Fully human BCMA CAR-T therapy in multiple myeloma: lessons from long-term follow-up

Relapsed/refractory multiple myeloma (RRMM) remains a significant clinical challenge, particularly in patients with high-risk cytogenetics or extramedullary disease (EMD). Over the past several years, B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed outcomes for heavily pretreated patients (1-4). However, both products incorporate murine-derived single-chain variable fragments (scFv), which can trigger immune responses against the CAR, limit persistence, and complicate re-dosing (5-7). Fully human BCMA CAR-T constructs have emerged as a promising strategy to overcome these limitations. In this context, the recently published phase I study of FCARH143 provides the longest reported follow-up of a fully human BCMA CAR-T therapy to date, offering important insights into durability, cellular persistence, and late toxicities. The study demonstrates sustained clinical responses and a manageable safety profile in a cohort enriched for high-risk disease features, supporting the hypothesis that reduced immunogenicity may contribute to improved long-term therapeutic performance (8).

Amid ongoing efforts to improve BCMA-directed therapies, Tuazon and colleagues evaluated FCARH143 in a heavily pre-treated patient cohort with substantial disease complexity. The FCARH143 is generated through lentiviral transduction of autologous CD4⁺ and CD8⁺ T cells with a fully human BCMA-specific scFv linked to a 4-1BB costimulatory domain and CD3-zeta signaling domain. In this single-center, open-label study, 28 patients underwent leukapheresis, and 25 ultimately received FCARH143. Nearly half of the cohort demonstrated EMD, over half harbored high-risk cytogenetic abnormalities, and patients had received a median of eight prior lines of therapy. The inclusion of a high-risk population enhances the clinical relevance of these findings and offers insight into how fully human CAR constructs may perform in biologically aggressive disease settings beyond the controlled environments of pivotal clinical trials.

From a safety perspective, FCARH143 demonstrated a toxicity profile consistent with, and in several respects potentially more favorable than, currently approved BCMA-directed CAR-T therapies. Cytokine release syndrome (CRS) occurred in most patients but was predominantly low grade, with only a small proportion developing severe CRS. Neurotoxicity was observed but remained manageable, and notably, no grade 4 or fatal neurologic events were reported. Hematologic toxicities were universal but reversible, mirroring experiences seen with other CAR-T platforms. Importantly, no cases of delayed neurotoxicity were observed during long-term follow-up, an adverse event reported in approximately 5% of patients in the CARTITUDE-1 trial and up to 10% in real-world cilta-cel cohorts (2,9). Although the underlying mechanisms remain incompletely understood, reduced immunogenicity associated with fully human scFv constructs may contribute to improved tolerability and reduced late inflammatory complications. Similar safety patterns have been reported with other fully human BCMA CAR-T products, including CT053 and anitocabtagene autoleucel, both of which demonstrated low rates of high-grade CRS and neurotoxicity (10,11). Collectively, these findings suggest that structural refinement of CAR constructs may meaningfully influence toxicity profiles without compromising antitumor activity.

The efficacy outcomes reported with FCARH143 are remarkable, particularly given the high-risk nature of the treated population. The overall response rate reached 100% among evaluable patients, with 64% achieving stringent complete response (sCR). Responses were observed across all administered dose levels, including the lowest dose cohort (50×10⁶ cells), suggesting potent antitumor activity even at lower doses. Reported measures of durability were encouraging, with a median duration of response of 14.6 months, median progression-free survival (PFS) of 15.5 months, and a reported median overall survival (OS) of 32.1 months, despite the high-risk features of the enrolled population. However, cross-trial comparisons must be interpreted cautiously (Table 1). In the CARTITUDE-1 study, cilta-cel demonstrated a median PFS of approximately 35 months; however, the FCARH143 cohort included a substantially higher proportion of patients with EMD (44% vs. 13%) and a greater median number of prior lines of therapy (8 vs. 6), both well-established adverse prognostic factors (18,19). Collectively, these outcomes reinforce the capacity of fully human CAR-T therapy to generate meaningful and durable responses in clinically challenging patient populations.

Subgroup analyses also highlight important biological questions. Patients with particularly high bone marrow tumor burden or lower BCMA expression appeared to experience shorter progression-free intervals. These findings align with emerging data suggesting that antigen density, tumor microenvironment, and intrinsic T-cell fitness likely influence CAR-T durability. Identifying predictive biomarkers that distinguish patients who achieve long-term remission from those who relapse early remains a major unmet clinical need. Such biomarkers could help guide when CAR-T therapy should be used, inform selection among available CAR-T products, and identify patients most likely to benefit from combination or consolidation approaches.

The study further emphasizes the potential clinical relevance of fully human CAR-T therapy in traditionally underserved subgroups. EMD represents one of the most difficult manifestations of multiple myeloma to treat and has historically been associated with inferior outcomes across therapeutic modalities. The demonstration of robust responses in patients with EMD in both FCARH143 and CT053 studies suggests that fully human CAR-T constructs may retain efficacy even in biologically aggressive disease settings (10). Additionally, the relatively favorable toxicity profile raises the possibility of expanding outpatient administration. As CAR-T therapy moves toward earlier lines of treatment, minimizing treatment-related morbidity and resource utilization will become increasingly important, and outpatient delivery may help expand access in community or resource-limited clinical settings (20).

Despite these promising results, several limitations warrant careful consideration. FCARH143 was evaluated in a single-center, phase I trial, and although extended follow-up strengthens the dataset, the overall sample size remains limited. Rare toxicities and late complications may therefore be underrepresented, and patient selection as well as institutional expertise may have influenced both efficacy and safety outcomes. Multicenter studies will be essential to confirm reproducibility and define generalizability across broader and more diverse patient populations. Another unresolved question relates to the biological basis of durable remission. While a subset of patients achieved prolonged disease control extending beyond five years, the determinants of these sustained responses remain unclear. Elucidating factors such as CAR-T cell fitness, persistence, antigen density, and tumor microenvironmental features may provide critical insights for optimizing long-term therapeutic benefit.

Taken together, the long-term outcomes of FCARH143 represent an important step forward in the evolution of BCMA-directed CAR-T therapy for multiple myeloma. These findings demonstrate that fully human CAR constructs can achieve deep and durable responses while maintaining a manageable safety profile, even in heavily pretreated and high-risk patient populations, supporting the premise that reduced immunogenicity can be achieved without compromising antitumor efficacy. Future studies should evaluate fully human BCMA CAR-T therapies in randomized or comparative settings against currently approved products to better define relative efficacy and safety. In parallel, rational combination strategies incorporating immune modulators, bispecific antibodies, or targeted metabolic approaches may further enhance response durability. As CAR-T therapy continues to move earlier in the treatment paradigm, defining optimal sequencing and integration with existing immunotherapies will be critical to maximizing long-term patient benefit.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0392/coif). L.W. reports that he served as a consultant for Abbvie, and is on the advisory board for Janssen. F.A. reports that he served as advisor for Bristol Myers Squibb, Celgene, Caribou biosciences, GI Innovation, Poseida Therapeutics, Gilead, Kite and Arcellx; and received research funding from Allogene Therapeutic, Celgene, Bristol Myers Squibb, and Cariou Biosciences. S.R. reports that he received research funding from Janssen Research Developments and Nexcella, and is on the advisory panels for Janssen, Nexcella, Prothena Biosciences. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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