Hughes Charlotte F M, Shah Gunjan L, Paul Barry A
Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Front Oncol. 2024 Mar 27;14:1373548. doi: 10.3389/fonc.2024.1373548. eCollection 2024.
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and long-term adverse effects, which may alter the disease course and patient's ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate.
嵌合抗原受体（CAR）T细胞疗法彻底改变了复发难治性骨髓瘤的治疗方式，疗效卓越且安全性可耐受。对于年轻且身体状况足以耐受高强度治疗的新诊断多发性骨髓瘤（NDMM）患者，高剂量化疗联合自体造血干细胞移植（AHCT）已成为治疗的主流。这一标准是基于在新型药物出现之前的时代，将AHCT与化疗进行比较的随机试验而制定的。最近，更多的研究主要表明 upfront AHCT 在无进展生存期（PFS）方面有获益，而非总生存期（OS）获益。对于这种缺乏OS获益的意义存在争议，同时也认识到该疾病的慢性本质、研究设计以及AHCT带来的相互竞争的危害和益处等潜在混杂因素。事实上， upfront AHCT可能并不像我们曾经认为的那样具有独特的益处，而且并非没有风险。新的四联药物方案在实现可测量残留病（MRD）所量化的深度缓解方面具有高度活性和有效性。与AHCT一起使用的高剂量化疗会带来短期和长期的不良反应负担，这可能会改变疾病进程以及患者耐受未来治疗的能力。一些高危亚组可能从AHCT中获得更有价值的益处，尽管最终结局仍然不佳。与CAR T细胞疗法的疗效相比，是否可以或确实应该推迟AHCT的问题已成为该领域的一个重要话题。对于实现MRD阴性的患者，推迟AHCT可能是一个个性化的决定，而MRD阴性现已被确认为PFS和OS的关键预后因素。在许多情况下，在复发时保留或重新进行AHCT是可行的，并且有望重置T细胞区室并为免疫重新参与开辟选择。个性化的MRD指导决策很可能会塑造我们未来的治疗顺序，不过还需要更多研究来确定何时这样做是安全和合适的。
