本文選題：多發(fā)性骨髓瘤 + 免疫球蛋白D　； 參考：《第二軍醫(yī)大學(xué)》2017年碩士論文

【摘要】：背景與目的:多發(fā)性骨髓瘤(multiple myeloma,MM)是一種好發(fā)于老年人的漿細(xì)胞惡性克隆增殖性疾病,約占所有腫瘤的1%,占血液系統(tǒng)惡性腫瘤的10%,目前仍不能治愈。MM以骨髓漿細(xì)胞惡性增殖、血和/或尿中出現(xiàn)單克隆免疫球蛋白為主要特征,典型臨床表現(xiàn)為CRAB癥狀:高鈣血癥(hyper Calcemia)、腎功能損害(Renal insufficiency)、貧血(Anemia)、骨病(Bone lesions);以及由于免疫力下降導(dǎo)致的感染、高粘滯血癥等靶器官損害等,其臨床經(jīng)過及預(yù)后差異很大,疾病呈現(xiàn)明顯的異質(zhì)性。近年來,隨著靶向藥物免疫調(diào)節(jié)劑(immunomodulatory drugs,IMi D)和蛋白酶體抑制劑的廣泛使用,使得MM的治療取得了很大進(jìn)展,完全緩解率自5%左右提高至30%以上,患者總生存期從不足3年延長至5-7年。IgD型MM是一種少見的骨髓瘤類型,國外報(bào)道約占全部類型骨髓瘤的2%,國內(nèi)報(bào)道發(fā)生率約8%~10%,預(yù)后較差。關(guān)于IgD型MM的臨床特點(diǎn)及生存情況等,目前國內(nèi)尚無大樣本研究。因此,本研究回顧性分析了130例IgD型MM患者的臨床特點(diǎn)、治療療效、生存及預(yù)后,旨在加強(qiáng)我們對(duì)此類MM生物學(xué)特性的學(xué)習(xí),有助于臨床醫(yī)生在診療過程中做出正確的診療決策,分層個(gè)體化治療,從而進(jìn)一步提高此類患者的預(yù)后。方法:收集2002年1月至2016年8月在我科初診的130例IgD型MM患者臨床資料。其中2008年1月至2015年12月于我科收治的初診IgD型MM患者86例,而同期其他類型MM患者共計(jì)838例,包括IgG型MM患者411例,IgA型MM患者207例,輕鏈型MM患者199例,不分泌型MM患者17例,IgM型MM患者2例,雙克隆型MM患者2例。分析130例IgD型MM患者的中位發(fā)病年齡、性別、輕鏈類型、DS分期、ISS分期、Hb、PLT、肌酐、LDH、β2微球蛋白、ALB、血鈣、血清游離輕鏈(sFLC)及FISH異常的特點(diǎn);同時(shí)分析其療效、生存情況及預(yù)后因素。對(duì)比同期IgD與IgG及IgA型MM患者臨床資料,觀察IgD型MM臨床特點(diǎn)及療效生存與其他類型MM的差異。此外,進(jìn)一步分析IgD定量與M蛋白及iFLC的一致性,IgD型MM患者各細(xì)胞遺傳學(xué)異常之間的相關(guān)性。采用SPSS 21.0軟件進(jìn)行統(tǒng)計(jì)分析,正態(tài)性檢驗(yàn)采用Kolmogorov-Smirov法,計(jì)量資料如符合正態(tài)分布,采用兩獨(dú)立樣本t檢驗(yàn),以均數(shù)±標(biāo)準(zhǔn)差表示,如不符合正態(tài)分布,采用兩獨(dú)立樣本的非參數(shù)檢驗(yàn)(Mann Whitney U檢驗(yàn)),以中位數(shù)表示;計(jì)數(shù)資料的比較采用卡方檢驗(yàn)或確切概率法比較;兩分類變量一致性檢驗(yàn)采用Kappa檢驗(yàn);相關(guān)性分析采用Spearman相關(guān)分析;采用Kaplan-Meier檢驗(yàn)進(jìn)行生存分析,壽命表法估計(jì)生存率;應(yīng)用log-rank檢驗(yàn)對(duì)觀察指標(biāo)進(jìn)行單因素分析;并采用cox比例回歸模型對(duì)單因素分析中存在影響的因素進(jìn)行多因素分析;以p0.05為差異有統(tǒng)計(jì)學(xué)意義。結(jié)果:(1)130例igd型mm患者的中位發(fā)病年齡為55.5(33~83歲),以λ輕鏈型(94.6%)為主。相較于同期(2008.01-2015.12)的igg及iga型mm患者,86例igd型mm初診時(shí)Ⅲ期多見(ds-Ⅲ期:93.1%,iss-Ⅲ期:66.3%),且貧血[hb:82.5(38.0-146.0)g/l]、腎功能損害[cr:122.5(27.0-1058.0)μmol/l]、高鈣血癥[血鈣:2.48(1.5-4.21)mmol/l]、髓外侵犯(7.0%,6/86)更為突出。此外,igd型mm患者初診時(shí)ldh(197.5u/l,91.0-1622.0u/l)、β2mg(6.755mg/l,1.4-52.42mg/l)水平、漿細(xì)胞比例(43.0%,0%~100%)也明顯高于同期igg及iga型mm。(2)130例igd型mm患者中有103例行fish檢測(cè),igh易位、1q21擴(kuò)增、17p缺失、13q缺失的發(fā)生率分別為82.5%(85/103)、68.0%(70/103)、15.5%(16/103)、28.2%(29/103)。對(duì)于igh易位患者,我們進(jìn)一步進(jìn)行t(11;14)(q13;q32)、t(4;14)(p16;q32)、t(14;16)(q32;q23)雙色雙融合探針雜交,結(jié)果示:t(11;14)、t(4;14)、t(14;16)的發(fā)生率分別為45.5%(40/88)、4.5%(4/88)、0%(0/88)。同時(shí)我們對(duì)比了同期igd型mm與igg及iga型mm患者fish結(jié)果發(fā)現(xiàn):igd型mm中1q21+、t(11;14)發(fā)生率均明顯高于其他兩種類型。接著我們進(jìn)一步分析1q21+、t(11;14)與各細(xì)胞遺傳學(xué)異常之間的相關(guān)性,結(jié)果示:1q21+比例與igh易位比例存在相關(guān)性(r=0.3921,p0.0001),而與17p-、13q-均無相關(guān)性(p值均0.05);t(11;14)與17p-、13q-、1q21+均無相關(guān)性(p值0.05)。(3)130例igd型mm患者中有53例行血清游離輕鏈(sflc)檢測(cè),初診時(shí)iflc水平為1910.0(4.49~65908.0)mg/l。我們分別對(duì)比同期(2008.01-2015.12)igd型mm與igg型mm及iga型mm患者iflc結(jié)果發(fā)現(xiàn):igd型mm患者初診時(shí)iflc水平(1910.0mg/l,4.49~53477.0mg/l)明顯高于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例同時(shí)行igd定量檢測(cè)與血清游離輕鏈檢測(cè)。28例igd型mm患者中,2療程后igd、m蛋白、iflc下降量≥90%/50%~89%/50%分別為6/14/8例、9/12/7例、8/13/7例;4療程后igd、m蛋白、iflc下降量≥90%/50%~89%/50%分別為14/8/6例、15/7/6例、10/14/5例。2療程后kappaigd/m蛋白=0.447,kappaigd/iflc=0.606;4療程后kappaigd/m蛋白=0.535,kappaigd/iflc=0.449(p值0.05);故igd定量與m蛋白及iflc的下降量具有一致性,但是一致性強(qiáng)度一般。(5)130例igd型mm患者中位隨訪時(shí)間為24.3(0.6~103.0)個(gè)月,其orr(總體反應(yīng)率)為82.3%(107/130)。同時(shí)我們對(duì)比了同期(2008.01-2015.12)igd型及igg和iga型mm患者療效發(fā)現(xiàn),igd型mm患者orr率和igg型及iga型患者無差別;但cr率(10.5%vs12.6%vs21.8%)和vgpr以上緩解率(27.9%vs41.1%vs60.4%)差于其他兩種類型,差異有統(tǒng)計(jì)學(xué)意義,p值0.05。(6)130例IgD型MM患者死亡71例,進(jìn)展/復(fù)發(fā)92例,中位PFS為19.3個(gè)月,中位OS為31.1個(gè)月。同期(2008.01-2015.12)IgD型MM患者中位PFS及OS明顯比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例采用傳統(tǒng)化療方案誘導(dǎo)治療,108例采用以硼替佐米為基礎(chǔ)的聯(lián)合化療方案誘導(dǎo)治療。結(jié)果示:兩組CR率及VGPR率差異無統(tǒng)計(jì)學(xué)意義;但硼替佐米為基礎(chǔ)的聯(lián)合化療組ORR率明顯高于傳統(tǒng)化療方案組,ORR分別為86.1%和63.6%,p=0.012,差異有統(tǒng)計(jì)學(xué)意義。我們又進(jìn)一步比較兩組的生存情況發(fā)現(xiàn),傳統(tǒng)方案化療組中位PFS為19.3個(gè)月,中位OS為30.6個(gè)月;硼替佐米為基礎(chǔ)的聯(lián)合方案化療組中位PFS為19.2個(gè)月,中位OS為31.1個(gè)月(p0.05),未發(fā)現(xiàn)硼替佐米在IgD型MM中位生存時(shí)間方面的益處。(8)130例IgD型MM患者單因素分析結(jié)果顯示:Hb、PLT、LDH可影響患者生存期。多因素結(jié)果顯示:LDH水平是影響IgD型MM患者PFS及OS的獨(dú)立因素。LDH正常組中位PFS(21.3 VS 12.5個(gè)月,p=0.008)、中位OS(39.5 VS 21.6個(gè)月,p0.0001)均明顯長于LDH增高組(≥245U/L)。結(jié)論:IgD型MM患者發(fā)病率較低,中位發(fā)病年齡較年輕,多以λ輕鏈型為主,初診時(shí)Ⅲ期多見,更易發(fā)生貧血、腎功能損害、高鈣血癥和髓外侵犯,且患者腫瘤負(fù)荷(LDH、β2MG、iFLC水平、漿細(xì)胞比例)較高,1q21+、t(11;14)發(fā)生率較高,療效較差;盡管采用蛋白酶體抑制劑化療可獲得較高的ORR率,但未延長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,故建議聯(lián)合IgD定量檢測(cè)應(yīng)用于其療效評(píng)估。LDH水平是IgD型MM患者的獨(dú)立預(yù)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.

【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R733.3

【參考文獻(xiàn)】

相關(guān)期刊論文 前3條

1 劉彥;克曉燕;王晶;景紅梅;王繼軍;董菲;萬文麗;張巍;;IgD型多發(fā)性骨髓瘤的臨床療效分析[J];中國實(shí)驗(yàn)血液學(xué)雜志;2014年06期

2 顏綿生;梁鑒波;王松子;廖慧芳;;56例IgD型多發(fā)性骨髓瘤的分型研究[J];中國醫(yī)藥指南;2013年20期

3 李娟;趙瑩;羅紹凱;黃蓓暉;張國材;彭愛華;鄭冬;蘇暢;許多榮;童秀珍;谷景立;丁艷;;223例新診斷多發(fā)性骨髓瘤臨床特點(diǎn)及療效分析[J];中華醫(yī)學(xué)雜志;2008年30期

，

本文編號(hào)：1789347