编者按：2023年6月8—11日，第28届欧洲血液学年会（EHA）在德国法兰克福以线上+线下的形式举行，会议由欧洲血液学会主办。作为欧洲血液学领域规模最大的国际会议，每年都有来自全球100多个国家的10000余名专业人士与会，一起分享并探讨有关血液学的创新理念及最新的科学和临床研究成果。在EHA会议现场，《肿瘤瞭望》特别邀请到阿姆斯特丹大学医学中心（AMC-UvA）Niels Van de Donk教授，就CAR-T在复发/难治多发性骨髓瘤（RRMM）治疗中的最新研究和未来方向进行解读。

 

Donk教授：目前有多种靶向BCMA的CAR-T细胞疗法。Cilta cel的长期随访数据显示，高度预处理（heavily pretreated）患者中位无进展生存期（PFS）为3年。这意味着由中国传奇生物（LEGN）公司开发的Cilta cel实际上是治疗三级难治性多发性骨髓瘤最有效的药物。我们还有Ide-cel细胞，在这种情况下也有效，但中位PFS稍短，约为11个月。在本次欧洲血液学协会（EHA）和美国临床肿瘤学会（ASCO）会议上，有一项非常有趣且重要的研究。该研究将Cilta cel被用于更早线治疗，即先前接受过1-3线治疗的患者。与标准治疗[如达雷妥尤单抗/泊马度胺/地塞米松（DPD）或泊马度胺/硼替佐米/地塞米松（PVD）]相比，Cilta cel表现出明显的优势。因此，希望在不久将来，Cilta cel被批准用于在1-3线治疗，这样我们就能够比现在更早地使用Cilta cel。另外还有一项研究——KARMMA研究，在稍后的阶段也显示出Ide-cel相较标准治疗的优势，但这种优势略小于CARTITUDE-4研究中看到的优势。

 

Oncology Frontier：As one of most important treatments for relapsed/refractory multiple myeloma(RRMM)，target exploration is a key issue for CAR-T.Firstly，Could you first talk about the current progress in RRMM CAR-T targets?

 

So various CAR-T cell therapies are targeting BCMA.So we have data from Cilta cel with prolonged follow up showing median progression free survival now of three years.So three year median PFS in heavily pretreated patients shows that Cilta cel is in fact the most effective agent in triple class refractory disease.And you know that the vector was originally developed by LEGN in China.We also have ID cell which is also effective in this setting，but the median PFS is a little bit less，it’s approximately eleven months.And at this EHA meeting and also shown at ASCO is a very interesting and important study where Cilta cel was given in earlier lines of treatment，namely patients with one to three prior lines of treatment.And Cilta cel was compared with standard of care treatment either with DPD or with PVD and there was a big advantage of Cilta cel over standard of care.So hopefully in the nearby future，Cilta cel will be approved for one to three prior lines of therapy and then we will be able to give Cilta cel earlier on than we are currently doing.And another study was the KARMMA study in a slightly later setting，also showing advantage of ID cell over standard of care，but the advantage was a little bit less than what you see in CARTITUDE-4.

Donk教授：我们进行了MAJESTEC-1研究，按II期推荐剂量，Teclistamab单药治疗165例患者。经过近两年的随访，我们观察到在接受过高度预处理的骨髓瘤患者中，总体反应率（ORR）达到63%，这些是既往接受过中位5线治疗的患者，其中3/4患者属于三级难治性多发性骨髓瘤。令人欣喜的是，Teclistamab单药治疗的患者不仅反应率高，而且反应深度也非常好，有45%的患者完全缓解，几乎所有患者的反应达到很好的部分缓解（VGPR）及以上。转化成中位PFS为11个月，中位反应持续时间为22个月。对于完全缓解的患者，中位反应持续时间甚至可达到27个月。在治疗过程中，细胞因子释放综合征（cytokine release syndrome）是一个显著的副作用，但可以通过使用Tocilizumab或类固醇进行很好的控制。此外，感染在这些患者中很常见，但我们对感染管理有了越来越多的了解，例如使用Cotrimoxazole和静脉免疫球蛋白（IVIG）补充剂的鸡尾酒疗法。

 

Oncology Frontier：An poster study reported by your team(P911)use TECLISTAMAB(TEC)targeting BCMA and CD3 in patients with relapsed/refractory multiple myeloma(RRMM).Could you talk about this study in detail?

 

We have done the MAJESTEC-1 study and in this study we have treated 165 patients at the recommended phase two dose with Teclistamab as a monotherapy.And now with a follow up of almost two years，we see overall response rate of 63%in very heavily pretreated myeloma patients，median of five lines of therapy，and three quarters being triple class refractory，and not only high response rate but also depth of response was very good with 45%complete remission and almost all the patients having a VGPR or better.And this translated into a median progression free survival of eleven months and a median response duration of 22 months.And if you achieve a complete remission then your median response duration was even 27 months.Cytokine release syndrome is an important side effect but this is very well managed with Tocilizumab if needed or steroids as an alternative.Infections are common，but we know more and more how to manage infections，for example with the cocktail of cotrimoxazole and IVIG supplementation.

 

Donk教授：基于CAR-T细胞疗法在RRMM患者中的卓越效果，CAR-T细胞疗法正朝着早线治疗发展。我们即将开展一项研究——CARTITUDE-6，将对Cilta cel与移植疗法进行比较，CARTITUDE-5研究已经评估了Cilta cel在不适合接受移植患者中的疗效，并与使用硼替佐米/来那度胺/地塞米松（VRD）方案的对照组进行比较。此外，我们还评估了Ide-cel在接受移植疗法后仍存在残留疾病的患者中的效果。因此，CAR-T细胞疗法正从疾病晚期治疗向早线治疗延伸。其他未来前景，我认为我们将使用不同的靶点，不仅仅是BCMA，而且希望能将靶点结合起来，实现双重靶向，防止抗原逃逸，从而改善PFS和反应持续时间。也许我们还将了解更多关于防止T细胞耗竭的策略，例如，使用来那度胺等药物来改善T细胞功能并防止T细胞耗竭。

 

Oncology Frontier：Could you please talk about the future research direction of CAR-T treatment in RRMM，and the subsequent research ideas of your team?

 

Based on the high efficacy of CAR-T cell therapy in patients with relapse refractory myeloma，CAR-T cell therapy is now also moving to earlier lines.So soon a study will start where we will test Cilta cel versus transplant CARTITUDE six，and the CARTITUDE Five study is already evaluating Cilta cel in transplant ineligible patients with a comparative arm VRD and also Ide-cel is being evaluated post transplant in patients that still have residual disease.So CAR-T cells are moving from advanced states of disease to earlier lines of therapy and other future prospects is that I think we will use different targets，not only BCMA，but hopefully we can combine targets so dual targeting to prevent antigen escape and thereby improve progression free survival response duration.And maybe we also will be learning more about strategies to prevent diesel exhaustion.For example with Lenalidomide，agents that can improve T cell function and prevent T cell exhaustion.

 

Niels Van de Donk教授

阿姆斯特丹大学医学中心（AMC-UvA）

首席研究员、血液学教授、癌症免疫学教授，阿姆斯特丹癌症中心（CCA）癌症治疗和生活质量医学专家、癌症生物学和免疫学医学专家