修订的国际分期系统（R-ISS）对初诊多发性骨髓瘤患者预后评估价值及局限性

Prognostic value and limitations of the revised international staging system in newly diagnosed multiple myeloma

    摘要
  • 摘要:
      目的  探讨修订的国际分期系统（revised international staging system，R-ISS）在真实世界中对初诊多发性骨髓瘤（multiplemyeloma，MM）患者预后评估价值及局限性。
      方法  回顾性分析2002年6月至2017年11月中国医学科学院血液病医院新诊断的568例MM患者临床资料。所有患者均接受基于硼替佐米或沙利度胺/来那度胺为主的方案诱导治疗≥4个疗程。以ISS分期为对照，分析R-ISS分期的预后意义。考虑到R-ISSⅡ期的MM患者之间存在较大的异质性，本研究将R-ISSⅡ期患者分成四组：第1组患者ISSⅠ期伴有乳酸脱氢酶（lactate dehydrogenase，LDH）水平升高或高危遗传学异常；第2组患者ISSⅡ期无LDH水平升高及高危遗传学异常；第3组患者ISSⅡ期伴有LDH水平升高或高危遗传学异常；第4组患者ISSⅢ期无LDH水平升高和高危遗传学异常。在此分组条件下对这部分患者进行生存分析。
      结果  568例MM患者中，男性347例，女性221例，中位发病年龄56（25~83）岁，中位随访33（4~203）个月。采用R-ISS分期，Ⅰ、Ⅱ、Ⅲ期患者分别为59例（12%）、310例（62%）、130例（26%），中位总体生存（median overall survival，mOS）时间分别为142、86和40个月（χ2=29.588，P < 0.001）；采用ISS分期，Ⅰ、Ⅱ和Ⅲ期患者分别为106例（19%）、210例（37%）和252例（44%），mOS时间分别为142、71和40个月（χ2=22.099，P < 0.001）。采用Cox回归分析，ISS分期Ⅲ期对Ⅰ期HR=2.903，P < 0.001，ISS分期Ⅱ期对Ⅰ期HR=1.985，P=0.005；而R-ISS分期Ⅲ期对Ⅰ期HR=5.441，P < 0.001，R-ISS分期Ⅱ期对Ⅰ期HR=2.844，P=0.003。R-ISS分期Ⅱ期的4组患者的mOS时间分别为126、83、49（95%CI：33~65）、65（95%CI：44~86）个月（P=0.131）。总体上，四组OS无显著性差异，但是第2组和第3组OS相比呈显著性差异（χ2=4.916，P=0.027）。
      结论  R-ISS分期相对于ISS分期能够更好地区分MM患者预后。对于有髓外浸润、有1q21扩增、不同年龄分组（年龄≥65岁和年龄 < 65岁）、不同治疗方案（硼替佐米治疗组及沙利度胺治疗组）、不同染色体倍数（低二倍体、非低二倍体）的患者OS均具有较高的预后判断价值。但R-ISS分期同为Ⅱ期患者的生存情况仍存在差异，需要临床上予以重视。

     

    Abstract:
      Objective  To evaluate the prognostic value and limitations of the revised international staging system (R-ISS) in newly diagnosed multiple myeloma (MM).
      Methods  The clinical data of 568 patients newly diagnosed with MM in Institute of Hematology & Blood Diseases Hospital from June 2002 to November 2017 were retrospectively analyzed. All patients received induction therapy with bortezomib or thalidomide/lenalidomide for at least 4 cycles. The prognostic significance of R-ISS was analyzed by comparing it to the international staging system (ISS). Considering the great heterogeneity between MM patients in R-ISS phase Ⅱ, we assigned the patients in this phase into four groups: the first group was characterized by elevated lactate dehydrogenase (LDH) levels or high-risk genetic abnormalities in ISS stage Ⅰ; the second group patients did not have elevated LDH levels and high-risk genetic abnormalities in ISS stage Ⅱ; the third group patients had elevated LDH levels or high-risk genetic abnormalities in ISS stage Ⅱ; and the fourth group patients had no LDH or high-risk genetic abnormalities in ISS stage Ⅲ. Survival analysis was performed among these groups.
      Results  Among the 568 newly diagnosed MM patients, 347 were male and 221 were female, with a median age of 56 (25-83) years. The median follow-up period was 33 (4-203) months. Under the R-ISS, 59 (12%), 310 (62%), and 130 (26%) patients had stage Ⅰ, Ⅱ, and Ⅲ disease, respectively. The median overall survival (mOS) in the corresponding patients were 142, 86, and 48 months, respectively (χ2=29.588, P < 0.001). Under the ISS, 106 (19%), 210 (37%), and 252 (44%) patients had stage Ⅰ, Ⅱ, and Ⅲ disease, respectively. The median OS in the corresponding patients were 142, 71, and 63 months, respectively (χ2=22.099, P < 0.001). The hazard ratio (HR) of Ⅲ vs. Ⅰ, Ⅱ vs. Ⅰ of ISS system were 2.903 (P < 0.001) and 1.985 (P=0.005). The HR of Ⅲ vs. Ⅰ, Ⅱ vs. Ⅰ of R-ISS system were 5.441 (P < 0.001) and 2.844 (P=0.003). The median OS of the four groups in R-ISS Ⅱ were 126, 83, 49 (95% CI: 33-65), and 65 (95% CI: 44-86) months (P=0.131), respectively. In general, there were no significant differences in OS between the four groups; however, there were significant differences between groups 2 and 3 (χ2=4.916, P=0.027).
      Conclusions  R-ISS is better than ISS for differentiating the prognosis of MM patients. The R-ISS has a strong prognostic value for OS in patients with extramedullary infiltration or 1q21 amplification, for those in different age groups (age ≥65 years and age < 65 years), for those with different treatment schemes (bortezomib and thalidomide treatment groups), and for those with different chromosome multiples (low diploid and non-low diploid). However, the survival differences between the R-ISS stage Ⅱ patients still need clinical concern.

     

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