编者按：具有高缓解率的诱导治疗、联合大剂量化疗及自体造血干细胞移植（ASCT）显著改善了多发性骨髓瘤（MM）患者的预后。尽管如此，患者仍难免出现疾病进展或复发。如何使诱导治疗及ASCT后获得缓解的患者持续缓解，是该研究领域的重要目标之一。2024年4月14日至17日，第50届欧洲血液和骨髓移植学会（EBMT）年会在英国格拉斯哥隆重举行。会议聚焦干细胞移植和细胞疗法的最新进展，推动着血液病及血液肿瘤患者向着更好的临床预后迈进。在本届大会上，法国国家卫生局主席、法国南特大学René Gauducheau癌症中心主任Jean-Luc Harousseau教授就如何优化诱导治疗方案做了精彩的专题报告。《血液时讯》特邀请Harousseau教授走进现场会客室，和广大读者分享针对多发性骨髓瘤患者不断优化的ASCT前诱导治疗策略。
《肿瘤瞭望–血液时讯》首先请您为我们介绍一下ASCT全流程是怎样的？其中，ASCT前预处理的主要目的是什么？以及这一步骤对于ASCT成功的重要性？
Harousseau教授：目前，ASCT仍然是没有合并症的年轻患者的标准治疗方法。大量的随机试验表明，除非引入新的治疗手段，优先进行ASCT较不进行移植的患者在疗效方面有显著获益，不仅可以提高疾病客观缓解率（ORR），更为重要的是，同时也可提高患者实现微小残留病（MRD）阴性的比例。这意味着患者可以获得更长的无进展生存期（PFS）。这就是为什么尽管ASCT治疗策略存在一定的风险，但是仍然受到青睐，尤其是在欧洲国家。
谈到ASCT方案的全流程，首先是在ASCT前进行诱导治疗，其目的在于最大限度清除或降低肿瘤负荷；接下来，在患者达到完全缓解（CR）后进行ASCR；在移植后，继续给予与诱导相同的治疗方案，以巩固疗效并进一步改善结局；最后是维持治疗，最长可达三年。有关诱导治疗方案的选择，往往对ASCT疗效的发挥具有巨大的影响。然而，ASCT预处理方案种类繁多，适用范围不尽相同。目前，经典的方案是三联疗法，即硼替佐米或卡非佐米，加来那度或沙利度胺，再加地塞米松（如VRd、VTd或KRd），通常为4-6个周期。
最近的研究表明，抗CD38单抗的加入，四联疗法的应用可使患者达到更深层次的肿瘤缓解，多发性骨髓瘤患者的生存获益得到了显著改善。在随机试验中，通过添加达雷妥尤单抗（daratumumab）或伊沙妥昔单抗（isatuximab）作为诱导和巩固的四联疗法，可以进一步提高治疗疗效，尤其是CR率、严格完全缓解率（sCR）和MRD阴性率均有改善。
Currently, autologous stem cell transplantation remains the standard-of-care for younger patients without comorbidity. The reason is that randomized trials have shown that autologous transplantation given up-front, in addition to a new treatment, yields better results than this new treatment without transplant. It increases the response rate, and, more importantly, the proportion of patients achieving minimal residual disease negativity, which translates into a longer progression-free survival. That is the reason why, despite the risk of this strategy, it is still preferred, particularly in European countries.
The design of the ASCT programs is, first, an induction treatment to reduce the tumor burden prior to autologous transplantation, and after transplant, to give the same regimen as for induction to consolidate results and further improve the outcome. Finally, there is a maintenance treatment, which can be as long as three years. To answer your question regarding induction treatment, the classical regimen was a triplet - Velcade (bortezomib) or even carfilzomib, plus lenalidomide or thalidomide, plus dexamethasone (VRD, VTD or KRD) - usually 4-6 cycles.
But recently, anti-CD38 antibodies were added to this triplet standard, and in randomized trials, quadruplets by the addition of daratumumab or isatuximab as both induction and consolidation, further improved the results, especially the rate of deep responses, complete responses, stringent complete responses, and, more importantly, negative minimal residual disease.
《肿瘤瞭望–血液时讯》在预处理方案的选择上，过去人们通常采用的策略是什么，从而达到最大限度地清除肿瘤细胞、降低疾病负荷？
Harousseau教授：预处理是关系到其移植成败的重要环节之一。所谓“预处理”是指在移植前对患者进行的放疗、化疗和免疫抑制治疗，以使移植物顺利植入并最大限度清除异常细胞或肿瘤细胞。预处理的主要目的是消灭患者体内的异常细胞或肿瘤细胞，最大限度减少复发。在过去，人们尝试通过化疗来净化骨髓，甚至使用移植物中的抗体，但最终这太复杂，毒性太大。因此，我们决定使用外周血干细胞，以减少移植物中恶性细胞的比例。然而，即使使用外周血干细胞，移植物中仍然可能存在恶性细胞，采用高剂量疗法的好处在于，当我们破坏了患者的骨髓时，在大多数情况下，重新填充骨髓的细胞都是好的细胞。综上所述，在移植前尽可能地减少肿瘤负荷始终是非常重要的，这也是进行移植前诱导治疗的目标。
At the beginning of the transplantation process when we take the marrow, which is contaminated by malignant plasma cells, the first way was to try to purge the marrow by chemotherapy in the graft, or even using antibodies in the graft, but in the end, this was too complicated and too toxic. So we decided to use peripheral blood stem cells in order to reduce the proportion of malignant cells in the graft, but there are still malignant cells in the graft even using peripheral blood stem cells. The beauty of high-dose therapy is that when you destroy the marrow of the patient, the first cell to repopulate the marrow in the majority of cases are the good cells. Nevertheless, it is always important to reduce the tumor burden prior to autologous transplantation, and that is the objective of induction treatment.
《肿瘤瞭望–血液时讯》目前，提高ASCT疗效的探索主要聚焦在优化诱导治疗方案以提高完全缓解率，请您为我们介绍一下这方面的主要进展？
Harousseau教授：如我们前面所提到的，这是一个逐步改进的过程。在多发性骨髓瘤患者中，我们从VAD化疗方案（长春新碱、阿霉素和地塞米松）开始，而后自2000 年起逐步引入了沙利度胺、硼替佐米，以及双药组合——沙利度胺-地塞米松或硼替佐米-地塞米松。接着，我们在2005年之后开始使用三联方案（VRd、VTd或KRd）。最后，我们现在拥有了联合抗 CD38 抗体的四联方案。归根结底，其目标是提高患者的CR率，同时增加移植后实现MRD阴性的患者比例。值得一提的是，经过诱导治疗、自体移植、巩固治疗后，我们还有维持治疗。移植后的维持治疗是多发性骨髓瘤患者治疗全程中的一个非常重要的环节，常用的方案如来那度胺或者新近的来那度胺联合抗 CD38 抗体，其目的是延长缓解持续时间，甚至进一步加深缓解水平。综上所述，目前我们针对年轻的多发性骨髓瘤患者，采取的治疗策略包括诱导治疗、自体移植和巩固治疗，然后长期维持治疗，以此有望实现患者的长期无进展生存。
As I mentioned, this has been a gradual improvement. We started with chemotherapy with VAD, then we introduced thalidomide and bortezomib after 2000 with doublets - thalidomide-dexamethasone or bortezomib-dexamethasone. Then we used triplets after 2005 both for induction and consolidation. Finally, we now have quadruplets with anti-CD38 antibodies. The objective is to increase the proportion of patients achieving complete response, but more than that, the proportion of patients achieving minimal residual disease negativity after transplant. An important part of the treatment is maintenance. After induction treatment, autologous transplantation and consolidation treatment, we do have maintenance treatment. The objective of maintenance treatment - lenalidomide, or more recently, lenalidomide plus anti-CD38 antibodies - is to prolong remission duration, and sometimes, to deepen the level of response. So the current treatment in younger patients is induction, autologous transplantation and consolidation followed by long-term maintenance. This yields very long progression-free survivals, mostly in patients with standard risk, and especially standard risk cytogenetics.
