《肿瘤瞭望》：新的检验技术发现了MM很多基因组学的改变，您认为哪些可能成为驱动MM发生发展的关键？

　　Munshi教授：MM的确有很多突变，每位患者大约有58个突变。其中，最常见的是RAS突变，包括NRAS和KRAS，大约1/4的患者会出现这种改变，所以MM不是一个单个基因驱动的疾病。如果尝试从这些基因中挑选出比较有意义的致病机制，那么最重要的是MEK/ERK通路，包括 NRAS、KRAS、BRAF 等等，大约45%~50% 的患者都存在这条信号通路的突变。研究表明，一些患者可以通过抑制该信号通路达到治疗的目的。

　　Multiple myeloma shows a lot of mutations， around 58 mutations per patient. However， no one single mutation is frequently observed. The commonest one is the RAS mutation， KRAS and NRAS. That occurs in 25% of patients. So it is not a disease that is driven by one mutation. If we try to make some sense out of all of this data， the commonest pathway (not the single mutation) that is mutated is the MEK/ERK pathway which includes NRAS， KRAS， BRAF and a few others. Around 45-50% of patients have involvement of this pathway by mutation and in some of those we can use treatment to inhibit the pathway to gain benefit.

　　《肿瘤瞭望》：虽然我们发现了MM中很多基因组改变，但是可转化为临床应用却非常少，是什么阻碍了这一转化过程？

　　Munshi教授：主要原因是由于不是所有的基因突变都具有意义。正如我的报告中提到，仅25~30%的基因突变是表达的，而70%不表达，对于不表达的基因我们无需阻滞，因为它们并不重要。虽然每个患者有50余种基因突变，但对细胞有作用的约有10~15个，这些才是我们需要进行阻滞的突变。而这部分突变也并不都在MM的发生发展中发挥重要作用。因此，我们的任务是发现哪些突变是功能性的并能驱动MM的发生发展，只有这样的突变受到抑制以后，才能发挥抗肿瘤作用。

　　另一个重要的原因是我们还要学会如何衡量诊断靶向突变的新型药物的治疗反应。如果一个患者的RAS突变细胞只占所有肿瘤细胞的30%，此时采用RAS特异性的药物治疗，这种药物只能抑制30%的肿瘤细胞，对其他的肿瘤细胞则无治疗作用，所以我们需要鉴定的是对那30%的细胞，药物能否发挥良好的作用，然后对余下的细胞再寻找其特异性的突变和恰当的药物，最后将上述药物联合进行治疗以达到最佳的治疗效果。这是最理想的治疗策略。还有一些突变的功能并不多，但它可以表达某种蛋白，此时应当采用免疫治疗策略进行治疗。所有的突变都可以通过免疫学方法鉴定是否具有功能，然后通过免疫学反应获得有效的治疗，这是未来的发展方向。

　　The main reason is that not all mutations are functional. In the data I showed today， only 25-30% of mutations are expressed. For the 70% that are not expressed， there is nothing you can do to block them because they are not important mutations. Even if there are 50 mutations， there are only 10 or 15 that are functional mutations that have an effect on the cell. Those are the ones that we can or should be able to block. Not all of the mutations that are expressed have an important role in myeloma. They may just be bystanders. So for us to find out which mutations are functional and which mutations are drivers so that when they are inhibited， we will see an effect. Another important point with all of these new studies into drugs that target mutations is that we also need to learn how to measure the response. If a patient has a RAS mutation that is present in only 30% of the cells and if we use a RAS-specific drug， it is only going to inhibit those 30%， not the other 70%. So we need to be able to identify how well a drug is working on that 30% and then work out how to best treat the remaining 70% by finding a second mutation and its inhibitor and a third mutation and its inhibitor. Then we can use a combination of specific inhibitors to get the best response. That is the best way to overcome that block. Finally， even if the mutation doesn’t have too much function but it makes the protein， then we can use the immunotherapy strategies that have been highlighted at this meeting. Immunology can be used to identify all the mutations and whether they are functional or not and then we can use the immune response to obtain an effective response. That is for the future.

　　《肿瘤瞭望》：关于MM的克隆进化存在一些假说，请阐明您的观点。

　　Munshi教授：MM克隆进化发生的原因很多，最重要的原因是肿瘤细胞的本质。细胞基因组不稳定性是一个发展的过程，基因组不稳定性导致了突变，其中有3个过程最重要：碱基切除修复、核酸切除修复和误配修复，它们是DNA修复中的3种不同途径。如果上述途径不能良好工作，则易于出现突变和克隆进化。这一理论非常重要，几十年前其发现者也因此获得诺贝尔奖。当然也有其他的方法，例如同源性重组、非同源性末端联合，也与克隆进化有关。目前，研究的重点是上述机制如何促进肿瘤克隆进化，以便可以通过干预阻止肿瘤克隆的进化。

　　Clonal evolution happens for many reasons. The most important reason is inherent in the cell. There are processes in the cell that make the genome unstable. Because of that instability， mutations occur. There are many processes but three of them are important – base excision repair， nucleotide excision repair and mismatch repair. Those three are DNA repair pathways. When they don’t function well， they can lead to mutation and clonal evolution. That’s important because those three processes which were identified several decades occur， got their discoverers the Nobel Prize for Chemistry this year. There are other methods like homologous recombination and non-homologous end joining that are also responsible for clonal evolution. Our research should be focusing on how they are causing the clonal evolution so that we might stop it.

　　《肿瘤瞭望》：硼替佐米是治疗MM的常用药，随着时间进展会出现耐药。我们是否应根据一些可以预测耐药的标志物来进行用药选择？

　　Munshi教授：目前，尚未有好的指标可以预测MM耐药。现有的蛋白酶体负荷和蛋白酶体功能这两指标还称不上是最好的标志物，至少目前我不会因为患者的一项指标而使用硼替佐米，事实是每位患者都该用硼替佐米，以便观察是否有效。现在有几种功能性分析方法用以测量蛋白酶体的活性，如果活性不高，说明药物不能很好地发挥作用。但是，耐药机制是多方面的，HDAC6活性增加时，患者出现聚积体途径活化，这有助于理解为什么患者会出现蛋白酶体抑制耐药，它也可以成为耐药的标志。就目前而言，我认为每位患者都应使用硼替佐米进行治疗，而无需根据指标进行选择。

　　There is no good biomarker for predicting when a patient would be resistant to bortezomib and when they are not. There is proteasome load or proteasome function but this is not the best biomarker. Right now， I will not use bortezomib because of a biomarker. We need to use it in everybody and see if it works or not. There are several functional assays being developed that measure proteasomal activity and if activity is not high， then the drug may not work. But additionally， there are various mechanisms of resistance. Patients can develop the aggresome pathway activation with higher HDAC6 activity， which may help us to understand why patients develop proteasome inhibition resistance and then they can be become markers for resistance. But right now， I think we should use bortezomib in everyone without selecting them for treatment or not based on markers.

　　《肿瘤瞭望》：对早期复发的MM，应当注意哪些方面？

　　Munshi教授：对于复发的MM，要考虑的问题很多，要想达到最好的疗效，应当注意以下的几个因素：（1）患者的初始治疗方案，这是最重要的影响因素，在MM复发后则应采用不同的治疗策略；（2）药物的副作用，如果患者已出现神经毒副作用，则应该采用硼替佐米以外的其他药物，如果患者的血细胞计数很低，则不应该再应用马法兰，来那度胺的剂量也需要调整；（3）基因组学，根据基因组学的特征，考虑相应的治疗手段，判定患者是高危还是低危，侵袭性是大还是小。

　　具体来说，如果患者在复发前接受的是移植治疗，再复发时我可能就不会再采用移植治疗。如果患者以往没有接受过移植治疗，复发时就应当考虑移植治疗。当然，临床工作中还有很多因素都要考虑，但是上述因素决定了我们应选用哪些药物进行治疗。目前，有十余种药物用于治疗MM，即便所有的药物都可以应用，使用时也要依照一定的次序，而且通常是联合用药。如果患者使用卡非佐米联合地塞米松治疗成功后复发，我还会在上述方案的基础上联合来那度胺或泊马度胺，以期获得更好的治疗反应。所以采用正确的药物组合也是非常关键的。

　　In relapsed myeloma， there are a number of considerations to look at. For the best course of treatment when somebody relapses， there are several factors to look at in making our decision. One of the main factors is what treatment did the patient receive initially， so in the case of relapse， something different can be used. Next we need to consider the side effects of the drug. If someone has developed neuropathy， then you will want to use something else other than Velcade (bortezomib). If patients had low blood counts， then you don’t want to use melphalan. If patients had kidney problems， then maybe you don’t want to use lenalidomide at the standard dose and you will need to modify it. Thirdly， there is genomics. If we know what the alterations are， we can begin to think about alternative treatments - high-risk versus low-risk， more aggressive versus less aggressive. If the patient received a transplant prior to relapse then I probably wouldn’t do a transplant at relapse. If the patient had not had a previous transplant， then at the time of relapse， I think we should consider using a transplant. There are many more factors but these are some of the factors that help us decide which drugs to use. The bottom line is， of the ten or so drugs we now have for myeloma， we have to use them in some succession， even use all of them if available， and often we will use them in combination. If a patient gets carfilzomib and dexamethasone and responds and eventually relapses， I would use the same combination but add lenalidomide or pomalidomide to get a better response. So using the right combinations is also very important.

　　专家简介

　　Nikhil C. Munshi， MD 哈佛医学院医学教授，基础及相关科学主任，Dana Farber癌症机构Jerome Lipper骨髓瘤中心副主任，美国NCI多发性骨髓瘤联合组长，国际骨髓瘤学会创始人之一，主要研究肿瘤基因不稳定性的分子机制，旨在帮助评价预后，提高诊断、治疗水平，目前的研究重点是多发性骨髓瘤的癌基因组学以及新型靶向治疗，包括针对抗原的疫苗、免疫治疗和小分子药物，已发表论文350余篇。