The Safety and Efficacy of Commercial BCMA‐Directed CAR T‐Cell Therapy in Systemic AL Amyloidosis With Concurrent Myeloma

Light-chain (AL) amyloidosis is a rare and life-threatening plasma cell dyscrasia characterized by the production of immunoglobulin free light chains (FLCs) that misfold and deposit in vital organs, leading to organ failure 1. The mainstay of treatment is the suppression of amyloidogenic FLC production using anti-plasma cell therapy. Achieving a rapid and deep hematologic response is essential for improving organ function and reducing early-mortality 2. While daratumumab has transformed the management of newly-diagnosed disease, many daratumumab-treated patients will not obtain a complete response (CR) or will relapse 3, 4. Chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen (BCMA) is a highly active modality in multiple myeloma (MM), capable of inducing deep and durable remissions 5. Presently, two commercially approved CAR T-cell therapies exist in the United States (US), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Whether these treatments can be safely and effectively adopted in AL amyloidosis remains an important unanswered question. This multicenter retrospective study evaluated all patients with systemic AL amyloidosis and concurrent MM who received commercial BCMA-directed CAR T-cell therapy at eight US academic medical centers within the US MM Immunotherapy Consortium between 2021 and 2025. Five patients with isolated amyloid deposits limited to the bone marrow or fat without other organ involvement were excluded but have been reported previously 6. Each center obtained Institutional Review Board approval for participation. Cyclophosphamide and fludarabine were used for lymphodepletion in all but one patient, who received bendamustine due to renal impairment. Infectious disease prophylaxis, the use of growth colony-stimulating factor, treatment of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were according to institutional guidelines 7. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria 8. Other toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE), v5.0. Hematologic responses were defined according to consensus response criteria 2. Hematologic progression was defined as a dFLC increase > 10% from the value at diagnosis or > 15 mg/L from the best hematologic response; we also considered the commencement of any new anti-plasma cell therapy as a progression event 2, 9. Organ responses were defined according to the graded response criteria 10, and cardiac staging per the European-modification of the Mayo 2004 model 11. Measurable residual disease (MRD) was determined by next generation flow-cytometry or ClonoSeq from bone marrow (BM) aspirate with a minimum sensitivity of 10−5 nucleated cells as per each center's standard practice. Twenty-eight patients with AL amyloidosis and concurrent MM treated with CAR T-cell therapy were included: ide-cel (n = 8) and cilta-cel (n = 20). All patients who underwent leukapheresis received CAR T-cell infusion; there were no cases of manufacturing failure. Baseline patient, disease, and treatment characteristics are summarized in Table 1. The median age was 69 years (IQR: 61, 72). Cardiac and renal involvement were noted in 39% and 32% of patients, respectively; of patients with known cardiac staging prior to CAR T-cell infusion (n = 13), six had stage 3A but none had stage 3B disease. Most patients were kappa light-chain isotype (57%); 15% had the t(11;14) translocation. Although the diagnostic BM plasma cell (BMPC) burden was unknown in two cases, all patients had a concurrent diagnosis of MM (BMPCs ≥ 10%) and 23 patients had ≥ 1 myeloma-defining diagnostic feature. Five patients had previously received BCMA-directed therapy (n = 3 T-cell engagers, n = 2 antibody drug-conjugates). Twenty-two patients received bridging therapy following apheresis, detailed in Table S1. Of patients who received bridging therapy, two had a hematologic CR, six a partial response (PR), five stable disease, and eight progressive disease. Twenty-three patients had a BM performed prior to lymphodepletion with a median BMPC burden of 7% (IQR: 1, 20); two patients had ≥ 60% BMPCs. At the time of lymphodepletion, the median dFLC was 88.4 mg/L (IQR: 12.0, 278.5). CRS occurred in 64% of patients (Grade 1: n = 13, Grade 2: n = 4, Grade 3: n = 1), while ICANS was observed in 15% (Grade 1: n = 3, Grade 3: n = 1). The incidence of CRS was 62% for ide-cel (Grade 1: n = 3, Grade 2: n = 2) and 65% with cilta-cel (Grade 1: n = 10, Grade 2: n = 2, Grade 3: n = 1, Figure S1). The median time to CRS onset was 1-day for ide-cel and 6-days for cilta-cel. The median duration of CRS was 1-day for ide-cel (IQR: 1, 1) and 2-days for cilta-cel (IQR: 1, 3). Tocilizumab was administered to 39%, and steroids to 36% of patients. Any-grade CRS was numerically but not significantly higher among patients with versus without cardiac involvement, 73% vs. 58%, p = 0.5. Among four patients with ≥ 3 organs involved, all developed CRS (Grade 3: n = 1, Grade 2: n = 2, Grade 1: n = 1). One patient developed immune effector cell-associated hemophagocytic syndrome (IEC-HS); she had 90% BMPCs at lymphodepletion, gastrointestinal, soft-tissue, and cardiac involvement, and experienced a grade ≥ 3 infection. She was managed with steroids, tocilizumab, and anakinra. ICANS incidences were 12% for ide-cel (Grade 1: n = 1) and 15% for cilta-cel (Grade 1: n = 2, Grade 3: n = 1); no non-ICANS neurotoxicity occurred. Overall, infections were reported in 32% of patients (Grade ≥ 3: n = 2). Among patients with cardiac involvement (n = 11), 36% experienced infections (Grade ≥ 3: n = 2). Rates of grade ≥ 3 neutropenia, anemia, and thrombocytopenia at day-30 following CAR T-cell infusion were 25%, 11%, and 32%, respectively. Day-90 rates of hematologic toxicity, use of granulocyte-colony stimulating factors, thrombopoietin receptor agonists, and stem-cell boosts are provided (Table S2). A cilta-cel patient with isolated gastrointestinal amyloid received bendamustine lymphodepletion for renal impairment, experienced no CRS or ICANS, and achieved an MRD-negative CR. The overall response rate (ORR) by AL amyloidosis criteria was 93%, comprising five very good partial responses (VGPRs) and 20 CRs (Figure 1). The ORR for ide-cel was 75% (5 CRs, 1 VGPR) and for cilta-cel was 100% (15 CRs, 4 VGPRs, 1 PR). Among responders, the median time to a hematologic VGPR or better was 30 days (IQR: 29, 32). Fourteen patients had MRD assessment at 1 month post-infusion, of whom 12 (86%) were MRD negative (8 in CR and 4 in VGPR). Of seven patients eligible for cardiac response assessment at the time of CAR T elevated B-type natriuretic peptide (BNP) > 150 ng/L or N-terminal pro-BNP > 650 ng/L, three obtained a response (Cardiac PR, n = 1; Cardiac VGPR, n = 2). By the Kaplan–Meier method, the median time to cardiac response was 13 months (95% CI 1-Not reached). Of three patients eligible for renal response assessment at the time of CAR T (> 1 g/day proteinuria), two achieved a response (Renal PR, n = 1; Renal VGPR, n = 1), with a median time to renal response of 11 months (95% CI 1-Not reached). Six-month landmark organ responses were observed in two evaluable cardiac and one evaluable renal patient. A swimmer plot of CAR T-cell hematologic responses, progression, and survival is shown in (Figure 2). There were six deaths: five related to underlying disease, and one unrelated (12-months following cilta-cel, while in hematologic CR). The deaths related to underlying disease included an ide-cel recipient with no hematologic response who died secondary to cardiac amyloidosis 9-months post-infusion; a cilta-cel recipient with cardiac involvement who died of a cardiac arrest at 124-days post-infusion in a hematologic VGPR; an ide-cel recipient who relapsed at 5-months post-infusion and died of myeloma-related complications; and two cilta-cel recipients who relapsed ≥ 9-months post-infusion and died of myeloma-related complications. There were no deaths within the first 100-days following CAR T-cell infusion, and no cases of treatment-related mortality (TRM). At a median follow-up of 26.5 months (95% CI: 19.7–34.5), the 12 and 18-month overall survival (OS) rates were 85% (95% CI: 73%–100%) and 81% (95% CI: 67%–99%) and progression-free survival rates 70% (95% CI: 54%–90%) and 65% (95% CI: 49%–87%), respectively (Figure S2). Two patients were lost to follow-up after CAR T infusion after 10 and 19-months. We report deep and rapid hematologic responses in the largest real-world cohort of heavily pretreated patients with AL amyloidosis that received commercial BCMA-targeted CAR T-cell therapy. Although all patients exhibited features of concurrent MM, CAR T-cell therapy was feasible to administer, with isolated cases of severe CRS, ICANS, and IEC-HS. Nearly all patients achieved a hematologic VGPR or better, and this frequently translated into organ responses in evaluable patients. Approximately one-quarter of patients treated with daratumumab-based induction fail to achieve a hematologic VGPR, and for those individuals, changing treatment approach improves outcomes 4, 12. Alternative regimens for relapsed AL amyloidosis, such as carfilzomib, pomalidomide, and belantamab mafodotin, produce a ≥ hematologic VGPR in 29%–46% of daratumumab naïve patients 13-15. Venetoclax, a BCL2 inhibitor, has demonstrated promising activity in t(11;14)-positive disease, with a ≥ VGPR rate of 75% and excellent tolerability 16. By comparison, CAR T-cell therapy achieved ≥ VGPR in 89% of patients, consistent with early-phase clinical trials and other real-world series 17-20. However, unlike our cohort, other CAR T-cell studies have reported a concerning mortality signal; in the largest phase I clinical trial, median OS was approximately 10 months, with deaths primarily attributable to cardiac disease rather than treatment-related toxicity 18. In contrast, we observed an encouraging 18-month OS rate of 81%, with one case of IEC-HS, and no cases of TRM. Collectively, these findings suggest that with appropriate patient selection, CAR T-cell therapy may be safely incorporated into the therapeutic armamentarium for AL amyloidosis 17-19. As a retrospective analysis, limitations of this study include selection bias and incomplete toxicity reporting. Our cohort comprised heavily-pretreated patients with concurrent MM; this influenced the baseline characteristics of our cohort, which are distinct from the general AL amyloidosis population. As such, caution should be exercised when applying these results to the broader AL amyloidosis population, who may have less aggressive clones but greater organ dysfunction (including advanced cardiac disease). We report the largest real-world cohort of commercial BCMA-directed CAR T-cell therapy in patients with relapsed AL amyloidosis and concurrent MM. These data support CAR T-cell therapy as an effective and tolerable option for previously treated AL amyloidosis; however, optimal patient selection and sequencing remain to be defined. M.J.R., and R.C.C. wrote the first draft of the manuscript. M.J.R. analyzed the data. All of the authors contributed patients to this analysis, provided critical feedback, edited and wrote the manuscript, and approved the final manuscript. The authors acknowledge the patients who contributed data, as well as the research personnel at all study sites. Surbhi Sidana was supported by Blood Cancer United/Leukemia Lymphoma Society Scholar in Clinical Research Award (S.S, Grant #2353–26). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Patient consent was waived by the institutional review board due to the retrospective design of the study. M.J.R., R.C.C., M.T., E.Z., J.K., O.P., M.S.R., C.F., and S.Z. declare no conflicts of interest. S.S. reports consultancy with BMS, Kite, Novartis, Sanofi, Legend, Oncopeptides, Takeda, Janssen, Pfizer, Regeneron, BioLineRx, AbbVie, Magenta, Roche, Genentech, and Allogene. D.D. reports consultancy with Karyopharm. A.A. reports consultancy with BMS, Sanofi, Pfizer, Johnson and research funding from Johnson has served as a consultant with no personal payments for AbbVie, Amgen, ArcellX, BeiGene, Bristol Myers Squibb, Carsgen, Apizyme, Glycostem, GSK, K36, Menarini, Moderna, Pfizer, Regeneron, Genentech–Roche, Sanofi, Takeda, Telogenomics, Trillium, and Window Therapeutics; has served as a consultant with personal payments for Antengene, Calyx, and CVS Caremark; and has participation on an Independent Review Committee for Oncopeptides. A.K. reports consultancy with Genzyme (Sanofi) and research funding from Johnson and research funding from AbbVie, BMS, Janssen, Novartis, Pack Health, Prothena, and Sanofi. K.P. reports consultancy with Oricell, Kite, Genentech, BMS, Janssen, Takeda, Caribou, AbbVie, Poseida, Legend Biotech, Sanofi, AstraZeneca, Regeneron, and Novartis. L.A. reports consultancy with Pfizer, Amgen, BMS, Janssen, BeiGene, Sanofi, Karyopharm, Celgene, Prothena, Cellectar, GSK, and AbbVie; and honoraria from Amgen, BMS, Janssen, BeiGene, Sanofi, Karyopharm, Celgene, Prothena, Cellectar, GSK, and AbbVie. O.C. reports consultancy with Janssen, Legend Biotech, and BMS. N.B. reports consultancy with Johnson and research funding from Merck, Karyopharm, Sanofi, BMS, Pfizer, Celgene, and GSK. L.S. reports consultancy with Johnson and research funding from BMS and Janssen. D.H. reports research funding from Adaptive Biotechnologies, Janssen, Karyopharm, Kite, and BMS; and consultancy with Janssen, AstraZeneca, Karyopharm, Kite, Legend Biotech, BMS, and Pfizer. Original data will be shared upon reasonable request please contact email protected. Table S1: Bridging therapy received following apheresis and prior to lymphodepletion. Table S2: Rates of hematologic toxicity at day 30 and 90 post chimeric antigen receptor T-cell infusion, rates of granulocyte colony stimulating factor, thrombopoietin receptor agonist and stem cell boost use. Figure S1: Rates of cytokine release syndrome and immune cell associated neurotoxicity syndrome for patients with relapse AL amyloidosis and concurrent multiple myeloma treated with chimeric antigen receptor T-cell therapy. CRS, cytokine release syndrome; ICANS, immune cell associated neurotoxicity syndrome. Figure S2: (A) Overall and (B) progression-free survival of 28 patients with systemic AL amyloidosis and concurrent multiple myeloma treated with chimeric antigen receptor T-cell therapy. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.