《肿瘤瞭望》：活动期多发性骨髓瘤、冒烟型骨髓瘤以及意义未明的单克隆免疫球蛋白增高（MGUS）的患者，哪些监测指标有利于诊断和预测疾病进展？

　　Rajkumar教授：冒烟型骨髓瘤中高危的患者需每3~4个月监测一次血清单克隆M蛋白、游离轻链（FLC）比值，以及血常规、肌酐、钙离子浓度情况；每1~2年，进行低剂量CT或PET-CT的骨检测以排除疾病进展的可能。

　　In patients with smoldering multiple myeloma， for the high-risk patients you need to follow the serum monoclonal (M) protein， the serum free light chain (FLC) ratio， CBC， creatinine and calcium and monitor those every 3-4 months. Every year or two， you need to check the bones with either a low-dose CT-scan or PET CT-scan to make sure there is no progression.

　　《肿瘤瞭望》：冒烟型骨髓瘤患者的治疗干预时机？

　　Rajkumar教授：冒烟型骨髓瘤患者当符合骨髓瘤的诊断标准后需要进行治疗。鉴于骨髓瘤诊断标准已完成更新，我们可以在患者出现器官损伤前进行干预。对于高危的冒烟型骨髓瘤患者，我们应仔细监测，当有证据证实其已发展成为多发性骨髓瘤时，我们才开始治疗。

　　The intervention for smoldering multiple myeloma should start when patients meet the actual diagnostic criteria for myeloma. The diagnostic criteria for myeloma have been revised so you can actually start therapy before end-organ damage happens. So， monitor high-risk smoldering myeloma patients carefully and the moment they develop actual evidence of multiple myeloma in terms of meeting the myeloma defining events， then you start therapy. You start therapy in the same way you do for myeloma therapy.

　　《肿瘤瞭望》：体细胞突变在骨髓瘤疾病进展中起到何种作用？

　　Rajkumar教授：骨髓瘤的进展与其说是体细胞突变（SHM），不如说是浆细胞突变更确切。浆细胞发生的一系列突变累积到一定程度，便由良性的克隆细胞转化为恶性的多发性骨髓瘤细胞。这其中的突变包括：BRAF突变、p53突变、MYC突变以及DKK1的异常，此外还有许多各不相同的改变在突变的浆细胞中，致使其最终成为多发性骨髓瘤细胞。

　　目前我们尚不明确利用二代测序对于冒烟型骨髓瘤以及MGUS病人进行免疫球蛋白重链重排进行密切监测是否有意义。因为众多的突变浆细胞所携带的遗传信息可能不同于单个细胞的突变，而比较单个突变浆细胞与多发性骨髓瘤细胞的差异可能我们还不能做到。因此，目前有关多发性骨髓瘤的诊断我们多应用临床上的分子标志物，如FLC比值、del(17p)、 t(4:14) 等，而非分子细胞学标志物。

　　It is more like mutations within the plasma cells rather than somatic hypermutation. There are a number of mutations that happen in the plasma cell from the stage of embers that cause the embers， the benign clonal cells， to become malignant multiple myeloma cells. These include BRAF mutations， p53 mutations， mutations in MYC and then there are DKK1 abnormalities. Many different changes happen that make an embers clonal cell a multiple myeloma cell.</p> <p>&nbsp;</p> <p>　　We don&rsquo;t know yet whether to detect evidence of oligoclonality at the Ig heavy chain loci by next-generation sequencing (NGS) for patients make sense or not. The problem is that the ember cells almost always have all the genetic changes that a malignant cell has， so if you try to differentiate between a pre-malignant ember cell and a myeloma cell on a cellular basis， we are not able to. There are only some changes that are really specific for a myeloma cell. At present， we are using more clinical biomarkers like the serum free light chain ratio， the cytogenetic abnormalities [like del(17p)， t(4:14)， gain 1q]， and circulating plasma cells to classify patients into high-risk or low-risk， rather than molecular cellular biomarkers.

　　《肿瘤瞭望》：您如何看以优化疗效为目的基于异质性的差异分析以及个体化治疗？

　　Rajkumar教授：骨髓瘤是一种异质性疾病，每位患者的基因改变可能不同，因此才有现在的众多克隆。本届ASH年会的一个重要议题就是优化治疗的应用，目前我们已经表明三联治疗在多发性骨髓瘤治疗中有重要作用，加之造血胞干细胞移植治疗和维持治疗，可以将疗效进一步提高。骨髓瘤的异质性已是不争的事实，我们也没有必要在这上面深究或是比较哪种克隆更具有优势。这需要更多的研究来检测。

　　We have seen that there is heterogeneity in all patient myelomas. In every patient with myeloma， when you see a clone， it is already heterogeneous; there are many clones already present. The real point is to apply the best available treatments and at this meeting， we have shown that triplet therapies are important. We are using three drugs. Hopefully one will target one clone and then followed with stem cell transplantation and maintenance. We assume clonal heterogeneity is there in all patients with myeloma. We don&rsquo;t need to check for it; we assume it is there. I don&rsquo;t think monitoring different clones over time to see which is more dominant is practical. It is more of a research test.

　　专家简介：S. Vincent Rajkumar，MD 美国东部肿瘤协作组（ECOG）骨髓瘤委员会主席，梅奥诊所癌症中心多发性骨髓瘤淀粉样蛋白异常血症组主席，血液肿瘤专家，内科学教授，主要从事多发性骨髓瘤的临床试验与新的治疗策略研究，以及多发性骨髓瘤淀粉样蛋白异常血症的研究，担任Leukemia杂志编委，已发表文章374篇。</p>