【作者】 李春霞；

【导师】 孙慧；

【作者基本信息】 郑州大学 ， 临床医学（专业学位）， 2013， 硕士

【摘要】 前言多发性骨髓瘤(multiple myeloma,MM)是骨髓中单克隆浆细胞异常增生并分泌M蛋白,导致相关器官或组织损伤的造血系统恶性肿瘤,约占造血系统肿瘤的10%,排名第二,多发于中老年人,发病中位年龄约为65岁,其男女比例约3：2。我国每年约有1.4万例新诊断的患者。未经治疗的MM患者的中位生存时间仅约6至12个月。多发性骨髓瘤因患者年龄较大,治疗完全缓解率低,易耐药,且复发率较高的特点,临床疗效不佳。治疗上,大剂量化疗联合自体造血干细胞移植,虽能提高完全缓解率,但易复发,不能从根本上治愈多发性骨髓瘤。异基因造血干细胞移植理论上可能治愈多发性骨髓瘤,但常因患者年龄较大,重要脏器功能不全及移植相关死亡率高等因素限制了其临床应用。大多数多发性骨髓瘤患者的治疗目的仍是延长生命,改善生活质量。化疗仍是最基本、最常用的治疗方法,可明显延长生存期。目前仍然以联合化疗为主,VAD是用于多发性骨髓瘤诱导治疗的经典化疗方案,强调长春新碱及多柔比星持续静脉点滴,以杀灭更多瘤细胞,但完全缓解率较低,不能明显延长生存期。近年来,随着硼替佐米等靶向治疗的新药在临床上的应用,MM的治疗进入了一个崭新的时代。硼替佐米是一种可逆的蛋白酶体抑制剂,其与地塞米松联用具有抗肿瘤作用,其能通过多种途径使细胞增殖的相关基因的表达下调,使瘤细胞凋亡,从而达到治疗的目的,使多发性骨髓瘤的治疗缓解率较前有大大的提高,生存期也明显延长,其应用给多发性骨髓瘤的靶向治疗带来了新的希望。许多研究证明,以硼替佐米为主的联合治疗可以有效提高多发性骨髓瘤的缓解率。众多联合新药方案被列入NCCN指南,MM患者的治疗已经有了更多的选择,选择不仅能提高疗效且能降低不良反应的化疗方案有重要意义。因此,以硼替佐米为主的BD化疗方案及其与传统的VAD化疗方案的临床疗效及不良反应率的对比具有了极其重要的意义,为临床选择化疗方案提供了可靠的依据。目的比较BD方案(硼替佐米+地塞米松)和VAD方案(长春新碱+多柔比星+地塞米松)或(长春地辛+吡柔比星+地塞米松)治疗多发性骨髓瘤患者的临床疗效和不良反应,为临床选择化疗方案提供依据。对象和方法1.病例资料：回顾性分析2008年1月至2012年12月郑州大学第一附属医院及信阳市中心医院血液科82例诊断为多发性骨髓瘤并给予BD方案或VAD方案规律治疗2-6周期的患者。82例患者均依据多发性骨髓瘤国内诊断标准[1]经骨髓细胞形态学、血清单克隆免疫球蛋白(M蛋白)检查确诊,并根据多发性骨髓瘤国际分期标准(ISS)[2]进行分期,按照免疫球蛋白和轻链类型进行分型。对82例患者进行信息采集,包括性别、年龄、血常规、血清蛋白电泳、免疫固定电泳、血(尿)轻链水平、白蛋白、β2微球蛋白、电解质、尿素氮、肌酐,骨髓象,胸部、颅骨、骨盆X线片,全身骨骼ECT等,并对这些资料进行统计分析。82例患者分为BD组与VAD组,两组患者年龄、性别、疾病分期、分型无明显统计学差异。BD组36例,其中男性20例,女性16例,年龄36至81岁,中位年龄58岁；IgG型20例,IgA型7例,IgM型1例,轻链型8例(κ轻链2例,λ轻链6例)；Ⅰ期3例,Ⅱ期10例,m期23例；初治20例,复发难治16例。VAD组46例,其中男性22例,女性24例,年龄40至83岁,中位年龄61岁；IgG型24例,IgA型12例,IgM型1例,轻链型9例(κ轻链3例,λ轻链6例)；Ⅰ期5例,Ⅱ期12例,Ⅲ期29例；其中初治34例,复发难治12例。2.治疗方案：BD方案：硼替佐米1.3mg/m2于3至5秒内静脉注射第1,4,8,11天,地塞米松20mg/d静脉滴注第1,2,4,5,8,9,11,12天,之后休息10天,21天一周期；郑州大学第一附属医院VAD方案：长春地辛针4mg静脉注射第1天,吡柔比星10mg/d静脉滴注第1-4天,地塞米松针20mg/d静脉滴注或口服,第1-4、9～12、17～20天,28天为一周期；信阳市中心医院VAD方案：长春新碱针0.4mg/m2·d持续静脉滴注24h第1-4天,多柔比星9mg/m·d持续静脉滴注24h第1-4天,地塞米松针40mg/d静脉滴注,第1-4、9-12、17～20天,28天为一周期。化疗过程中予以保肝、护胃、止吐等支持治疗,根据患者年龄、血糖、血压、感染及耐受情况适当调整激素用量,并给予双膦酸盐类药物治疗骨损害。两治疗组患者均应用沙利度胺片口服。3.观察指标：各治疗组化疗有效率及不良反应发生率。4.疗效判定：化疗2-6个疗程后全面评价疗效及不良反应；根据国际多发性骨髓瘤工作组(IMWG)疗效标准[3]进行疗效评价；按照国际肿瘤组织毒副作用统一命名法的标准NCICTCAE[4]第3版判断不良反应。5.统计学处理：应用SPSS17.0软件进行统计学处理,治疗有效率及不良反应率的比较采用X2检验和Fisher确切概率法,P<0.05为差异有统计学意义。结果1.多发性骨髓瘤患者经2-6个疗程BD方案或VAD方案化疗后骨痛症状、贫血、肾功能不全、高钙血症有不同程度的改善。BD治疗组：治疗总有效率为80.6%(29/36),CR27.8%(10/36),PR52.8%(19/36),其中肾功能不全患者、肾功能正常患者、轻链型患者、非轻链型患者、ISS Ⅰ期和Ⅱ期的患者、ISSⅢ期的患者治疗有效率分别为66.7%(8/12)、87.5%(21/24)、75.0%(6/8)、82.1%(23/28)、84.6%(11/13)、78.3%(18/23)；VAD治疗组：治疗总有效率为45.7%(21/46),CR8.7%(4/46),PR37.0%(17/46),其中肾功能不全患者、肾功能正常患者、轻链型患者、非轻链型患者、ISS Ⅰ期和Ⅱ期的患者、ISS Ⅲ期的患者治疗有效率分别为23.5%(4/17)、58.6%(17/29)、22.2%(2/9)、51.3%(19/37)、64.7%(11/17)、34.5%(10/29)。经X2检验和Fisher确切概率法处理,两种化疗方案治疗多发性骨髓瘤的总有效率差异有统计学意义(X2=10.339,P=0.001)；在肾功能不全组(P=0.022),肾功能正常组(X2=5.397,P=0.02),轻链型患者(P=0.035),非轻链型患者(X2=6.609,P=0.01),ISSⅢ期的患者(X2=9.702,P=0.002)治疗有效率差异均有统计学意义。而ISS Ⅰ期和Ⅱ期的患者(P=0.230)治疗有效率差异无统计学意义。2.化疗期间各治疗组不良反应发生率：BD治疗组患者出现血液学毒性6例(16.7%)；肝功能损害1例(2.8%)；感染8例(22.2%),其中3-4级2例(5.6%)；心脏毒性0例；外周神经毒性10例(27.8%),其中3-4级2例(5.6%)；消化道反应5例(13.9%)；乏力5例(13.9%)；水肿4例(11.1%)。VAD治疗组患者出现血液学毒性22例(47.8%),其中3-4级4例(8.7%)；肝功能损害9例(19.6%)；感染11例(23.9%),其中3-4级3例(6.5%)；心脏毒性7例(15.2%)；外周神经毒性10例(21.7%),其中3～4级1例(2.1%)；消化道反应19例(41.3%),其中3-4级2例(4.3%)；乏力13例(28.3%)；水肿3例(6.5%)。发生不良反应的患者总计：BD治疗组13例(36.1%),VAD治疗组29例(63.0%),两组总不良反应发生率差异有统计学意义(X2=5.863,P=0.015)。BD治疗组3-4级不良反应少见。结论1、BD治疗组的化疗总体有效率高于VAD治疗组,无论肾功能正常与否,疾病分期是否为轻链型。ISS分期为Ⅲ期的患者BD治疗组的化疗有效率高于VAD治疗组。2、与VAD治疗组相比,BD治疗组治疗过程中的不良反应发生率低,且多为轻度,严重毒副作用少见。更多还原

【Abstract】 ForewordMultiple myeloma is a hematopoietic malignancy, which is characterized by the hyperplasia of monoclonal plasma cell in bone marrow. It accounts for approximately10%of all hematologic malignancies. It happens in the elderly prone mostly, with a median age about65years old, male to female ratio is approximately3:2. In China, about14,000patients are newly diagnosed as multiple myeloma every year. The median survival time of untreated patients with multiple myeloma is six months to twelve months.Multiple myeloma has no good curative effect because of old age, low complete remission, high drug resistance, and high recurrence rate. Large dose chemotherapy combined with auto-HSCT can improve complete remission, but multiple myeloma is easy to recurrence, so it cann’t cue MM basically. Allo-HSCT may cure multiple myeloma in theory, but it is limited in clinical because of old age, significant organ insufficiency, and high transplant-related morality. The treatment goal of most MM patients is to prolong life, and improve the quality of life. Chemotherapy is the most basic and common choice, which can significantly improve survival time. Now, Combination chemotherapy is the most used treatment. VAD regimen is widely used, because the continuous intravenous injection of vincrinstine and doxorubicin can kill more tumor cells, but it can’t sharply improve the remission rate of MM or prolong survival.With clinical application of bortezomib and other new drugs, there is a rapid development in the treatment of multiple myeloma. Bortezomib is an ubiquitin-proteasome inhibitor, and the combination use with dexamethasone can have an anti-tumor effect. It can down-regulate the expression of cell proliferation genes through multiple methods, so as to cure MM, and shows new hope to the target therapy of MM. It can greatly improve the response rate, and prolong the lifetime. Many studies have proved that combination therapy with bortezomib can improve the remission rate of MM effectively. Accompanied with the emergence of these new drugs, many new drugs’combination regimens have been included in the NCCN guidelines, so patients with multiple myeloma have more choices. It is so important to choose a chemotherapy regimen, which can improve efficacy and reduce adverse reactions.Therefore, the observation of clinical efficacy and adverse reactions of BD regimen and traditional VAD regimen is so important, and it can provide reliable basis for the choice of clinical therapy.ObjectiveTo compare the therapeutic effects and side-effects in patients with multiple myeloma who are treated by BD regimen (bortozomib+dexamethasone) and VAD regimen (vincristine+doxorubicin+dexamethasone) or (vindesine+pirarubicin+dexamethasone), and provide reliable basis for the choice of clinical therapy.Methods1.Clinic data:82patients who were diagnosed multiple myeloma from January2008to December2012in Hematology of the first affliliated hospital of Zhengzhou university and Xinyang cenral hospital were analysed retrospectively, and were given regular treatment of BD regimen or VAD regimen2to6cycles.82patients were diagnosed according to the domestic diagnostic criteria for multiple myeloma through the bone marrow cell morphology, serum monoclonal immunoglobulin (M protein), were staged according to the Multiple Myeloma International Staging Standard (ISS) criterion, were classified according to the type of immunoglobulin and light chain, and were divided into BD regimen and VAD regimen according to their treatments. Collecting the information of the82patients, including gender, age, blood routine, serum protein electrophoresis, immunofixation electrophoresis, blood (urine) light chain levels, albumin, P2-microglobulin, electrolyte, urea nitrogen, creatinine, etc. There were no statistical differences of age, sex, stage and type between the two groups. There were36patients in BD group, including20males and16females, IgG20cases, IgA7cases, IgM1cases, light chain8cases (kappa light chain2cases and lambda light chain6cases); stage I3cases, stage Ⅱ10cases, stage Ⅲ23cases. There were46patients in the VAD group, including22males and24females, IgG24cases, IgA12cases, IgM1case, light chain9cases (kappa light chain3cases and lambda light chain6cases); stage15cases, stageⅡ12cases, stage Ⅲ29cases.2. Chemotherapy regimens:BD regimen:bortezomib1.3mg/m2intravenous injection (3-5second) dl, d4, d8, dll;dexamethasone20mg intravenous drip d1,2, d4,5, d8,9, dll,12; then rest10days,21days a period. VAD regimen of the first affiliated hospital of Zhengzhou university:vindesine4mg intravenous injection dl; pirarubicin10md/d intravenous drip d1～4; dexamethasone20mg/d intravenous drip d1～4, d9～12, d17～20,28days a period. VAD regimen of Xinyang central hospital: vincrinstine0.4mg/m2/d continuous intravenous injection24h, d1～4; doxorubicin9mg/m2/d continuous intravenous drip24h, d1～4; dexamethasone40mg/d intravenous drip d1～4, d9～12, d17～20,28days a period. Supporting treatments, such as protecting liver, PPI and antiemetics, were used in the chemotherapy course. The dexamethasone’s dosage was adjusted, depending on patients’age, glucose, blood pressure, infection, tolerance. Disphosphonate drugs were used to cure bone damage. Thalidomide tablets were taked by the patients of the two regimens.3. Obvervation index:the response rate and side effect rate of every regimen group.4. Efficacy criterion:The therapeutic effect and side effects of the two groups were evaluated comprehensively after2to6courses of chemotherapy. IMWG and NCICTCAE criteria were used to access therapeutic effect and side effects respectively.5. Statistical processing:The results were analyzed by SPSS17.0softwareX2test and Fisher exact propability were used to compare the response rate and side effect of the two regimen groups. P<0.05was considered to be statistically significant.Results1. Through2to6courses of BD regimen or VAD regimen chemotherapy, symptoms of multiple myeloma such as bone pain, anemia, renal insufficiency, hypercalcemia were relieved to some extent. BD regimen group:There were an overall response rate80.6%(29/36), CR27.8%(10/36), PR52.8%(19/36), patients with renal insufficiency response rate66.7%(8/12), patients with normal renal function response rate87.5%(21/24), patients with light chain response rate75.0%(6/8), patients without light chain response rate82.1%(23/28), ISS stage Ⅰ and ISS stage Ⅱ patients response rate84.6%(11/13),ISS stage Ⅲpatients response rate78.3%(18/23). VAD regimen group:overall response rate45.7%(21/46), CR8.7%(4/46), PR37.0%(17/46),renal insufficiency patients response rate23.5%(4/17), stable renal function patients response rate58.6%(17/29), light chain type patients response rate22.2%(2/9), patients without light chain response rate51.3%(19/37), ISS stage Ⅰ and ISS stage Ⅱ patients response rate64.7%(11/17), ISS stage Ⅲ patients response rate34.5%(10/29). Response rates were compared by x2test and Fisher exact propability, there was significant difference of the overall response rate between the BD regimen group and VAD regimen group(x2=10.339, P=0.001); and there were significant differences between groups of patients with renal insufficiency(P=0.022) and patients with normal renal function(X2=5.397,P=0.02), as well as light chain type patients(P=0.035), patients without light chain(%2=6.609, P=0.01), and ISS stage III patients(x2=9.702,P=0.002). But there was no significant difference between ISS stage Ⅰ and ISS stage Ⅱ patients (P=0.230).2. The side effects of everey group during the period of chemotherapy:the patients of BD regimen presented the following side effects:hematological toxicity6cases(16.7%); liver function damage1case(2.8%), infection8cases(22.2%),3to4 grade2cases(5.6%); cardiotoxicity0case; peripheral neuropathy10cases(27.8%),3to4grade2cases(5.6%); gastrointestinal reaction5cases(13.9%); weakness5cases (13.9%); edema4cases(11.1%). The patients of VAD regimen appeared side effects: hematological toxicity22cases(47.8%),3to4grade4cases(8.7%); liver function damage9cases(19.6%); infection11cases(23.9%),3to4grade3cases(6.5%); cardiotoxicity7cases(15.2%); peripheral neuropathy10cases(21.7%),3to4grade1cases(2.1%); gastrointestinal reaction19cases(41.3%),3to4grade2cases(4.3%); weakness13cases(28.3%), edema3cases (6.5%). Thirteen out of total36patients received BD regimen experienced side effects(36.1%), and twenty-nine out of total36patients received VAD regimen experienced side effects(63.0%). There was significant difference between the two groups’side effect rate(X2=5.863,P=0.015). BD regimen group had less3to4grade side effect.Conclusion1The overall response rate of BD regimen group is higher than that of VAD regimen group, regardless of renal function and disease’s type. In the treatment of patients with ISS stage Ⅲ the BD regimen is superior to VAD regimen.2Compared to VAD regimen, the side effect of the BD regimen is low and mild during the treatment, and serious side effects are rare.更多还原