IgD型多发性骨髓瘤临床特点、疗效及预后分析

发布时间：2018-04-22 23:08

本文选题：多发性骨髓瘤 + 免疫球蛋白D　；参考：《第二军医大学》2017年硕士论文

【摘要】：背景与目的:多发性骨髓瘤(multiple myeloma,MM)是一种好发于老年人的浆细胞恶性克隆增殖性疾病,约占所有肿瘤的1%,占血液系统恶性肿瘤的10%,目前仍不能治愈。MM以骨髓浆细胞恶性增殖、血和/或尿中出现单克隆免疫球蛋白为主要特征,典型临床表现为CRAB症状:高钙血症(hyper Calcemia)、肾功能损害(Renal insufficiency)、贫血(Anemia)、骨病(Bone lesions);以及由于免疫力下降导致的感染、高粘滞血症等靶器官损害等,其临床经过及预后差异很大,疾病呈现明显的异质性。近年来,随着靶向药物免疫调节剂(immunomodulatory drugs,IMi D)和蛋白酶体抑制剂的广泛使用,使得MM的治疗取得了很大进展,完全缓解率自5%左右提高至30%以上,患者总生存期从不足3年延长至5-7年。IgD型MM是一种少见的骨髓瘤类型,国外报道约占全部类型骨髓瘤的2%,国内报道发生率约8%~10%,预后较差。关于IgD型MM的临床特点及生存情况等,目前国内尚无大样本研究。因此,本研究回顾性分析了130例IgD型MM患者的临床特点、治疗疗效、生存及预后,旨在加强我们对此类MM生物学特性的学习,有助于临床医生在诊疗过程中做出正确的诊疗决策,分层个体化治疗,从而进一步提高此类患者的预后。方法:收集2002年1月至2016年8月在我科初诊的130例IgD型MM患者临床资料。其中2008年1月至2015年12月于我科收治的初诊IgD型MM患者86例,而同期其他类型MM患者共计838例,包括IgG型MM患者411例,IgA型MM患者207例,轻链型MM患者199例,不分泌型MM患者17例,IgM型MM患者2例,双克隆型MM患者2例。分析130例IgD型MM患者的中位发病年龄、性别、轻链类型、DS分期、ISS分期、Hb、PLT、肌酐、LDH、β2微球蛋白、ALB、血钙、血清游离轻链(sFLC)及FISH异常的特点;同时分析其疗效、生存情况及预后因素。对比同期IgD与IgG及IgA型MM患者临床资料,观察IgD型MM临床特点及疗效生存与其他类型MM的差异。此外,进一步分析IgD定量与M蛋白及iFLC的一致性,IgD型MM患者各细胞遗传学异常之间的相关性。采用SPSS 21.0软件进行统计分析,正态性检验采用Kolmogorov-Smirov法,计量资料如符合正态分布,采用两独立样本t检验,以均数±标准差表示,如不符合正态分布,采用两独立样本的非参数检验(Mann Whitney U检验),以中位数表示;计数资料的比较采用卡方检验或确切概率法比较;两分类变量一致性检验采用Kappa检验;相关性分析采用Spearman相关分析;采用Kaplan-Meier检验进行生存分析,寿命表法估计生存率;应用log-rank检验对观察指标进行单因素分析;并采用cox比例回归模型对单因素分析中存在影响的因素进行多因素分析;以p0.05为差异有统计学意义。结果:(1)130例igd型mm患者的中位发病年龄为55.5(33~83岁),以λ轻链型(94.6%)为主。相较于同期(2008.01-2015.12)的igg及iga型mm患者,86例igd型mm初诊时Ⅲ期多见(ds-Ⅲ期:93.1%,iss-Ⅲ期:66.3%),且贫血[hb:82.5(38.0-146.0)g/l]、肾功能损害[cr:122.5(27.0-1058.0)μmol/l]、高钙血症[血钙:2.48(1.5-4.21)mmol/l]、髓外侵犯(7.0%,6/86)更为突出。此外,igd型mm患者初诊时ldh(197.5u/l,91.0-1622.0u/l)、β2mg(6.755mg/l,1.4-52.42mg/l)水平、浆细胞比例(43.0%,0%~100%)也明显高于同期igg及iga型mm。(2)130例igd型mm患者中有103例行fish检测,igh易位、1q21扩增、17p缺失、13q缺失的发生率分别为82.5%(85/103)、68.0%(70/103)、15.5%(16/103)、28.2%(29/103)。对于igh易位患者,我们进一步进行t(11;14)(q13;q32)、t(4;14)(p16;q32)、t(14;16)(q32;q23)双色双融合探针杂交,结果示:t(11;14)、t(4;14)、t(14;16)的发生率分别为45.5%(40/88)、4.5%(4/88)、0%(0/88)。同时我们对比了同期igd型mm与igg及iga型mm患者fish结果发现:igd型mm中1q21+、t(11;14)发生率均明显高于其他两种类型。接着我们进一步分析1q21+、t(11;14)与各细胞遗传学异常之间的相关性,结果示:1q21+比例与igh易位比例存在相关性(r=0.3921,p0.0001),而与17p-、13q-均无相关性(p值均0.05);t(11;14)与17p-、13q-、1q21+均无相关性(p值0.05)。(3)130例igd型mm患者中有53例行血清游离轻链(sflc)检测,初诊时iflc水平为1910.0(4.49~65908.0)mg/l。我们分别对比同期(2008.01-2015.12)igd型mm与igg型mm及iga型mm患者iflc结果发现:igd型mm患者初诊时iflc水平(1910.0mg/l,4.49~53477.0mg/l)明显高于igg型mm(524.0mg/l,1.01~24569.0mg/l)及iga型mm患者iflc水平(269.9mg/l,2.10~30027.0mg/l),p0.0001。(4)130例igd型mm患者中有28例同时行igd定量检测与血清游离轻链检测。28例igd型mm患者中,2疗程后igd、m蛋白、iflc下降量≥90%/50%~89%/50%分别为6/14/8例、9/12/7例、8/13/7例;4疗程后igd、m蛋白、iflc下降量≥90%/50%~89%/50%分别为14/8/6例、15/7/6例、10/14/5例。2疗程后kappaigd/m蛋白=0.447,kappaigd/iflc=0.606;4疗程后kappaigd/m蛋白=0.535,kappaigd/iflc=0.449(p值0.05);故igd定量与m蛋白及iflc的下降量具有一致性,但是一致性强度一般。(5)130例igd型mm患者中位随访时间为24.3(0.6~103.0)个月,其orr(总体反应率)为82.3%(107/130)。同时我们对比了同期(2008.01-2015.12)igd型及igg和iga型mm患者疗效发现,igd型mm患者orr率和igg型及iga型患者无差别;但cr率(10.5%vs12.6%vs21.8%)和vgpr以上缓解率(27.9%vs41.1%vs60.4%)差于其他两种类型,差异有统计学意义,p值0.05。(6)130例IgD型MM患者死亡71例,进展/复发92例,中位PFS为19.3个月,中位OS为31.1个月。同期(2008.01-2015.12)IgD型MM患者中位PFS及OS明显比IgG型及IgA型MM患者生存期短,p值均0.0001。(7)130例IgD型MM患者中,22例采用传统化疗方案诱导治疗,108例采用以硼替佐米为基础的联合化疗方案诱导治疗。结果示:两组CR率及VGPR率差异无统计学意义;但硼替佐米为基础的联合化疗组ORR率明显高于传统化疗方案组,ORR分别为86.1%和63.6%,p=0.012,差异有统计学意义。我们又进一步比较两组的生存情况发现,传统方案化疗组中位PFS为19.3个月,中位OS为30.6个月;硼替佐米为基础的联合方案化疗组中位PFS为19.2个月,中位OS为31.1个月(p0.05),未发现硼替佐米在IgD型MM中位生存时间方面的益处。(8)130例IgD型MM患者单因素分析结果显示:Hb、PLT、LDH可影响患者生存期。多因素结果显示:LDH水平是影响IgD型MM患者PFS及OS的独立因素。LDH正常组中位PFS(21.3 VS 12.5个月,p=0.008)、中位OS(39.5 VS 21.6个月,p0.0001)均明显长于LDH增高组(≥245U/L)。结论:IgD型MM患者发病率较低,中位发病年龄较年轻,多以λ轻链型为主,初诊时Ⅲ期多见,更易发生贫血、肾功能损害、高钙血症和髓外侵犯,且患者肿瘤负荷(LDH、β2MG、iFLC水平、浆细胞比例)较高,1q21+、t(11;14)发生率较高,疗效较差;尽管采用蛋白酶体抑制剂化疗可获得较高的ORR率,但未延长IgD型MM患者生存期。IgD定量和M蛋白及iFLC下降量具有一定的一致性,故建议联合IgD定量检测应用于其疗效评估。LDH水平是IgD型MM患者的独立预后因素。
[Abstract]:Background and purpose: multiple myeloma (MM) is a malignant and proliferative disease of plasma cell, which accounts for about 1% of all tumors, accounting for 10% of the malignant tumor of the blood system. At present, it is still unable to cure the malignant proliferation of.MM with myeloid cells, and the main characteristics of the monoclonal immunoglobulin in blood and / or urine. Typical clinical manifestations are CRAB symptoms: hypercalcemia (hyper Calcemia), renal dysfunction (Renal insufficiency), anemia (Anemia), bone disease (Bone lesions), and target organ damage, such as infection caused by reduced immunity, high viscosity and other target organ damage, and its clinical and prognosis differ greatly. The extensive use of targeted drug immunomodulators (immunomodulatory drugs, IMi D) and proteasome inhibitors made great progress in the treatment of MM. The total remission rate increased from about 5% to more than 30%. The total survival period from less than 3 years to 5-7 years.IgD MM was a rare type of myeloma. Foreign reports accounted for about all types of myeloma. 2% of the type of myeloma, the domestic reported rate is about 8%~10%, the prognosis is poor. There is no large sample study on the clinical characteristics and survival of IgD type MM. Therefore, this study reviewed the clinical characteristics, therapeutic effect, survival and prognosis of 130 cases of MM patients, aimed at strengthening our study of the biological characteristics of this kind of MM. It is helpful for clinicians to make correct diagnosis and treatment decisions in the process of diagnosis and treatment, and to further improve the prognosis of these patients. Methods: to collect the clinical data of 130 patients with type IgD MM from January 2002 to August 2016 in our department. From January 2008 to December 2015, 86 cases of IgD type MM were treated in our department. In the same period, there were 838 patients with other types of MM, including 411 cases of IgG MM, 207 IgA MM patients, 199 light chain type MM patients, 17 non secretory MM patients, 2 IgM MM patients, and 2 double cloned MM patients. The characteristics of protein, ALB, blood calcium, serum free light chain (sFLC) and abnormal FISH, and the analysis of its efficacy, survival and prognostic factors. Compare the clinical data of IgD with IgG and IgA type MM patients at the same time, observe the clinical characteristics of IgD type MM and the difference between the survival and other types of MM in IgD, and further analyze the consistency of IgD quantitative and M protein and IgA. Correlation between cytogenetic abnormalities in type MM patients. Statistical analysis was made with SPSS 21 software. The normality test was used by Kolmogorov-Smirov method, measurement data such as Fu Hezheng distribution and two independent sample t test, with mean mean difference of standard deviation, such as non normal distribution, and non parametric test of two independent samples (Mann Whi). Tney U test), expressed in the median; the comparison of the count data was compared with the chi square test or the exact probability method; the two classification variable consistency test adopted the Kappa test; the correlation analysis adopted the Spearman correlation analysis; the survival analysis was carried out by the Kaplan-Meier test, the life table method was used to estimate the survival rate; the log-rank test was applied to the observation index. Single factor analysis and Cox proportional regression model were used to analyze the factors affecting the single factor analysis. The difference was statistically significant with P0.05. Results: (1) the median age of the 130 patients with IgD type mm was 55.5 (33~83 years), and was mainly of lambda light chain type (94.6%). Compared to the IgG and IgA type MM patients in the same period (2008.01-2015.12), 86 cases of type IgD mm were found in stage III (ds- III: 93.1%, iss- III: 66.3%), and anemia [hb:82.5 (38.0-146.0) g/l], renal function damage [cr:122.5 (27.0-1058.0) mu mol/l], hypercalcemia [blood calcium: 2.48 (1.5-4.21) mmol/l], and extramedullary invasion (7%). /l, 1.4-52.42mg/l) level, plasma cell ratio (43%, 0%~100%) also significantly higher than IgG and IgA mm. (2) 130 cases of IgD type MM patients, 103 cases of fish detection, igh translocation, 1q21 amplification, 17p deletion, 68% (103), 15.5% (28.2%), 28.2% (28.2%). For patients with translocation, we further proceed T (11; 14) (q13; q32), t (4; 14) (p16; q32), t (14; 16) (q32; q23) double color dual fusion probe hybridization, the results show that t (11; 14), t (4; 14), t (14; 16) respectively. Two types. Then we further analyzed the correlation between 1q21+, t (11; 14) and the cytogenetic abnormalities. The results showed that there was a correlation between the proportion of 1q21+ and igh translocation (r=0.3921, P0.0001), but no correlation with 17p-, 13q- (P value 0.05); t (11; 14) and 17p-, 13q-, (3) 130 patients with 5 The serum free light chain (SFLC) was detected in 3 cases, and the level of iflc was 1910 (4.49~65908.0) mg/l. at the first diagnosis. We compared the iflc results with the same period (2008.01-2015.12) IgD mm and IgG type mm and IgA mm. The iflc level of m patients (269.9mg/l, 2.10~30027.0mg/l), p0.0001. (4) 130 cases of IgD MM patients were detected simultaneously with IgD quantitative detection and serum free light chain detection in.28 cases IgD MM patients. %~89%/50% was 14/8/6, 15/7/6, kappaigd/m protein =0.447, kappaigd/iflc=0.606, kappaigd/m protein =0.535, kappaigd/iflc=0.449 (P value 0.05) after 4 course of treatment, so the quantitative consistency was consistent, but the consistency was general. (5) the median follow-up time of 130 patients was 24.3 (1). 0.6~103.0) for months, its orr (overall response rate) was 82.3% (107/130). At the same time, we compared the efficacy of the same period (2008.01-2015.12) IgD and IgG and IgA MM patients. The orr rate of IgD type MM patients was not different from those of the IgG type and the type of patients. Statistically significant, P value 0.05. (6) 130 cases of IgD type MM patients died in 71 cases, progression / recurrence 92 cases, median PFS for 19.3 months, OS for 31.1 months. Guided therapy, 108 cases were treated with bortezomib based chemotherapy. The results showed that there was no significant difference in the CR rate and the VGPR rate in the two groups, but the ORR rate in the bortezomizomi based combined chemotherapy group was significantly higher than that of the traditional chemotherapy regimen, and the ORR was 86.1% and 63.6%, and P =0.012, respectively, with statistical significance. We were further compared. Compared with the two groups, the median PFS in the traditional regimen chemotherapy group was 19.3 months and the median OS was 30.6 months. The median PFS of the bortezomizomi based combined regimen chemotherapy group was 19.2 months and the median OS was 31.1 months (P0.05). (8) the single factor analysis of 130 cases of IgD type MM patients was not found. The results showed that Hb, PLT and LDH could affect the patient's survival time. The results of multiple factors showed that the level of LDH was the independent factor of PFS and OS in IgD MM patients, the median PFS (21.3 VS 12.5 months, p=0.008). The age of the disease was much younger, mostly with lambda light chain type, more common in stage III at first diagnosis, more prone to anemia, renal impairment, hypercalcemia and extramedullary invasion, and the patient's tumor load (LDH, beta 2MG, iFLC level, plasma cell ratio) was higher, 1q21+, t (11; 14) had a higher incidence and poor curative effect, although chemotherapy with proteasome inhibitor could obtain higher ORR Rate, but there is a certain consistency between.IgD quantification and M protein and iFLC decline in the survival period of IgD type MM patients. Therefore, it is suggested that the combination of IgD quantitative detection and.LDH level in its efficacy assessment is an independent prognostic factor for patients with IgD type MM.

【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R733.3

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