltuximab, and basiliximab for IEC-HS.
Patient 3 experienced delayed neurotoxicity on day +56, manifesting as diplopia with cranial nerve (CN) VI palsy after grade 3 CRS and a peak absolute lymphocyte count of 6.53 × 10 9 /L. No patients developed immune effector cell–associated neurotoxicity syndrome, immune effector cell–associated enterocolitis, secondary malignancies, or clinically significant deterioration in AL-related organ function.
Of the 8 patients evaluable for hematologic response, 6 achieved an amyloidosis hematologic complete response (CR), and one achieved a very good partial response (VGPR) (involved free light chain [FLC] <10 mg/L with mass-fix positive). The median time to best hematologic response was 31 days (range, 26-138; Figure 1 ). Minimal residual disease negativity at a sensitivity of 10 −5 by flow cytometry was achieved in 8 of 9 patients at a median of 29 days (range, 26-103); 1 patient did not undergo bone marrow assessment.
Of the 3 patients evaluable for cardiac response, 1 achieved a CR, 1 VGPR, and 1 partial response (PR), with a median time to best cardiac response of 9.2 months (range, 0.9-20). Of the 2 evaluable for renal response: 1 achieved CR and the other, PR. At a median follow-up of 19 months (range, 0-28; idecabtagene vicleucel, 19 months [range, 4-22]; ciltacabtagene autoleucel, 6 months [range, 0-28]), no relapses or deaths have occurred ( supplemental Table 1 ). The median progression-free survival and overall survival (OS) were not reached, and the 1-year progression-free survival and OS were both 100%.
In this real-world cohort, commercial BCMA CAR-T was associated with encouraging hematologic response rates and a manageable safety profile in patients with systemic AL amyloidosis, including those with advanced cardiac involvement. These findings are comparable to the safety and efficacy profiles in previous retrospective studies, 4 , 11 , 12 and prospective clinical trials with academic BCMA CAR-T (HBI0101 also known as NXC-201) 13 , which has reported mainly low-grade CRS and rapid hematologic responses in all participants. 14 However, the interpretation of organ responses in AL amyloidosis is limited by both the small sample size and high proportion of patients with concomitant MM.
In our cohort, patient 1, with 90% bone marrow plasma cell involvement at LD, developed IEC-HS, whereas patient 3 experienced delayed IEC-CN palsy after grade 3 CRS and a high peak absolute lymphocyte count (≥3 × 10 9 /L). Both had AL amyloidosis with concomitant MM. Compared to our institutional CAR-T cohort of patients with MM, the rates of IEC-HS (AL, 11.1%; MM, 7/197 [3.5%]; unpublished) and IEC-CN palsy (AL, 11.1%; MM, 5.1% 15 ) were not significantly different. These complications may be mitigated through optimized bridging to reduce disease burden and early interventions, such as corticosteroids, to control CAR-T expansion. 16
In their prospective clinical trial of 16 patients with AL amyloidosis, Lebel et al 13 reported encouraging hematologic and organ responses using HB10101 anti-BCMA CAR-T; however, their median response duration was 9.6 months, and the median OS was 10.1 months, reflecting the heterogeneity of the patient cohort (proportion with advanced [stage 3a/3b] cardiac involvement being higher in the trial), differences in the CAR-T construct used, and the small sample size. These observations suggest that earlier intervention, before irreversible organ dysfunction, may warrant consideration.
Additionally, the lower BCMA expression in AL plasma cells highlights the need for novel strategies, including alternative or dual-targeting approaches, such as BCMA/CD19 CAR-T constructs (ClinicalTrials.gov identifiers: NCT05263817 and NCT05978661 ), to improve efficacy in relapsed/refractory AL amyloidosis. Although preliminary, our findings contribute to the growing body of evidence supporting the feasibility, safety, and therapeutic potential of CAR-T therapy in this high-risk population with great unmet need.
Conflict-of-interest disclosure: R.P. reports advisory board role for Sanofi and AstraZeneca; and research funding from Bristol Myers Squibb (BMS) Foundation and GlaxoSmithKline. T.K. reports research funding from Novartis. E.M. reports consultancy fees from Protego. P.K. reports honoraria from Pharmacyclics, Sanofi, BeiGene, MustangBio, AstraZeneca, and AbbVie; consulting or advisory role fees from Sanofi; and research funding from Amgen, Takeda, Sanofi, AbbVie, GlaxoSmithKline, and Sorrento Therapeutics. D.D. reports consulting or advisory role fees from Alexion Pharmaceuticals, Apellis Pharmaceuticals, BMS, Johnson & Johnson Innovative Medicine, Legend Biotech, Novartis, and Sanofi; and research funding from K36 Therapeutics (institutional), Karyopharm Therapeutics, Regeneron, Ichnos Sciences, and BMS/Celgene. S.C. reports honoraria from Sanofi, Ascentage Pharma, Sobi, Legend Biotech, Pfizer, and BMS; and research funding from Johnson & Johnson, Takeda, C4 Therapeutics, AbbVie, Ascentage Pharma, and AstraZeneca. R.F. reports consultancy fees from AbbVie, Adaptive Biotechnologies, Amgen, Apple, BMS/Celgene, GSK, Janssen, Karyopharm, Pfizer, RA Capital, Regeneron, and Sanofi; scientific advisory board fees from Caris Life Sciences; membership in an entity’s board of directors for Antengene; and a patent for fluorescence in situ hybridization in multiple myeloma. V.R. reports honoraria from Research To Practice and Medscape; and receives authorship royalties from UpToDate. S.K. reports consulting or advisory role fees from Takeda (institutional), Janssen Oncology (institutional), Genentech/Roche (institutional), AbbVie (institutional), BMS/Celgene (institutional), Pfizer (institutional), Regeneron (institutional), Sanofi (institutional), and K36 Therapeutics (institutional); research funding from Takeda (institutional), AbbVie (institutional), Novartis (institutional), Sanofi (institutional), Janssen Oncology (institutional), MedImmune (institutional), Roche/Genentech (institutional), CARsgen Therapeutics (institutional), Allogene Therapeutics (institutional), GlaxoSmithKline (institutional), Regeneron (institutional), and BMS/Celgene (institutional); and support for travel, accommodations, and expenses from AbbVie and Pfizer. M.G. reports honoraria from Celgene, Med Learning Group, Research to Practice, Prothena, Apellis Pharmaceuticals, Amgen, AbbVie, Akcea Therapeutics, Sanofi, Telix Pharmaceuticals, Janssen Oncology, Juno/Celgene, and Alnylam Pharmaceuticals; consulting or advisory role fees from Prothena and BMS/Sanofi; and support for travel, accommodations, and expenses from Prothena, Celgene, and Novartis. Y.L. reports consultancy fees and research funding from bluebird bio, Celgene, Janssen, and Kite; consultancy fees from Gamida Cell, Novartis, Juno, Legend, Sorrento, and Vineti; research funding from Merck, Takeda, Kite, Merck, Novartis, Roche, and Sanofi; membership on an entity’s board of directors or advisory committees for AbbVie, Celgene, Janssen, Takeda, Adaptive, and MedImmune/AstraZeneca; and a role on an independent review committee for Oncopeptides. A.D. reports advisory board and independent review committee fees from Janssen; research funding from Alnylam Pharmaceuticals, Pfizer, Takeda, BMS, and AbbVie; and scientific advisory board fees from HaemaLogiX. The remaining authors declare no competing financial interests.
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Supplementary Material
Supplemental Table
Contribution: M.S.Y.T. and A.D. contributed to conceptualization, data curation, and formal analysis, and wrote the original draft; R.W., R.P., E.M., T.K., F.B., W.G., J.C., P.K., S.H., D.D., M.B., T.S., N.L., V.R., S.C., E.W.-N., R.F., N.A., S.V.R., S.K.K., M.G., and Y.L. contributed resources and reviewed and edited the manuscript; and all authors made substantial contributions to the acquisition of data, critically revised the manuscript, and approved the final manuscript.
The data that support the findings of this study are available from the corresponding author, Angela Dispenzieri ( dispenzieri.angela@mayo.edu ), on request. Deidentified patient data access will be shared with qualified researchers after approval of a written proposal and data use agreement.
The full-text version of this article contains a data supplement.