国际骨髓瘤基金会（IMF）主席Brian Durie教授

　　《肿瘤瞭望》：细胞遗传学对于多发性骨髓瘤的预后影响极大，目前有无基于细胞遗传学的分层治疗？

　　Dr.Durie：The risk stratification of myeloma is very important in attempting to provide the best treatment options for each patient. The problem is that even when we have some classification like mSMART (developed by the Mayo Clinic using cytogenetics and FISH to classify high- and low-risk)， the question remains which treatment we should use for high- and low-risk. Currently， we really don’t have a good treatment for high-risk patients. In the clinical trials in the US in the Southwest Oncology Group (SWOG)， we classify high-risk using a few features - 17P-， high-risk by gene expression profiling， high-risk based on high LDH or development of plasma cell leukemia or disease outside the bone marrow (extramedullary disease). For these patients we use standard therapy VRD (velcade， revlimid and dexamethasone) plus a new drug， alemtuzumab. Or we have a new protocol， VRD plus daratumumab (an antibody against CD38). We have new trials underway for the best treatment for high-risk myeloma but right now we don’t have a clear recommendation for individual patients coming into the clinic. For now， one strategy that is practical is to diagnose high-risk based on patients who relapse early. Lesser-risk patients can stay in remission for two years or longer. High-risk patients will relapse after one or two years. This is a very simple approach. For people with early relapse， we will introduce new drugs using multi-drug combinations. But this remains a major unmet need - how to treat high-risk versus low-risk patients?

　　Durie教授：多发性骨髓瘤的危险分层对患者提供最好的治疗选择十分重要。但尽管我们有像mSMART（由梅奥诊所利用细胞遗传学和FISH来划分的高低危患者）这样的分级系统，仍然存在一些疑问。对于高危我们确实还没有很好的治疗方案。在美国SWOG的临床研究中，我们将携带17p-、高风险基因表达、LDH水平高、进展为浆细胞白血病、有髓外进展者定义为高危组。对于这些患者，我们常使用标准的VRD化疗方案（包括硼替佐米、来那度胺和地塞米松）联合一种新药阿伦单抗或者daratumumab（CD38单抗）。我们正在进行一些新的对高危骨髓瘤患者最佳治疗方案的临床试验，但是目前对于临床上的个体化治疗我们并没有明确推荐。目前，一个诊断高危患者较实用的方法就是看是否早期复发，一般危险程度低的患者可以处于缓解状态达两年甚至以上，而高危患者将在一年或者两年后复发。对于早期复发的患者，我们推荐使用新药并且多药联合使用，但是这仍然是一个有待解决的问题。

　　《肿瘤瞭望》：今年3月，NCCN在血液肿瘤更新的指南中，强调微小残留病（MRD）的检测。请您谈谈MRD检测重要性和意义？

　　Dr.Durie：The IMF (International Myeloma Foundation) is very pleased to collaborate with several groups to develop the best MRD test. The most successful collaboration has been with the Spanish team and we are very pleased at this meeting here in Beijing， Dr Bruno Paiva from the Navarra University in Pamplona， Spain will discuss the use of next-generation flow for the assessment of MRD. This is a method using a special cocktail of monoclonal antibodies to identify the amount of minimal residual disease in the bone marrow.

　　With this standardized cocktail， we can have a very accurate way to identify myeloma at the level of one-in-a-million (one myeloma cell in one million cells counted). This is sufficient to identify patients who are having an extremely deep response and is a goal of the new approaches to treatment to achieve the maximum response and the maximum length of remission and survival. There is a new overall goal with MRD-negative as the best treatment goal for patients with myeloma. We are hopeful that the next-generation flow technique can be widely applied and will allow groups everywhere around the world to integrate this testing into their treatment protocols.

　　Durie教授：国际骨髓瘤基金会（IMF）非常愿意联合多个合作组制定最佳MRD检测方案，目前最成功的合作是同西班牙团队，我们很高兴在北京的这次大会上，来自西班牙纳瓦拉大学的Bruno Paiva博士介绍使用新一代流式技术对MRD的检测。这种方法采用独特的多种单抗方法来鉴定骨髓中的微小残留病灶量。通过这种标准化方案，我们能在百万数量级（一百万细胞中有一个骨髓瘤细胞）上对骨髓瘤进行精确的测定。这种方法可以鉴别出有较深治疗反应者，并且新的治疗方案的目的在于获得最大治疗反应和最长缓解及生存时间。未来，可能将MRD检测阴性作为骨髓瘤患者最佳治疗目标。我们希望下一代流式技术得到广泛应用，并且推动全世界各合作组将MRD检测应用于多发性骨髓瘤治疗方案的决策中。

　　《肿瘤瞭望》：对于MGUS/Smoldering MM早期无症状型MM患者，对于预后不良者的肿瘤及患者的影响因素有哪些？如何随访、早期治疗？

　　Dr.Durie：This is another important treatment strategy. How do we test and monitor and evaluate patients with early disease including MGUS and smoldering myeloma. We look very closely at patients with what we call high-risk smoldering MM. These are patients who have evidence of increasing disease and with abnormal immune testing in the bone marrow where there is a build-up of myeloma and suppression of the normal immune cells or where there is a significant increase in the abnormal free light chain ratio. We use these criteria to identify patients at the highest risk of developing active myeloma. This is very important because we know that if we want to achieve the best results， we should start early. The dilemma is to have treatment that is working well for patients who need it but we need to avoid giving therapy to patients who do not need therapy. For patients who could remain stable for one year or five years or even ten years， we don’t want to be giving them unnecessary treatment. So this is the key testing that we need to identify patients early in order to get the best results but only for patients who are really at risk for progressing in the near future (within eighteen months) to active myeloma. This is an extremely important area for research.

　　Durie教授：如何监测、评估疾病早期患者，如MGUS和冒烟型骨髓瘤。这是另一个重要的治疗困境。对于我们所谓的高危冒烟型MM患者，我们需要密切监测。这些患者在骨髓检测中显示骨髓瘤细胞增殖，正常免疫细胞受抑或者异常游离轻链比值增加。我们可以此鉴别出向活动性骨髓瘤高风险者。这一点非常重要，因为我们知道如果想获得最佳治疗结果，需要及早开始治疗。困境在于，我们需要弄清楚哪些患者需要治疗，而避免给予患者过度治疗。对于那些可以稳定一年，5年甚至10年的患者，我们不想给予不必要的治疗。因此，我们可以MRD检测为主要手段，在疾病早期将这类患者鉴别出来，以期获得最好的治疗结果。

　　《肿瘤瞭望》：疗效评估是骨髓瘤治疗的一个关键的决定因素。目前对于完全缓解（CR）的定义是否统一？

　　Dr.Durie：The criteria for complete remission are very important because we want to be able to be precise when comparing one treatment with another. Right now we need to have the best combinations so we use mostly triple therapies. Maybe the best one we have at the moment is Kyprolis (carfilzomib) with revlimid and dexamethasone. This achieves the highest level of complete remission. We can compare that to maybe just giving two drugs， revlimid and dexamethasone alone. The percentage that achieve a CR is obviously a lot higher with the three drugs versus two drugs. We need to have very precise definitions. So the International Myeloma Working Group has established these criteria and DrShaji Kumar is working on new criteria to make the stringent CR even better for use in clinical trials everywhere.

　　Durie教授：CR标准十分重要，凭借它我们可以比较哪种治疗方案更有效。目前，我们正需要找到最佳的联合方案。通常，我们以获得高标准的完全缓解作为目标。与单纯两药（如来那度胺和地塞米松）联合相比，三药联合CR率明显提高。对于CR，我们仍需要一个明确的定义，国际骨髓瘤工作组也制定了一些标准，目前Shaji Kumar博士正致力于建立严格的CR标准，以适应于各地的临床试验。

　　《肿瘤瞭望》：多发性骨髓瘤相关的周围神经病是骨髓瘤相关的最常见问题。对于该类重要的并发症有什么合适的应对措施？

　　Dr.Durie：Nerve damage can be caused by myeloma so there are patients in whom the myeloma protein damages the nerves to cause peripheral neuropathy. This is seen as loss of sensation (numbness of hands and feet) and sometimes is painful with pain in the hands and feet or arms and legs. Treatment for that is rather difficult. A key point is to diagnose early and avoid progression to severe neuropathy. Once there is nerve damage， it is difficult for the nerves to regenerate and recover well. This is also an area of active research and many labs are working to enhance nerve regeneration. For now though， the only two possibilities are: to treat early to avoid the development of peripheral neuropathy; or using medication to counter pain like gabapentin. If a patient has numbness， they need to be cautious of their activity to not cause damage to hands and feet because of the absence of pain or temperature sensation. This is a challenging problem and we strongly recommend that there is education for neurology teams so they would be aware that neuropathy can be caused by early myeloma and referrals are made for consultation and treatment for the myeloma. These are the current strategies to achieve the best outcomes in these cases.

　　Durie教授：由于骨髓瘤细胞分泌的蛋白会损害神经，因此骨髓瘤患者常引发外周神经病变。临床上可以表现为感觉丧失（手足麻木感），有时表现为手足或者四肢疼痛。对于这神经损害的治疗十分困难，重点在于早期诊断，避免进展为严重的神经病变。一旦发生神经损害，神经的再生和恢复非常困难。这也是研究的热点领域，很多实验室正致力于提升患者的神经再生功能。目前有两种可行方案：早期治疗避免外周神经病变的进展，以及使用加巴喷丁控制神经病理性疼痛。如果患者主诉麻木感，由于这些患者对疼痛或者温度感觉的缺失，因此在活动过程中需要注意避免对手足的损伤。这是一个具有挑战性的问题，在考虑骨髓瘤的治疗同时也需要神经科医生进行讨论，已达到治疗患者最好的效果。