《肿瘤瞭望》：近年来，多发性骨髓瘤在治疗上取得了重大突破，有专家预测骨髓瘤将成为一种慢性疾病，大部分患者可以获得持续的完全缓解。请介绍一下多发性骨髓瘤新的治疗策略？

　　Dr Grant:It is a very exciting time right now because over the last few years there have been a large number of quite promising new agents developed for the treatment of multiple myeloma. These include a number of agents that act as proteasome inhibitors like bortezomib and carfilzomib. The results with these agents， particularly in combination， are looking extremely promising both in the context of patients who have relapsed or refractory disease， and also where recent evidence has suggested that using these agents in combination in early stages of disease is an extremely effective strategy. That is very exciting， but in addition， there are a whole host of newer agents that show significant promise in multiple myeloma. These include a number of immune-based therapies such as anti-CD38 antibodies， which appear to be very effective. There is also tremendous interest in the use of agents that act as checkpoint inhibitors， the PD-1 and PD-L1 antagonists for example， which have shown impressive results in a number of solid tumors but may also have promise in multiple myeloma. There are a host of novel agents that areepigenetically acting agents (histone deacetylase inhibitors and a variety of kinase inhibitors) that may also be effective in myeloma.

　　So right now， there are many choices for new directions to pursue. I think the major challenge with these new agents that are showing efficacy is going to be finding the optimal way to use these agents， particularly in combination. There are many possibilities at this point. When we discover a new agent that looks to be effective， the initial tendency is to combine it with established regimens such as cytotoxic regimens and regimens employing dexamethasone and melphalan， which is certainly a logical approach.But right now we have a wealth of riches because there is the potential to combine these novel agents with each other. This is a very exciting area but it is going to be very challenging because we have so many agents to choose from to make up these combinations. On top of that， we have to consider the dosage of these agents and schedules of use. It is a daunting task but very exciting. It would be hard to believe that with these newer effective agents coming into clinical use that we weren’t going to be making significant inroads in converting multiple myeloma from a rapidly evolving disease in some cases into a more chronic disease that can be controlled.

　　Grant 教授：在过去几年里，针对多发性骨髓瘤治疗开发出了很多有治疗前景的新药，这令人鼓舞，包括蛋白酶体抑制剂，如硼替佐米和卡非佐米。这些药物的应用，尤其是联合用药的情况下，表现出极大地治疗前景，在复发难治患者中，以及最近有证据表明疾病早期的联合用药均十分有效。另外，还有很多新药也在多发性骨髓瘤的治疗中也显示明显的效果。这些包括一系列免疫治疗，如CD38单抗。目前对重要位点拮抗剂的使用也表现出极大兴趣，如PD-1和PD-L1拮抗剂，在对许多实体肿瘤中起抑制作用，对多发性骨髓瘤也有应用前景。此外，还有许多起表观遗传调控作用的新药出现，如去乙酰化酶抑制剂和一系列激酶抑制剂，对骨髓瘤的治疗也有效。因此，现在有很多治疗方向的选择。

　　对于这些新药，我认为最主要的挑战在于其使用方式，尤其在联合用药方面。这方面有很多可能性。当我们发现可能有效的新药时，我们首先考虑的就是其与现有治疗方案，如含细胞毒药物和包含地塞米松和马法兰的治疗方案的联合应用，这当然是合乎逻辑的选择。现在有很多治疗方案，在于这些新药的相互间的联合应用。这是一块令人鼓舞同时也颇具挑战的领域，因为我们有这么多的联合用药的治疗选择。同时，我们还需要考虑药物剂量和使用方式。机遇与挑战并存。通过这些新药临床使用，我们是否可以阻碍多发性骨髓瘤的进程，将其从迅速进展的疾病转向可以控制的慢性疾病，这仍有待长期的研究去验证。

　　《肿瘤瞭望》：新药，如卡非佐米（Carfilzomib）、泊马度胺（Pomalidomide）在治疗多发性骨髓瘤中的地位？

　　Dr Grant:These are two major success stories in the myeloma arena. With regard to carfilzomib， it is a proteasome inhibitor but a bit different from its predecessor， bortezomib， in that it is an irreversible inhibitor. The interest in carfilzomib has stemmed from observations that response rates in patients with relapsed or refractory myeloma are very impressive. In addition， a number of patients who have progressed on another proteasome inhibitor such as bortezomib have a very good chance of responding to carfilzomib so it can be used to overcome resistance to other proteasome inhibitors.

　　Pomalidomide is， in essence， a third-generation immunomodulatory agent. The immunomodulatory agents (originally thalidomide， subsequently revlimid) have shown activity and promise in multiple myeloma in combination. With pomalidomide again， excitement has stemmed from the fact that some patients who have progressed on earlier immunomodulatory agents， can respond to the newer agent. So there is quite a bit of excitement in incorporating these newer agents into combination regimens and even with each other.

　　Studies are showing that responses in patients with relapsed/refractory disease to these newer agents alone or in combination are very impressive， but response rates are also extremely high when using these agents upfront in the initial stages of disease. One of the challenges will be to determine the best way to use these agents. Should we reserve them for a time when patients have stopped responding to earlier generation agents or use them upfront in the hope of delaying or preventing the development of resistant disease? These two compounds are very promising and are undoubtedly going to be incorporated into combination regimens in the near future.

　　Grant 教授：这是骨髓瘤治疗中两大重要成果。卡非佐米，是蛋白酶体抑制剂，但是不同于前一代药物硼替佐米，它是一种不可逆抑制剂。对卡非佐米的研究兴趣来自于其在复发难治骨髓瘤中的有效率非常显著。另外，很多在使用硼替佐米后仍进展的患者中，对卡非佐米有效率高，因此可以用来治疗其他蛋白酶体抑制剂耐药者。

　　泊马度胺（Pomalidomide）事实上是三代免疫调节剂。免疫调节剂从最初的沙利度胺，到后来的来那度胺，在多发性骨髓瘤的联合治疗中表现出潜力。泊马度胺的出现令人鼓舞之处在于，一些在前两代免疫调节剂使用后仍进展的患者，对新一代药物仍有效。因此，将新药纳入联合治疗方案中，其治疗效果仍值得期待。

　　研究显示，无论是新药单用或者联合应用在复发难治患者中的有效率均十分明显，在疾病初始治疗阶段提前应用其有效率更高。问题之一在于使用这些新药的最佳方案。我们应当在前两代药物治疗无效时考虑应用，还是提前应用，以达到延缓或者阻止耐药性的发生？这两种药物的应用前景看好，毫无疑问，它们在不久将来会被纳入联合治疗方案中。

　　《肿瘤瞭望》：未来，MM治疗将在哪些方面有所突破？

　　Dr Grant: There are going to be many. Currently， there is a great deal of interest in specifically targeting certain subtypes of myeloma. It is a heterogeneous disease and investigators are very interested in looking at genetic abnormalities in myeloma and how they may predict response or non-response to particular targeted agents. That will undoubtedly be an area of active investigation. There is now also an appreciation that the karyotypic characterization (chromosomal aberrations， translocations， etc.) may also predict prognosis for myeloma and also allow physicians to treat patients with the appropriate agents. Patients who carry certain chromosomal aberrations such as t(11;14) may be responsive to regimens involving bortezomib， for instance. So we will be able to target patients both from the standpoint of genetic aberrations as well as chromosomal aberrations and so select the optimal agents and regimens to use. Finally， one area we are very interested in is the rational combination of agents. Agents should be combined not just because they are individually effective， but also because they interact at the molecular level to enhance each other’s activity resulting in synergistic anti-myeloma activity. With the abundance of new agents coming online， I think there will be tremendous opportunities for developing new and more effective molecularly rational combination regimens for patients with multiple myeloma.

　　Grant 教授：我认为未来在MM治疗上将会有很大突破。目前，大家的兴趣集中在骨髓瘤的分型上。这是一个异质性疾病，研究者专注于骨髓瘤遗传学异常以及这些异常为什么可以预测对特定药物的有效或者无效。这无疑是研究的重点。现在大家普遍认同依据染色体核型特征可以预测骨髓瘤预后，从而指导医生选择合适药物。对于携带特定染色体异常，如t(11;14)者对含有硼替佐米的治疗方案有效。因此，我们可以从基因、染色体异常角度选择合适药物和方案针对性地治疗患者。药物联合应用不仅仅是因为它们分别起效，同时它们在分子水平相互作用，增加对方效力，达到抗骨髓瘤的协同作用。随着大量新药的出现，我认为对骨髓瘤患者将有更多机会开发分子水平合理有效的新的联合用药方案。