Ferritin Levels Predict Survival in CAR-T Therapy for Multiple Myeloma

Understanding the Role of Ferritin in CAR-T Therapy Outcomes

Multiple myeloma is a complex and often aggressive cancer of plasma cells. When standard treatments no longer work—such as after chemotherapy, immunotherapy, or stem cell transplantation—the disease is considered relapsed or refractory (R/R). These patients face limited options and a poor prognosis. In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a breakthrough treatment for R/R multiple myeloma. This therapy involves modifying a patient’s own immune cells to recognize and destroy cancer cells expressing a protein called BCMA (B-cell maturation antigen).

Despite its promise, CAR-T therapy doesn’t work equally well for all patients. Outcomes can vary widely. Some patients respond with durable remissions, while others relapse quickly or experience severe treatment-related toxicities. Identifying biomarkers that can predict how a patient will respond to CAR-T therapy is a critical need in the field.

A new meta-analysis, published in Biomolecules and Biomedicine by Jing Cheng and Yuan Song from Nanchang University, addresses this challenge by evaluating the prognostic value of serum ferritin levels—a marker of both iron metabolism and systemic inflammation.

Why Ferritin?

Ferritin is commonly known as the protein that stores iron in the body. But it also acts as an acute-phase reactant, meaning its levels increase in response to inflammation, oxidative stress, and immune system activation. These are all conditions frequently observed in patients with advanced cancers or undergoing intensive therapies like CAR-T.

In this context, ferritin might not just reflect iron levels, but could signal underlying biological processes that impact treatment efficacy and safety. Previous small studies had hinted at a connection between high ferritin levels and poor outcomes in CAR-T-treated patients, but the evidence was inconsistent.

Meta-Analysis Reveals Clear Associations

To clarify the evidence, Cheng and Song conducted a systematic meta-analysis involving eight retrospective cohort studies published between 2023 and 2025. The analysis included 1,077 patients with relapsed or refractory multiple myeloma who were treated with various CAR-T products.

Key inclusion criteria were:

• Adult patients with R/R MM treated with CAR-T therapy

• Serum ferritin measured before infusion

• Reported outcomes in terms of progression-free survival (PFS) and overall survival (OS)

Using hazard ratios (HRs) and 95% confidence intervals (CIs), the authors assessed whether high ferritin levels—defined based on median values, upper limits of normal, or upper quartiles depending on the study—were linked to shorter survival.

Main Findings

The results were clear:

• Patients with high pre-infusion ferritin levels had significantly worse progression-free survival (HR: 2.15)

• They also experienced poorer overall survival (HR: 2.86) compared to those with lower ferritin levels

These findings were consistent across different subgroups, including:

• Commercial vs. academic CAR-T products

• Different ferritin cutoff values

• Various follow-up durations

The analysis showed low heterogeneity (i.e., variability) among the studies, strengthening the credibility of the results. Sensitivity analyses—where one study was removed at a time—further confirmed the robustness of the findings.

No direct quotes from the authors were included in the original article, but their conclusion was clear:

“Elevated serum ferritin levels before CAR-T infusion predict poorer survival outcomes in R/R MM patients.”

What Could Explain This Link?

While this was not the focus of the meta-analysis, the authors summarized several plausible biological mechanisms based on prior research:

1. Systemic Inflammation: High ferritin is often a marker of inflammation. Inflammatory environments may trigger more severe side effects like cytokine release syndrome (CRS) and neurotoxicity (ICANS), which are known complications of CAR-T therapy.

2. Oxidative Stress and Immune Suppression: Elevated ferritin levels may reflect increased oxidative stress, which could impair the function of CAR-T cells. This might also indicate an immunosuppressive tumor environment that reduces the treatment’s effectiveness.

3. Adverse Clinical Conditions: High ferritin has been linked to higher rates of infections, heart complications, cytopenias (low blood counts), and delayed recovery—all factors that can contribute to worse outcomes during CAR-T treatment.

Practical Implications for Researchers and Clinicians

The most immediate takeaway is that serum ferritin may serve as a useful and easily accessible biomarker to stratify risk in patients undergoing CAR-T therapy for multiple myeloma.

• Before treatment: Ferritin testing could help identify patients who may need closer monitoring or more aggressive supportive care.

• In research: Ferritin can be explored further in prospective trials as part of biomarker panels alongside other inflammatory and immune markers.

• In clinical trial design: Stratifying patients by ferritin level could enhance the interpretation of treatment efficacy and toxicity profiles.

It’s important to note that the current evidence comes from retrospective studies. The authors call for prospective research to validate ferritin’s predictive value and to explore its potential role in guiding treatment decisions.

Limitations Acknowledged by the Study

The authors were careful to note limitations of their meta-analysis:

• All included studies were retrospective, which may introduce biases.

• Data were reported at the study level, not the patient level, limiting insights into factors like comorbidities or genetic differences.

• Ferritin was only measured before CAR-T infusion—changes after infusion might also provide useful information but were not analyzed.

• Variations in assay methods for measuring ferritin were not accounted for.

Conclusion

This study provides strong evidence that elevated pre-infusion serum ferritin is a negative prognostic marker in CAR-T therapy for relapsed/refractory multiple myeloma. While more research is needed, especially prospective and mechanistic studies, ferritin has potential as a low-cost, clinically available tool to support risk stratification in a rapidly evolving therapeutic landscape.

The translation of the preceding English text in Chinese:

理解铁蛋白在CAR-T疗法结局中的作用

多发性骨髓瘤是一种复杂且常呈侵袭性的浆细胞癌。当标准治疗（如化疗、免疫治疗或造血干细胞移植）不再有效时，疾病被视为复发或难治（R/R）。这些患者的治疗选择有限，预后较差。近年来，嵌合抗原受体T细胞（CAR-T）疗法已成为R/R多发性骨髓瘤的一项突破性治疗手段。该疗法通过改造患者自身的免疫细胞，使其识别并杀伤表达B细胞成熟抗原（BCMA）的癌细胞。

尽管前景可期，CAR-T疗法的疗效在不同患者之间存在显著差异。一些患者获得了持久的缓解，而另一些患者则迅速复发，或经历严重的治疗相关毒性。因此，寻找可预测CAR-T疗效的生物标志物，是该领域亟需解决的问题。

一项由南昌大学程静与宋媛发表在《Biomolecules and Biomedicine》上的最新荟萃分析，针对这一挑战评估了血清铁蛋白水平的预后价值。铁蛋白既是铁代谢的标志物，也是全身炎症的指标。

为什么选择铁蛋白？

铁蛋白通常被认为是体内储存铁元素的蛋白质。但它同时也是一种急性期反应蛋白，意味着在炎症、氧化应激或免疫系统激活时，其水平会升高。这些情况在晚期癌症患者或接受CAR-T等高强度治疗者中很常见。

在这种背景下，铁蛋白的升高不仅反映铁代谢状况，还可能提示潜在的生物学过程，从而影响治疗的有效性与安全性。此前一些小型研究曾提示高铁蛋白水平与CAR-T疗效差有关，但证据并不一致。

荟萃分析揭示明确关联

为明确证据，程静与宋媛开展了系统荟萃分析，纳入了2023年至2025年间发表的8项回顾性队列研究，共计1,077名接受不同CAR-T产品治疗的R/R多发性骨髓瘤患者。

纳入标准包括：

• 接受CAR-T治疗的成年R/R MM患者

• 在输注前测量血清铁蛋白

• 报告无进展生存期（PFS）和总生存期（OS）等结局指标

作者利用风险比（HR）及95%置信区间（CI）分析高铁蛋白水平（依据中位数、正常上限或上四分位数等不同标准定义）与生存结局之间的关系。

主要发现

结果显示：

• 输注前铁蛋白水平较高的患者，其无进展生存期明显较差（HR：2.15）

• 总生存期也较低（HR：2.86），相比铁蛋白较低者

这些结论在不同亚组中一致，包括：

• 商业化 vs. 学术型CAR-T产品

• 不同的铁蛋白界值

• 不同的随访时间

分析显示研究间异质性较低，增强了结论的可靠性。敏感性分析（逐个剔除研究）也证实了结果的稳健性。

尽管原文未引用作者直接语句，但其结论明确：

“CAR-T输注前血清铁蛋白升高，预测R/R多发性骨髓瘤患者较差的生存结局。”

这一关联可能的生物学解释

虽然这不是荟萃分析的重点，作者总结了多个基于先前研究的合理机制：

• 全身炎症：高铁蛋白常为炎症标志。在此环境下，可能诱发细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS）等严重副作用。

• 氧化应激与免疫抑制：铁蛋白升高可能反映氧化应激增加，从而削弱CAR-T细胞功能。同时也可能暗示一种免疫抑制性肿瘤微环境，降低治疗效力。

• 临床不良状态：高铁蛋白水平与感染、心脏并发症、血细胞减少及恢复延迟相关，这些因素可能共同导致CAR-T治疗结局不佳。

对研究者与临床医生的现实启示

最直接的启示是：血清铁蛋白或可作为一种简便且易得的生物标志物，用于风险分层。

• 治疗前：铁蛋白检测可协助识别需密切监测或强化支持治疗的高风险患者

• 研究中：未来前瞻性研究中，铁蛋白可作为生物标志物面板的一部分，与炎症及免疫指标联用

• 临床试验设计中：按照铁蛋白水平分层可提高对疗效与毒性差异的解释力

需注意，目前的证据主要来自回顾性研究。作者呼吁未来进行前瞻性研究，以验证铁蛋白的预测价值，并探索其在治疗决策中的潜在指导作用。

研究承认的局限性

作者也明确指出本研究的局限：

• 所有纳入研究均为回顾性，可能存在偏倚

• 数据为研究层面汇总，而非患者个体数据，限制对共病或遗传因素的深入分析

• 铁蛋白仅在CAR-T输注前测量，未分析输注后变化

• 不同研究采用的铁蛋白测定方法可能存在差异，未加以统一考虑

结论

该研究提供了有力证据，表明CAR-T输注前血清铁蛋白升高是R/R多发性骨髓瘤患者生存预后的负向标志物。尽管仍需更多研究，特别是前瞻性与机制研究，但铁蛋白有望成为一种低成本、易获取的临床工具，用于支持在这一迅速发展的治疗领域中的风险评估与个体化管理。

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