Y染色体丢失在多发性骨髓瘤患者中的临床意义

Clinical significance of loss of chromosome Y in patients with multiple myeloma

目的探究Y染色体丢失(LOY)在多发性骨髓瘤(MM)患者中的风险分层及预后意义。方法回顾性分析2018年1月至2020年1月复旦大学附属中山医院收治的193例男性初诊MM患者的临床资料,根据初诊染色体核型结果分成正常核型组(178例)与伴LOY核型组(15例)。采用秩和检验、2×2列联表卡方检验和独立样本t检验比较2组间肝肾功能、免疫组化和细胞遗传学等实验室检查结果、治疗疗效及生存预后等情况,通过生存分析及Cox回归探究LOY的临床预后。结果初诊男性MM患者LOY的发生率为8%(15/178)。伴LOY组的修订的国际分期系统(R-ISS)Ⅲ期患者比例(8/15)高于正常核型组(40/178)(χ^(2)=7.052,P<0.01),且发生1q21扩增的比例(10/13)高于正常核型组(77/162)(χ^(2)=4.159,P<0.05)。正常核型组在完成第4周期化疗后达到完全缓解(CR)/严格意义的完全缓解(sCR)的比例(63/171)高于伴LOY组(1/15)(χ^(2)=5.564,P<0.05),发生疾病进展(PD)的比例(16/171)也低于伴LOY组(4/15)(χ^(2)=4.306,P<0.05)。伴LOY组MM患者的2年无进展生存期(PFS)较正常核型组短(Z=‒3.201,P<0.01)。单因素生存分析结果显示,肌酐≥93μmol/L、β2微球蛋白(β2-MG)≥4.0 mg/L、血清游离轻链比值(sFLC)<0.06、骨髓浆细胞(BMPC)比例≥30%、R-ISSⅢ期、化疗4周期后未达CR/sCR及伴LOY、1q21扩增、P53缺失和t(4;14)遗传学异常的初诊MM患者PFS缩短(P均<0.05);Cox回归分析显示,肌酐≥93μmol/L(HR=4.460,95%CI 1.615~12.314,P=0.004)、sFLC<0.06(HR=2.873,95%CI 1.206~6.849,P=0.017)、化疗4周期后未达CR/sCR(HR=3.522,95%CI 1.437~8.634,P=0.006)及伴LOY(HR=3.485,95%CI 1.473~8.249,P=0.006)为影响初诊MM患者PFS的独立危险因素。结论LOY对初治MM患者的疗效与预后有重要的临床意义,是不良预后的独立危险因素,或可成为新型的临床评估指标。

Objective To explore the risk stratification and prognostic significance of loss of chromosome Y(LOY)in patients with multiple myeloma(MM).Methods The clinical data of 193 male patients with newly diagnosed MM admitted to Zhongshan Hospital of Fudan University from January 2018 to January 2020 were analyzed retrospectively and divided into a normal karyotype group(178)and a LOY karyotype group(15)according to the results of their primary conventional cytogenetics.Rank sum test,2×2 chi-square test and independent sample t-test were used to compare laboratory findings,such as liver and kidney function,immunohistochemistry and cytogenetics,treatment efficacy and survival prognosis,between the two groups.The clinical prognostic significance of LOY was summarized through survival analysis and Cox regression.Results Among the newly diagnosed male MM patients,8%(15/178)were confirmed with LOY cases.The proportion of patients with Revised International Staging System(R-ISS)stageⅢwas significantly higher in the LOY group(8/15)than that in the normal karyotype group(40/178)(χ^(2)=7.052,P<0.01).A higher proportion of 1q21 amplification also occurred in the LOY group(10/13 vs 77/162)(χ^(2)=4.159,P<0.05).The proportion of complete response(CR)/stringent complete response(sCR)in the normal karyotype group after the fourth chemotherapy(63/171)was significantly higher than that in the LOY group(1/15)(χ^(2)=5.564,P<0.05).The proportion of progressive disease(PD)was lower in the normal karyotype group(16/171 vs 4/15)(χ^(2)=4.306,P<0.05).The 2-year progression-free survival(PFS)of MM patients for the LOY group was significantly shorter compared to that for the normal karyotype group(Z=‒3.201,P<0.01).Univariate survival analysis showed that PFS was significantly shorter in newly diagnosed MM patients with Creatinine(Cr)≥93μmol/L,β2-microglobulin(β2-MG)≥4.0 mg/L,serum free light chain(sFLC)<0.06,bone marrow plasma cells(BMPC)≥30%,R-ISS stageⅢ,failure to achieve CR/sCR after the fourth chemotherapy,with LOY,1q21 amplification,P53 deletion and t(4;14)(P<0.05).Cox regression analysis showed that Cr≥93μmol/L(HR=4.460,95%CI 1.615-12.314,P=0.004),sFLC<0.06(HR=2.873,95%CI 1.206-6.849,P=0.017),failure to achieve CR/sCR after the fourth chemotherapy(HR=3.522,95%CI 1.437-8.634,P=0.006)and with LOY(HR=3.485,95%CI 1.473-8.249,P=0.006)were independent risk factors for PFS in newly diagnosed MM patients.Conclusions LOY is an independent risk factor for poor prognosis.It is important for the clinical outcome and prognosis of patients with newly diagnosed MM,and may become a novel clinical assessment indicator.