AbstractIntroduction:The success of CAR-T in multiple myeloma suggests potential in other challenging plasma cell disorders like systemic AL amyloidosis (AL) and plasma cell leukemia (PCL). CAR-T experience in these indications is limited by the rarity of these diseases.Methods:A systematic review examined publications and clinical trials from 2014 to 2024 to gauge clinical outcomes and safety of CAR-T in AL and PCL. Studies of plasma cell-directed CAR-T with safety and efficacy outcomes were included.Results:We identified a total of 21 AL patients from 6 publications and 23 PCL patients from 5 publications. All patients were treated with anti-BCMA CAR-T; 9 different products were administered. Among AL patients, 12 had cardiac amyloidosis, and 6 had at least stage 3. At a median follow-up of 9 months (2.5-26.4), 16 of 21 AL patients (76%) had a response of VGPR or better: 2 had MRD-negative sCR with organ response, 8 CR, 6 VGPR, 1 PR, and 3 not evaluable. From a safety standpoint, CRS occurred in 71%, with 57% experiencing grades 1-2 and 14% grade 3. ICANS occurred in 2 patients (10%): one grade 1, one grade unknown. Of 11 patients treated with HBI0101, 5 patients died of cardiac disease within 1 year of CAR-T (3 PD, 1 VGPR, 1 PR). Hematologic events were common, with neutropenia in 76% (52% grades 3-4), anemia in 38% (19% grade 2-3, 5% grade 1), and thrombocytopenia in 24% (10% grade 2, 5% grade 3, and one grade 4 worsening thrombocytopenia). Infections were also seen, including BK virus hemorrhagic cystitis, SARS-CoV-2 pneumonia, severe respiratory infection, respiratory viral infection, and sepsis, each affecting 5-14%. A review of CAR-T in PCL included 6 patients with primary PCL and 17 with secondary PCL, with a median of 4.5 (range: 0-15) prior lines of therapy. Overall response at a median follow-up of 6.5 (range: 0-15) months was 17/23 (78%): 2 patients with sCR, 2 CR, 7 VGPR, and 7 PR. Adverse events were only described in 20 of the 23 PCL patients. CRS was frequent, with any grade CRS occurring in 18 of 20 (90%); CRS grade was only reported in 10 (4 grade 1, 3 grade 2, 1 grade 3, 2 grade 4, 8 grade unknown). ICANS grade 1 was reported in 4 patients (20%), and infection (any grade) in 8 (40%). Hematologic events of any grade were frequent: neutropenia in 90% of patients (35% grade ≥ 3), anemia in 80% (40% grade ≥ 3), and thrombocytopenia in 70% (40% grade ≥ 3). Three deaths were reported, two due to infection (pneumonia and pulmonary aspergillosis) and one due to GI hemorrhage.Conclusions:BCMA-directed CAR-T has been used in AL and PCL with encouraging responses, though the durability of these responses is unknown. Our review suggests that CAR-T may be safe in AL in patients without significant cardiac disease. Patients with PCL may be at an increased risk of serious adverse events, especially in the setting of active progressive disease. Careful patient selection and potential dose adjustment may be warranted in these orphan indications.Citation Format:Heather T. Morgan, Benjamin Derman, Hong Ma, Shaji K. Kumar. CAR-T in high-risk plasma cell dyscrasias: A systematic review of AL amyloidosis and plasma cell leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3180.