Experimental hematology & oncology · 2026

Реальные данные о риске заражения в нескольких миэломах, обработанных БиТЕ и клетками CAR-T: метаанализ.

Название и аннотация: Машинный перевод · не проверен

Обработка статьи · этапы, ошибки и управление

Загрузка состояния…

История · было → стало

Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.

Spataro F, Desantis V, Dicuonzo G, Molica S, Einsele H, Vacca A, Ria R, Solimando AG

Аннотация

ЦЕНТРАЛЬНАЯ РАБОТА: Лечение перенаправления Т-клеток, в том числе использование биконкретных Т-клеток (BITEs) и химерика антигенного рецептора Т-клеток (CAR-T), значительно улучшило результаты лечения повторной или повторной миэломы (RRMMM). Вместе с тем инфекционные осложнения по-прежнему вызывают серьезную озабоченность в плане безопасности, особенно в реальных условиях, когда пациенты являются более разнородными, чем пациенты, проходящие клинические испытания. МЕТОДЫ: Мы провели систематический обзор и метаанализ ретроспективных исследований реального мира, в ходе которых была дана оценка степени серьезности (сортность). 3-4) инфекция у взрослых пациентов с ОРМ, обработанных утвержденными ДИТ или клеточной терапией CAR-T. Модели случайного воздействия были рассчитаны с использованием единых показателей событий. Гетерогенность была изучена с помощью анализа подгрупп, метарегрессии и анализа чувствительности. Результаты: Sixteen исследования, охватывающие 2,097 Включены пациенты. В целом, 24.2% Число пациентов, достигших определенного уровня 3-4 Инфекции (количество случаев) 0.24; 95% CI, 0.21-0.28). Среди пациентов, проходящих лечение по методу " БИТЕ " (n = 1,602), совокупный резкий уровень инфицирования 0.26 (В тыс.95% CI, 0.23-0.30), с более высокими показателями по БИТ, ориентированным на БЦМ (BCMA)0.27) по сравнению с GPRC5D-directed Бити (Bittes)0.25). CAR-T - клеточная терапия (n = 495) были связаны с более низким коэффициентом объединенной инфекции (см.0.19; 95% CI, 0.12-0.27).ВЫВОДЫ: В реальном мире при рецидивном множественном моноцитарном лейкемии (РММ) примерно одна из четырех пациентов подвергается серьезным инфекциям при применении терапий, направленных на Т-клетки. Наблюдаемые различия в показателях инфекций между платформами и целями следует интерпретировать с осторожностью, так как они возникают из косвенных сравнений в неслучайных, гетерогенных группах пациентов. Тем не менее, эти данные подтверждают необходимость включения в терапевтическое решение факторов усталости пациента и его истории инфекций. При высоком риске инфекции в индивидуализированной и контекстной терапевтической стратегии могут быть рациональными варианты: терапия CAR-T или BiTE, ориентированные на GPRC5D, при невозможности применения CAR-T.

Оригинал публикации

Real-world evidence on infection risk in multiple myeloma treated with BiTEs and CAR-T cells: a meta-analysis.

BACKGROUND: T-cell-redirecting therapies, including bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, have substantially improved outcomes in relapsed or refractory multiple myeloma (RRMM). However, infectious complications remain a major safety concern, particularly in real-world settings, where patients are more heterogeneous than those enrolled in clinical trials.

METHODS: We conducted a systematic review and meta-analysis of real-world retrospective studies evaluating severe (grade 3-4) infections in adult patients with RRMM treated with approved BiTEs or CAR-T cell therapies. Pooled event rates were estimated using random-effects models. Heterogeneity was explored through subgroup analyses, meta-regression, and sensitivity analyses.

RESULTS: Sixteen studies encompassing 2,097 patients were included. Overall, 24.2% of patients developed grade 3-4 infections (pooled event rate 0.24; 95% CI, 0.21-0.28). Among BiTEs-treated patients (n = 1,602), the pooled severe infection rate was 0.26 (95% CI, 0.23-0.30), with higher rates observed for BCMA-directed BiTEs (0.27) compared with GPRC5D-directed BiTEs (0.25). CAR-T cell therapies (n = 495) were associated with a lower pooled infection rate (0.19; 95% CI, 0.12-0.27).

CONCLUSIONS: In real-world practice, severe infections affect approximately one in four patients receiving T-cell-redirecting therapies for RRMM. Observed differences in infection rates across platforms and targets should be interpreted with caution, as they derive from indirect comparisons in non-randomized, heterogeneous cohorts. Nevertheless, these data support incorporating patient frailty and prior infection history into therapeutic decision-making. CAR-T therapy, or GPRC5D-directed BiTEs when CAR-T is not feasible, may represent reasonable options in patients at higher infectious risk, within an individualized and context-dependent treatment strategy.

Перевод полного текста: Перевод в очереди

Читать найденный полный текст

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

To the Editor,

T-cell-redirecting immunotherapies, including bispecific antibodies (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, have substantially improved outcomes in relapsed/refractory multiple myeloma (RRMM) [ 1 ]. However, infectious complications remain a major safety concern, particularly in real-world settings, where patients are more heterogeneous and clinically vulnerable than those enrolled in prospective clinical trials. While severe infections have been extensively described in pivotal studies, comparative real-world evidence across approved T-cell-redirecting platforms remains limited [ 2 ].

We conducted a systematic review and meta-analysis of retrospective real-world studies, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, evaluating severe (grade 3–4) infections in adult patients with RRMM treated with approved BiTEs or CAR-T therapies, from inception through November 30, 2025 [ 3 ]. Detailed Methods, study selection, risk-of-bias assessment and certainty of evidence evaluation are provided in the Supplemental Appendix (S-Figure 1, S-Table 1 and S-Table 2).

Sixteen retrospective studies involving 2,097 patients were included, of whom 1,602 received BiTEs and 495 CAR-T therapies. Mean patient age was 66.3 years, 44.2% were female, and the weighted median follow-up was 8.3 months. Patients were heavily pretreated, with a mean of 6.1 prior lines of therapy. Prior autologous stem cell transplantation was reported in 77.4% of evaluable patients, while extramedullary disease, high-risk cytogenetics, and prior BCMA exposure were present in 39.2%, 48.8%, and 37.0% of evaluable patients, respectively. Additional baseline characteristics are summarized in S-Table 3 and S-Table 4 in the Supplemental Appendix.

Overall, 24.2% of patients developed grade 3–4 infections, corresponding to a pooled event rate of 0.24 (95% confidence interval [CI], 0.21–0.28) (Fig. 1 A). Severe infections occurred more frequently in patients treated with BiTEs (pooled event rate 0.26; 95% CI, 0.23–0.30) than in those receiving CAR-T therapies (pooled event rate 0.19; 95% CI, 0.12–0.27). Within the BiTEs cohort, predefined subgroup analyses according to target antigen demonstrated pooled infection rates of 0.27 (95% CI, 0.23–0.31) for BCMA-directed BiTEs and 0.25 (95% CI, 0.20–0.30) for GPRC5D-directed BiTEs (Fig. 1 B).

Fig. 1 Pooled incidence of grade 3–4 infections in patients with multiple myeloma treated with T-cell-redirecting therapies. A Forest plot of pooled event rates of grade 3–4 infec… — Fig. 1 Pooled incidence of grade 3–4 infections in patients with multiple myeloma treated with T-cell-redirecting therapies. A Forest plot of pooled event rates of grade 3–4 infections across included real-world studies in patients with multiple myeloma treated with BiTEs and CAR-T cell therapies. B Subgroup meta-analysis of pooled grade 3–4 infection rates in BiTEs-treated patients according to target antigen (BCMA-directed vs. GPRC5D-directed). Effect estimates are expressed as pooled proportions with corresponding 95% confidence intervals (CIs) using a random-effects model

Because moderate-to-high heterogeneity was observed, exploratory analyses were performed. In the BiTEs cohort, meta-regression identified an inverse association between severe infection rates and prior BCMA-directed therapy exposure (S-Figure 2), likely reflecting selection bias. Additional BiTEs- and CAR-T-related toxicities, ORR, and available immunoglobulin replacement treatment (IgRT) data are summarized in S-Table 5.

To contextualize our findings, we compared them with previously published meta-analysis on infectious complications associated with BiTEs and CAR-T therapies in RRMM [ 2 , 4 – 8 ]. Most available analyses included prospective trials, investigational agents, or mixed study designs. Across these studies, severe infection rates ranged from approximately 20% to 40% for BiTEs and from 17% to 25% for CAR-T therapies, supporting the consistency of our estimates (S-Table 6). BCMA-directed BiTEs showed numerically higher pooled infection rates compared with GPRC5D-directed BiTEs, while CAR-T therapies appeared associated with lower severe infectious burden overall. Although based on indirect comparisons across heterogeneous retrospective cohorts, these findings suggest that infectious toxicity may represent an additional dimension to consider when selecting T-cell-redirecting therapies in routine practice, particularly in patients with frailty, cumulative immunosuppression, cytopenias, or prior severe infections [ 9 ]. Notably, emerging evidence suggests that currently available frailty models may incompletely predict infectious vulnerability, further supporting the need for infection-oriented clinical stratification approaches [ 10 ].

On this basis, we propose a pragmatic conceptual framework integrating infectious vulnerability into therapeutic decision-making (Fig. 2 ). In clinically fit patients without major infectious history, either CAR-T or BiTEs therapy may represent reasonable options according to availability and clinical context. Conversely, in frail or immunologically vulnerable patients, CAR-T therapy, when feasible, or alternatively GPRC5D-directed BiTEs, may represent potentially safer strategies from an infectious standpoint.

Fig. 2 Proposed conceptual framework for interpreting infectious risk across T-cell-redirecting therapies in relapsed or refractory multiple myeloma. This figure illustrates a pra… — Fig. 2 Proposed conceptual framework for interpreting infectious risk across T-cell-redirecting therapies in relapsed or refractory multiple myeloma. This figure illustrates a pragmatic and conceptual framework integrating real-world infection risk to support treatment selection between BiTEs and CAR-T cell therapies in patients with relapsed or refractory multiple myeloma (RRMM). Assessment of patient frailty and prior history of severe or recurrent infections represents the first step in the decision-making process. In patients who are clinically fit and without a history of significant infectious complications, either T-cell-redirecting strategy may be considered appropriate, based on availability and clinical judgment. Conversely, in frail patients or in those with a documented history of severe or recurrent infections, CAR-T cell therapy may be preferentially considered when feasible. When CAR-T therapy is not available or not suitable, GPRC5D-directed BiTEs may represent a potentially safer alternative compared with BCMA-directed BiTEs. In all scenarios, appropriate vaccination strategies are recommended, while immunoglobulin replacement treatment (IgRT) could be taken in consideration for the frailest group. RRMM: relapsed or refractory multiple myeloma. IgRT: immunoglobulin replacement treatment

Our study has limitations inherent to retrospective real-world analyses, including moderate heterogeneity across cohorts, potential patient overlaps among multicenter consortium-based studies, and indirect comparisons between therapeutic platforms. In addition, supportive care variables, including IgRT, antimicrobial prophylaxis, and vaccination strategies, were inconsistently reported and could not be formally evaluated.

Overall, our findings underscore that severe infections remain a major and insufficiently standardized complication of T-cell-redirecting therapies in RRMM, affecting approximately one in four treated patients in real-world practice. Prospective registries with harmonized reporting of infections, antimicrobial prophylaxis, vaccination status, IgRT exposure, frailty-related variables, and infection-related mortality are urgently needed to refine patient selection and develop individualized supportive care strategies.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1.

Acknowledgements

The authors thank Drs. Giulio Giordano, Tommasina Perrone, Vanessa Innao and Massimo Martino for technical support and valuable discussions.

Abbreviations

B-cell maturation antigen

Bi-specific T-cell engager or bispecific antibodies

Chimeric antigen receptor T-cell

G protein-coupled receptor family C group 5 member D

Immunoglobulin replacement therapy

Multiple myeloma

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Relapsed or refractory multiple myeloma

Author contributions

F.S. and A.G.S. conceived the project; F.S. and A.G.S. designed the analyses; F.S., V.D. and G.D. acquired data; F.S. and G.D. verified the raw data before analyses and performed pre-processing informatic analysis; F.S. and A.G.S. performed the informatic analysis and interpreted data; F.S. and A.G.S. wrote the first manuscript draft; H.E, S.M., A.V. and R.R. reviewed the final manuscript, which has been revised and approved by all the authors.

Funding

European Union - NextGenerationEU - National Recovery and Resilience Plan (NRRP) – MISSION 4 COMPONENT 2, INVESTMENT N. 1.1, CALL PRIN 2022 PNRR D.D. 1409 14-09-2022 – VISIUMM (project n. 2022ZKKWLW) CUP: H53D23006570006 to AGS; Italian network of excellence for advanced diagnosis (INNOVA), Ministero della Salute (code PNC-E3-2022-23683266 PNC-HLS-DA) to V.D., A.V. and A.G.S.; Complementary National Plan PNC-I.1 “Research initiatives for innovative technologies and pathways in the health and welfare sector” D.D. 931 of 06/06/2022, DARE - DigitAl lifelong pRevEntion initiative (code PNC0000002) to A.V. and R.R.; PNRR-MCNT1-2023-12377893 DEMMO- “Deciphering multiple myeloma using multiomic approaches for immunotherapy modeling“ (CUP: H93C23001080006) to V.D. and A.G.S; European Union—Next Generation EU—PNRR M6C2— “Investimento 2.1 Potenziamento e rafforzamento della ricerca biomedica nel SSN” (project n. PNRR-POC-2022-12375862 FUSION-TARGET) to A.G.S. This work was also supported by independent research grants from Pfizer to A.G.S. Pfizer had no role in the design, conduct, analysis, or interpretation of the data, nor in the writing of the manuscript (study n. 97499737 SMART-BITE and study n. 101069601 BIS-HUB).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

SM received consulting honoraria from Janssen, AbbVie, Astra-Zeneca and Lilly. H.E. received honoraria for Bristol-Myers-Squibb, Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis, Roche, Research Funding (BMS/Celgene, Janssen, Sanofi; GSK, Amgen) Consultancy (Amgen, BMS, Celgene, Janssen, GSK, Novartis, Roche, Sanofi, Takeda); A.V. received speaker honorariums from Pfizer, Sanofi, Bristol Myers Squibb, Takeda, Janssen Cilag, AstraZeneca, Menarini, and Amgen; R.R. has served as a speaker or consultant for Amgen, BMS-Celgene, CSL Behring, Janssen Cilag, Octapharma, Pfizer, Sanofi, Takeda; A.G.S. has received speaker honorariums from Sanofi, Amgen, and AstraZeneca. He has also participated on advisory boards for Pfizer and Menarini. He received travel support for educational purposes from Janssen Cilag. These potential conflicts of interest do not imply bias or influence on the authors’ opinions or actions. The authors are aware of the importance of transparency in the scientific field and are committed to defending their integrity and the trust in them within the scientific community.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Raje NS, Anaissie E, Kumar SK, et al. Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol. 2022;9:e143–61.

2. Vandenboom H, Akhtar O, Szabo A, et al. Safety and efficacy of BCMA CAR-T vs. bispecific antibodies in patients with relapsed multiple myeloma: a systematic review and meta-analysis. Haematologica. 2025. 10.3324/haematol.2025.288174.

3. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021. 10.1136/bmj.n71.

4. Reynolds G, Cliff ERS, Mohyuddin GR, et al. Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis. Blood Adv. 2023;7:5898–903.

5. Wang X, Zhao A, Zhu J, et al. Efficacy and safety of bispecific antibodies therapy for relapsed or refractory multiple myeloma: a systematic review and meta-analysis of prospective clinical trials. Front Immunol. 2024;15:1348955.

6. Li W, Zhao D, Jiao Y, et al. Effectiveness and safety of teclistamab for relapsed or refractory multiple myeloma: a systematic review and meta-analysis. Front Immunol. 2025;16:1565407.

7. Bakogeorgou S, Filippatos C, Malandrakis P, et al. Safety and Efficacy of Bispecific Antibody Treatment in Relapsed/Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis of Proportions from Clinical Trials. Cancers (Basel). 2025;17:2727.

8. Techaapornkun P, Rojpalakorn W, Mejun N, et al. Comparative efficacy and safety of BCMA-targeted CAR T cells and BiTEs in relapsed/refractory multiple myeloma: a meta-analysis of interventional and real-world studies. Ann Hematol. 2025;104:4791–809.

9. Rodriguez-Otero P, Usmani S, Cohen AD, et al. International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma. Lancet Oncol. 2024;25:e205–16.

10. Spataro F, Armentaro G, Di Gioia G. Impact of frailty on infection risk in non-transplant eligible multiple myeloma patients: a systematic review and meta-analysis. Leukemia. 2026;40:1072–5. 10.1038/s41375-026-02880-y.