肿瘤细胞治疗研究
英文原题：Endless possibilities and how to exploit them? What is the optimal treatment sequence?
对于适合移植、延迟移植以及适合但不适合移植且年龄小于80岁的患者，我们使用基于抗CD38单克隆抗体、来那度胺和硼替佐米/卡非佐米的四联方案作为诱导方案。
多发性骨髓瘤的治疗格局已发生深刻变革，一线治疗中引入了基于抗CD38单克隆抗体（mAb）的四联方案，复发治疗中则引入了T细胞重定向免疫疗法。本文综合关键临床试验的证据，为贯穿疾病全程的治疗决策和序贯治疗提供指导。对于适合移植、延迟移植以及不适合移植但体能状态良好且年龄小于80岁的患者，我们采用基于抗CD38 mAb、来那度胺和硼替佐米/卡非佐米的四联方案作为诱导治疗。对于早期复发（既往1-3线治疗），靶向B细胞成熟抗原（BCMA）的CAR-T 细胞疗法已显示出优于标准方案的疗效，其中ciltacabtagene autoleucel（cilta-cel）是目前最有效的产品，尽管存在一些独特毒性如帕金森综合征。基于belantamab mafadotin的三联方案在对来那度胺和抗CD38 mAb难治的患者中显示出令人瞩目的疗效，但眼部毒性仍是一个关注点。基于抗CD38 mAb和卡非佐米的三联方案在对anti-CD38 mAb未难治的患者中仍是重要的治疗选择。在晚期复发（既往≥4线治疗）中，靶向BCMA（teclistamab、elranatamab和linvoseltamab）和GPRC5D（talquetamab）的双特异性抗体（BsAbs）已显示出令人瞩目的单药活性，且具有不同的毒性特征。新出现的证据支持在临床可行时优先使用CAR-T 细胞疗法而非BsAbs，因为反向序贯时疗效似乎会受损。对于BCMA和GPRC5D难治性疾病的患者，靶向FcRH5的BsAb（cevostamab）、用于t(11;14)阳性疾病的BCL2抑制剂以及新型三特异性抗体（BCMAXCD38；BCMAXGPRC5D）提供了有前景的选择。战略性序贯试验代表了一个关键的未满足需求，PFS-2可能作为有价值的中间终点，在等待成熟生存数据的同时指导临床决策。
The therapeutic landscape of multiple myeloma has undergone a profound transformation with the incorporation of anti-CD38 monoclonal antibody (mAb)-based quadruplet regimens in the frontline setting and T-cell redirecting immunotherapies in the relapsed setting. In this article, we synthesize evidence from pivotal trials to guide treatment decisions and sequencing across the disease trajectory. For transplant-eligible, transplant-deferred, and fit transplant-ineligible patients who are younger than 80 years old, we use anti-CD38 mAb-, lenalidomide-, and bortezomib/carfilzomib-based quadruplets as an induction regimen. For early relapse (1-3 prior lines), chimeric antigen receptor T-cell therapies targeting B-cell maturation antigen (BCMA) have demonstrated superiority over standard regimens, with ciltacabtagene autoleucel (cilta-cel) being the most efficacious product currently, albeit with some unique toxicities such as parkinsomism. Belantamab mafadotin-based triplets have shown impressive efficacy in lenalidomide and anti-CD38 mAb-refractory patients, although ocular toxicity remains a concern. Anti-CD38 mAb and carfilzomib-based triplets remain an essential therapeutic option in patients not refractory to anti-CD38 mAb. In late relapse (≥4 prior lines), bispecific antibodies (BsAbs) targeting BCMA (teclistamab, elranatamab, and linvoseltamab) and GPRC5D (talquetamab) have demonstrated impressive single-agent activity with distinct toxicity profiles. Emerging evidence supports prioritizing chimeric antigen receptor T-cell therapy before BsAbs when clinically feasible, as sequential efficacy appears compromised in the reverse sequence. For patients with BCMA- and GPRC5D-refractory disease, FcRH5-targeting BsAb (cevostamab), BCL2 inhibitors for t(11;14)-positive disease, and novel trispecific antibodies (BCMAXCD38; BCMAXGPRC5D) offer promising options. Strategic sequencing trials represent a critical unmet need, with PFS (progression-free survival)-2 potentially serving as a valuable intermediate end point to guide clinical decision-making while waiting for mature survival data.
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