编者按：多发性骨髓瘤是克隆性浆细胞异常增殖性疾病，近几十年来随着生物学特性研究不断深入，其治疗模式发生了显著的改变。随着蛋白酶体抑制剂、免疫调节剂、单克隆抗体、嵌合抗原受体T细胞（CAR-T）疗法和新药物的研发，多发性骨髓瘤患者的生存和预后发生了里程碑式的改变。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。会上，来自英国伦敦国王学院医院的Reuben Benjamin教授针对造血干细胞移植、CAR-T细胞治疗在多发性骨髓瘤患者中的临床应用及未来发展前景进行了专题报告。《血液时讯》特邀请Benjamin教授走进现场会客室，和广大读者分享他的真知灼见。

 

Benjamin教授：人类采用干细胞移植治疗恶性血液肿瘤已经有相当长的一段时间。在过去的几十年中，我们在移植方式以及移植预后方面都取得了长足进步。在本届EBMT大会上，我们共同回顾了干细胞移植领域的主要进展。首先，寻找到合适的干细胞移植捐献者是我们取得的主要进展之一。现在，我们能够更好地了解谁是最好的移植捐赠者，这也最终决定了移植的结局。我们在全球已拥有更好的捐赠者登记库，因此寻找到适合的捐赠者也变得更加容易。其次，我们在移植类型，尤其是单倍体移植（半相合移植）方面取得了显著进展，这彻底改变了移植领域的格局，因为不再需要找到一个完全相合的捐赠者，我们可以通过患者的母亲/父亲/孩子（即人人都可以找到捐献者），尽管是以单倍体相合的方式，但仍然可以安全地进行干细胞移植。这些都是我们在干细胞移植领域取得的主要进步。

 

Stem cell transplantation has been around for quite some time，but we have seen significant improvements both in the way we deliver the transplant as well as in the outcomes following the transplant over the last couple of decades.Today I was at a session where Dr Mary Horowitz was talking to us about where we have come in the field of stem cell transplantation.One of the major advances we have had is on identifying appropriate donors for stem cell transplants.We are now able to have a much better idea of who our best donor would be for transplant，and that ultimately then determines outcomes.We have much better donor registries internationally now，so finding a donor is becoming a lot easier.Then we have had advances in the type of transplant，namely haploidentical transplants.This has revolutionized the field，because no longer is it the case that you have to find an unrelated donor，but you can now approach your mother/father/children，who may only be matched in a haploidentical manner to you and nevertheless，we can safely do a stem cell transplant.I would say that identifying appropriate donors，moving into haploidentical stem cell transplants，delivering transplants more safely these have led to the success of stem cell transplantation in recent years.

 

Benjamin教授：对于细胞治疗领域来说，这是一个非常激动人心的时刻，我们拥有CAR-T细胞疗法以及其他形式的靶向细胞疗法，如CAR-NK细胞疗法、CAR-巨噬细胞和CAR-恒定自然杀伤T（iNKT）细胞，以及T细胞受体嵌合T细胞（TCR-T）疗法等等。目前，我们已经拥有了许多款被批准用于治疗淋巴瘤、白血病和多发性骨髓瘤的CAR-T细胞产品，而且这一数量一定会持续不断地增加。去年，我们在CAR-T细胞治疗自身免疫性疾病方面也获得了非常令人兴奋的数据，并且在未来两三年内，人们将可能拥有获得批准的应用于治疗狼疮关节炎的CAR-T细胞产品。不过，个人认为在可预见的将来，干细胞移植的地位仍不会被取代，干细胞移植仍将成为治疗白血病等许多恶性血液肿瘤的支柱，尽管我们没有这些CAR-T细胞治疗的长期数据。因为，四五年后我们可能还会看到晚期复发的患者，仍然需要干细胞移植。此外，CAR-T细胞治疗还存在一些潜在的安全性问题。最近，人们对于T细胞淋巴瘤患者和其他类型的血液肿瘤患者进行CAR-T细胞治疗的安全性感到担忧。这种情况会更频繁地发生吗？我们还不知道，但这也可能意味着干细胞移植仍将是大多数血液肿瘤接受的主要治疗方法。

 

These are really exciting times for the field of cell therapy，predominantly with CAR T-cell therapy，but also with other forms of targeted cellular therapy like CAR NK-cell therapies，CAR macrophages and CAR iNKT-cells，as well as TCR(T-cell receptor)therapies.We now have established approved CAR T-cell products for lymphoma，leukemia and myeloma，and I think that is only going to increase.In the last year，we have had very exciting data with CAR T-cells in autoimmune disease，and it is not impossible to think that in the next two or three years，we may have a licensed product for lupus arthritis，for instance.I don’t think we are going to see replacement of stem cell transplant for the foreseeable future.Stem cell transplants are still going to be the backbone of treatment for many blood cancers like leukemias.We don’t have long-term data on these cell therapies.I could be that four or five years down the line，we may see late relapses occurring，and then stem cell transplants may still be required.There are also potential safety issues with cell therapies that we are currently unaware of.There have been recent safety concerns about T-cell lymphomas in patients who have had CAR T-cells，and other types of blood cancers.Will this happen more frequently?We don’t know yet，but that could also mean that transplants will remain a mainstay of treatment for most blood cancers.

 

Benjamin教授：在多发性骨髓瘤方面我们非常幸运拥有很多不同类型的治疗方法。过去十年中，多发性骨髓瘤患者的生存率翻了一番，不过我们仍然无法彻底治愈这一疾病。这就是CAR-T细胞疗法可能改变“游戏规则”的地方，因为即使是遗传风险较高的患者，对CAR-T细胞治疗也能获得很好的治疗效果。问题是，针对CAR-T细胞治疗能否在疾病早期进行治疗，甚至它能否取代一些传统疗法？这仍然是一个悬而未决的问题。目前，人们正在进行一项比较干细胞移植与CAR-T细胞治疗的临床研究，一些临床研究将考察CAR-T细胞治疗能否作为一线治疗方案，还有一些针对无症状型多发性骨髓瘤患者采用CAR-T细胞治疗的临床试验。我们必须等待这些研究的结果才能明确地说CAR-T细胞治疗能否取代其他形式的药物治疗。但目前来说，CAR-T细胞疗法为多发性骨髓瘤患者提供了另一种选择。此外，我们还可以将CAR-T与其他药物治疗相结合。例如，在CAR-T细胞治疗后使用来那度胺或其他免疫调节药物可能会提高患者的生存率，同时可能提高CAR-T细胞治疗的有效性。但同样，我们必须等待这些研究的结果才能得出结论。总而言之，个人认为对于多发性骨髓瘤患者来说，细胞治疗的兴起的确为我们带来了非常激动人心的时刻。

 

I think we have been very lucky in multiple myeloma that we have lots of different types of therapies.The survival in myeloma has doubled in the last ten years.But we still cannot cure multiple myeloma.This is where the introduction of cellular therapies like CAR T-cells for myeloma are potentially game-changers，because they are blind to the genetics of the condition.Even poor risk genetics patients are responding really well to CAR T-cells for multiple myeloma.The question is，can CAR T-cells for myeloma be given earlier in the disease，and can it even replace some of the conventional treatments?That is still an open question.There is an ongoing trial comparing transplant versus CAR-T in myeloma.There are trials looking at CAR T-cells as first-line treatment.And there are also CAR T-cell trials looking at smoldering myeloma.We will have to wait for the results of these trials before we can say definitively that CAR T-cells will replace other forms of drug treatment，but currently，it is offering another option on top of the other treatments.We are also combining CAR T-cells with other drugs.The use of lenalidomide or other immunomodulatory drugs following CAR T-cells may improve survival and may improve the effectiveness of these CAR T-cell treatments.But again，we have to wait for the results of these studies before we can conclusively say that.I think these are really exciting times for myeloma with regards to cellular therapy.