BD方案与VAD方案治疗多发性骨髓瘤的临床观察
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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。
Foreword
Multiple 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.
Objective
To 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.
Methods
1.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.
Results
1. 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.
Conclusion
1The 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.
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。
Foreword
Multiple 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.
Objective
To 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.
Methods
1.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.
Results
1. 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.
Conclusion
1The 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.
引文
[1]张之南,沈悌.血液病诊断及疗效标准.第3版[M].北京：科学出版社,2007.232-233.
[2]Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma[J]. J Clin Oncol,2005,23(15):3412-3420
[3]Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma[J].Leukemia,2006,20(9):1467-1473
[4]Raab MS, Podar K, Breitkreutz I et al.Multiple myeloma[J].Lancet,2009,374(9686):324-39
[5]胡豫,孙春艳.多发性骨髓瘤的诊断进展[J].临床血液学杂志,2012,25(7)：406-410
[6]王吉耀,廖二元,黄从新等.内科学.第2版[M].北京：人民卫生出版社,2010.825
[7]中国多发性骨髓瘤工作组.中国多发性性骨髓瘤诊治指南(2011年修订)[J].中华内科杂志,2011,50(10)：892-896
[8]Zervas K, Mihou D, Katodritou E, et al. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma:results of a multicenter randomized trial of the Greek myeloma study group[J]. Ann Oncol,2007,18 (4):1369-1375
[9]王惠君,刘传方.T-VAD与T-VD方案治疗多发性骨髓瘤的临床分析[J].临床血液学杂志,2012,25(5)：311-313
[10]Lane SW,Gill D,Mollee PN, et al. Role of VAD in the initial treatment of multiple myeloma[J].Blood,2005,106(10):3674; author reply 3674-3675
[11]Myeloma trialist collaboration Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma:an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists'Collaborative Group[J].J Clin Oncol,1998,16(12): 3832-3842
[12]Blade J, Rosinol L, Cibeira MT, et al. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010[J]. Blood,2010,115(18):3655-3663
[13]Jimenez-Zepeda VH,Reece DE, Trudel S, et al. Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for heavily pretreated relapsed or refractory multiple myeloma[J]. Leuk Lymphoma,2013,54(3):555-560
[14]Held LA, Rizzieri D, Long GD, et al. A Phase I Study of Arsenic Trioxide (Trisenox), Ascorbic Acid, and Bortezomib (Velcade) Combination Therapy in Patients With Relapsed/Refractory Multiple Myeloma[J].Cancer Invest,2013,(Epub ahead of print)
[15]Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma[J]. Br J Haematol,2013, 160(5):649-659
[16]Lancaster S.Bortezomib:the evidence of its clinical impact in multiple myeloma[J]. Core Evid,2006,1(4):265-277
[17]廖爱军,王晓彬,王慧涵等.硼替佐米联合地塞米松治疗初诊多发性骨髓瘤的初步观察[J].中华肿瘤防治杂志,2009,16(6)：466-469
[18]黄月华.硼替佐米的作用机制、临床应用及其疗效进展[J].使用诊断与治疗杂志,2008,22(4)：280-282
[19]黄红铭,侯健,周帆,等.硼替佐米对多发性骨髓瘤患者破骨细胞分化和功能的影响[J].首都医科大学学报,2008,29(2)：124-127
[20]Eda H, Aoki K, Kato S, et al. The proteasome inhibitor bortezomib inhibits FGE-2-induced reduction of TAZ levels in osteoblast-like cells [J]. Eur J Haematol,2010,85 (3):68-75
[21]Hideshima T, Ikeda H, Chauhan D,et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells [J]. Blood,2009,114 (10):1046-1052
[22]Roccaro AM, Hideshima T, Raje N, et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells [J]. Cancer Res, 2006,66(1):184-191
[23]Meister S,Schubert U,Neubert K, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition [J]. Cancer Res,2007,67(4):1783-1792
[24]Manochakian R, Miller KC, Chanan-Khan AA. Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma [J]. Oncologist,2007,12(8):978-990
[25]刘爱军,李利红,黄仲夏,等.硼替佐米、地塞米松加或不加沙利度胺治疗多发性骨髓瘤67例疗效分析[J].中华血液学杂志,2010,31(7)：486-488
[26]Rosinol L,Oriol A, Mateos MV, et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma:efficacy and clinical implications of tumor response kinetics[J]. J Clin Oncol,2007,25 (8):4452-4458
[27]Gasparetto C, Gockerman JP, Diehl LF et al. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma [J]. Biol Blood Marrow Transplant,2010,16(1):70-77
[28]钟玉萍,陈世伦,李新,等.硼替佐米为主的化疗方案治疗60例多发性骨髓瘤患者的临床分析[J].中国实验血液学杂志,2009,17(1)：214-217.
[29]何群,赵谢兰,贺艳娟,等.硼替佐米联合地塞米松治疗多发性骨髓瘤的临床分析[J].中南大学学报(医学版),2010,35(8)：864-867
[30]纪春岩,陈晨,赵川莉,等.硼替佐米为主方案治疗多发性骨髓瘤患者的临床研究[J].中华血液学杂志,2011,32(4)：265-267
[31]Moumas E, Hanf W, Desport E, et al. New insights in the treatment of myeloma with renal failure. Nephrol Ther,2011,7(8):457-466
[32]Chanan-Khan A A, Kaufman J L, Mehtaj, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failures multi-center retrospective study[J]. Blood,2007,109(5):2604-2606
[33]高大,肖镇.大剂量地塞米松联合硼替佐米及沙利度胺治疗多发性骨髓瘤合并肾衰竭的临床研究[J].白血病·淋巴瘤,2012,21(10)：604-606
[34]San-Miguel JF, Richardson PG, Sonneveld P, et al. Efficacy and safety of bortezomib in patients with renal impairment:results from the APEX phase 3 study[J]. Leukemia,2008, 22(4):842-849
[35]Drayson M, Begum G, Basu S, et al. Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma:an analysis of patients receiving conventional dose chemotherapy in Medical Research Council UK multiple myeloma trials [J]. Blood, 2006,108(6):2013-2019
[36]Ohguchi H, Sugawara T, Ishikawa I, et al. A retrospective analysis of bortezomib therapy for Japanese patients with relapsed or refractory multiple myeloma:beta2-microglobulin associated with time to progression [J]. Int J Hematol,2009,89(3):342-347
[37]Kastritis E, Zervas K, Symeonidis A, et al. Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS):an analysis of the Greek Myeloma Study Group (GMSG)[J]. Leukemia,2009,23(6):1152-1157
[38]Yang GZ, Chen WM. Bortezomib-based regimen for the treatment of 110 multiple myeloma patients [J]. Zhonghua Yi Xue Za Zhi,2010,90(38):2671-2674
[39]Field-Smith A, Morgan GJ, Davies FE. Bortezomib (Velcade trade mark) in the treatment of multiple myeloma [J]. Ther Clin Risk Manag,2006,2(3):271-279
[40]Giralt S, Aleman A, Anagnostopoulos A, et al. Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma [J]. Bone Marrow Transplant, 2002,30(6):367-373
[41]李彩霞,吴德沛,孙爱宁,等.硼替佐米治疗多发性骨髓瘤的初步临床研究.白血病·淋巴瘤,2006,15(3)：349-350
[42]Corso A, Mangiacavalli S, Varettoni M, et al. Bortezomib-induced peripheral neuropathy in multiple myeloma:a comparison between previously treated and untreated patients [J]. Leuk Res,2010,34(4):471-474
[43]Corthals SL, Kuiper R, Johnson DC, et al.Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients[J]. Haematologica,2011,96 (11):1728-1732
[44]Topp KS, Tanner KD, Levine JD. Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat[J]. J Comp Neurol,2000,424(4):563-576
[45]Kruczynski A, Barret JM, Etievant C, et al. Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid[J].Biochem Pharmacol,1998,55(5):635-648
[46]Dyke RW, Nelson RL. Phase I Anti-cancer agents Vindesine [J].Cancer Treat REV,1977; 4 (5):135
[47]王洪涛,刘卓刚,杨伟,等.硼替佐米致周围神经病变的机制及还原型谷胱甘肽逆转神经毒性的研究[J].中华血液学杂志,2011,32(2)：107-111
[48]王建芳,王洪涛,刘卓刚.硼替佐米致周围神经病变的研究进展[J].中华血液学杂志,2012,33(2)：157-159
[49]Mateos MV, Richardson PG,Schlag R et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial [J]. J Clin Oncol.2010,28(13):2259-66
[50]Basler M, Lauer C, Beck U, et al. The proteasome inhibitor bortezomib enhances the susceptibility to viral infection [J]. J Immunol,2009,183(10):6145-6150
[51]Jung SH, Bae SY, Ahn JS, et al. Lymphocytopenia is associated with an increased risk of severe infections in patients with multiple myeloma treated with bortezomib-based regimens[J]. Int J Hematol,2013,(Epub ahead of print)
[52]崔秀珍,高秀珍.吡喃阿霉素和阿霉素临床观察对比[J].中国肿瘤临床,1994,21(9)：642-644
[1]Rajkumar SV.Treatment of multiple myeloma [J]. Nat Rev Clin Oncol,2011,8(8):479-491
[2]Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma:a clash of philosophies [J]. Blood,2011,118(12):3205-3211
[3]Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/Latinos,2012 [J]. CA Cancer J Clin,2012,62(5):283-298
[4]Kyle RA, Therneau TM, Rajkumar SV, et al. Incidence of multiple myeloma in Olmsted County, Minnesota:Trend over 6 decades [J]. Cancer,2004,101(11):2667-2674
[5]Ludwig H, Viterbo L, Greil R, et al. Randomized phase Ⅱ study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma [J]. J Clin Oncol,2013,31(2):247-255
[6]胡豫,孙春艳.多发性骨髓瘤的诊断进展[J].临床血液学杂志,2012,25(7)：406-410
[7]耿传营,陈文明.新诊断多发性骨髓瘤的危险分层治疗：来自2012年美国临床肿瘤学会年会的报道[J].白血病·淋巴瘤,2012,21(7)：390-392
[8]Barlogie B, Jagannath S, Deaikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma [J]. Blood,1999,93(1):55-56
[9]Myeloma trialist collaboration Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma:an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists'Collaborative Group [J]. J Clin Oncol,1998,16(12): 3832-3842
[10]Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma [J].Br J Haematol, 2013,160(5):649-659
[11]Roccaro AM, Hideshima T, Raje N, et al.Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells [J]. Cancer Res,2006,66(1): 184-191
[12]Meister S, Schubert U, Neubert K, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition [J].Cancer Res,2007,67(4):1783-1792
[13]Manochakian R, Miller KC, Chanan-Khan AA. Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma [J]. Oncologist,2007,12(8):978-990
[14]NCCN Multiple Myeloma Panel. NCCN clinical practice guideline in oncology:multiple myeloma national comprehensive cancer[M].Net-work,2009:2
[15]刘爱军,李利红,黄仲夏,等.硼替佐米、地塞米松加或不加沙利度胺治疗多发性骨髓瘤67例疗效分析[J].中国血液学杂志,2010,31(7)：484-486
[16]Rosinol L,Oriol A, Mateos MV, et al. Phase ⅡPETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma:efficacy and clinical implications of tumor response kinetics[J]. J Clin Oncol,2007,25(12):4452-4458
[17]Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma:results of the IFM 2005-01 phase III trial [J]. J Clin Oncol,2010,28(30):4621-4629
[18]Richardson PQ Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma [J]. Blood,2010, 116(5):679-686
[19]Cavo M,Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma:a randomised phase 3 study [J]. Lancet,2010,376(9758):2075-2085
[20]Moreau P, Avet-Loiseau H, Facon T,et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma [J]:Blood,2011, 118(22):5752-5758
[21]Reeder CB, Reece DE, Kukreti V, et al.Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma:high response rates in a phase II clinical trial [J]. Leukemia,2009,23(7):1337-1341
[22]Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma[J]. Blood,2012,119(19):4375-4382
[23]Fayers PM, Palumbo A, Hulin C, et al. Thalidomide for previously untreated elderly patients with multiple myeloma:meta-analysis of 1685 individual patient data from 6 randomized clinical trials [J]. Blood,2011,118(5):1239-1247
[24]San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma [J].N Engl J Med,2008,359(9):906-917
[25]Mateos MV, Richardson PQ Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial[J]. J Clin Oncol,2010,28(13):2259-2266
[26]Mateos MV, Oriol A, Martinez-Lopez J. Bortezomib/melphalan/prednisone (BMP) versus bortezomib/thalidomide/prednisone (BTP) as induction therapy followed by maintenance treatment with bortezomib/thalidomide(BT) versus bortezomib/prednisone(BP):A randomised trial in elderly untreated patients with multiple myeloma older than 65 years[J]. Lancet Oncol,2010,11(10):934-941
[27]Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib- melphalan-prednisone for initial treatment of multiple myeloma:a randomized controlled trial[J]. J Clin Oncol,2010,28(34):5101-5109
[28]Moreau P, Karamanesht II, Domnikova N, et al. Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma [J]. Clin Pharmacokinet,2012,51(12):823-829
[29]Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma:a randomised, phase 3, non-inferiority study [J]. Lancet Oncol,2011,12(5):431-440
[30]Morabito F, Gentile M, Mazzone C, et al. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment[J]. Blood,2011,118(22):5759-5766
[31]Moreau P, Hulin C, Marit G, et al. Stem cell collection in patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation according to IFM 2005-01 trial [J]. Leukemia,2010, 24(6):1233-1235
[32]Mukherjee S, Raje N, Schoonmaker JA, et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice [J].J Clin Invest, 2008,118(2):491-504
[33]Zonder J A, Barlogie B, Durie B G,et al. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone:benefit of aspirin prophylaxis [J]. Blood,2006,108(1):403-403
[34]Kumar S, Rajkumar SV, Thalidomide and lenalidomide in the treatment of multiple myeloma [J]. Eur J Cancer,2006,42(5):1612-1622
[35]Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological maligancies[J]. J Hematol Oncol,2009,2(7):36
[36]Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia[J]. Blood,2008,111(12):5291-5297
[37]Verhelle D, Corral LG, Wong K, et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+progenitor cells [J]. Cancer Res, 2007,67(6):746-755
[38]Spina F, Montefusco V, Crippa C, et al. Lenalidomide can induce long-term responses in patients with multiple myeloma relapsing after multiple chemotherapy lines, in particular after allogeneic transplant [J]. Leuk Lymphoma,2011;52(7):1262-1270
[39]Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma:an open-label randomized controlled trial [J]. Lancet Oncol,2010, 11(4):29-37
[40]Kumar S, Giralt S, Stadtmauer EA, et al. Mobilization in myeloma revisited:IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens [J].Blood,2009,114(9):1729-1735
[41]Giralt S, Stadtmauer EA, Harousseau JL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100)[J].Leukemia,2009,23(10):1904-1912
[42]Palumbo A, Cavo M,Bringhen s, et al.Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide:a phase III, open-label, randomized trial[J]. Clin Oncol,2011,29(8):986-993
[43]Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide [J]. Blood,2012, 119(4):933-939
[44]Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide-and lenalidomide-associated thrombosis in myeloma [J]. Leukemia,2008,22(2):414-423
[45]Alexander M, Teoh KC, Lingaratnam S, et al. Thromboprophylaxis prescribing and thrombotic event rates in multiple myeloma patients treated with lenalidomide or thalidomide at a specialist cancer hospital [J]. Asia Pac J Clin Oncol,2012,(Epub ahead of print)
[46]Palumbo A,Cavo M,Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide:a phase Ⅲ,open-label, randomized trial[J]. J Clin Oncol,2011,29(8):986-993
[47]Breitkrutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma [J].Leukermia,2008,22(7): 1925-1932
[48]中曼,王晶,阳光中,等.雷利度胺为主方案治疗多发性骨髓瘤25例疗效分析[J].白血病·淋巴瘤,2010,19(7)：401-403
[49]侯健,李荣.多发性骨髓瘤的化疗进展[J].临床血液学杂志,2012,25(7)：403-405
[50]Podar K, Gouil SL, Zhang J, et al. A pivotal role for Mcl-1 in bortezomib-induced apoptosis [J].Oncogene,2008,27(6):721-731
[51]欧阳桂芳,林茂芳.三氧化二砷增强硼替佐米、地塞米松对多发性骨髓瘤细胞的作用[J].中华血液学杂志,2010,31(4)：240-243
[52]Scroggins BT, Bobzyk K, Wang D, et al. An acetylation site in the middle domain of HSP90 regulates chaperone function [J].Mol cell,2007,25(1):151
[53]Hayden PT, Mitsiades CS, Anderson KS, et al. Novel therapies in myeloma [J]. curr opin hematol,2007,14(6):609
[54]Richardson PG, Chanan-khan AA, Lonial S, et al. Tanespimycin (T)+bortezomib(BZ) in multiple myeloma(MM):confirrmation of the recommended dose using a novel formulation [J].Blood,2007,110(abstr):1165
[55]罗云,娄世锋,王导新.单克隆抗体治疗多发性骨髓瘤研究进展[J].中国免疫学杂志,2012；28(1)：94-96
[56]Di Bemardo A, Macor P, Guarnotta C, et al. Humoral immunotherapy of multiple myeloma: perspectives and perplexities[J]. Expert Opin Biol Ther,2010;10(6):863-873
[57]Jagannath S, Chanan-Khan AA, Heffner LT, et al. BTO62, an antibody-drug conjugate direct against CD138, shows clinical activity in a phase I study in patients with relapsed or replased/refractory multiple myeloma [J]. Blood,2010;116(21):3060-3061
[58]Rosenblatt J, Vasir B, Uhl L, et al. Vaccination with dendritic cell/tumor fusion cells in cellular and humoral antitumor immune responses in patients with multiple myeloma [J]. Blood,2011,17(12):393-402
[59]Rosenblatt J, Avigan D. Cellular immunotherapy for multiple myeloma [J]. Best Pract Res Clin Haematol,2008,21(11):559-577
[60]钟国成,颜斌,孙薏,等.DC-CIK过继免疫联合化疗治疗多发性骨髓瘤的疗效分析[J].中华血液学杂志,2012,33(12)：1000-1003
[61]Mahindra A, Laubach J, Raje N, et al. Latest advances and current challenges in the treatment of multiple myeloma [J]. Nat Rev Clin Oncol,2012,9(3):135-143
[62]Mastyi W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma cells [J]. Blood,2004,103(7):2332-2336
[63]Pilarski LM, Seeberger K, Coupland RW, et al. Leukemiac B cells clonally identical to myeloma plasma cells are myeloma genic in NOD/SCID mice [J]. Exp Hematol,2002,30(5): 221-228
[64]Mastui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance [J].Cancer Res,2008,68(6):190-197
[65]Ghosh N, Matsui W. Cancer stem cells in multiple myeloma [J].Cancer Lett,2009,277:1-7
[66]姜鸾,陈文明.多发性骨髓瘤干细胞的研究现状[J].中华血液学杂志,2012,33(4)：343-346
[67]Tircot G, Yang Y, Xu CY, et al. Targeting myeloma stem cells through simultaneous inhibition of Wnt and Hedgehog (Hh) signaling pathways [J]. Blood (ASH Annual Meeting Abstracts),2010,116(11):Abstract 615
[68]Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains atumor stem cell compartment in multiple myeloma [J]. Proc Natl Acad Sci USA,2007,104:4048-4053
[69]谢振卿,李斯丹,徐燕,等.多发性骨髓瘤骨病的发生机制和靶向治疗研究进展[J].中华血液学杂志,2012,33(3)：247-249
[70]中华医学血液学分会.多发性骨髓瘤骨病诊治指南[J].中华血液学杂志,2011,32(10)：721-723
[71]Anderson KC. Oncogenomics to target myeloma in the bone marrow microenvironment[J]. Clin Caner Res,2011,17(6):1225-1233
[72]Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma [J]. J Clin Oncol,2011, 29(11):1125-1132
[73]Fulciniti M, Tassone P, Hideshima T, et al. Anti-DKKl mAb(BHQ880) as a potential therapeutic agent for multiple myeloma[J]. Blood,2009,114(2):371-379
[74]Breitkrutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma [J]. Leukermia,2008,22(6): 1925-1932
[75]Vallet S, Smith MR, Raje N. Novel bone-targeted strategies in oncology [J]. Clin Cancer Res,2010,16(3):4084-4093
[76]Jemal A, Bray F, Center M M, et al. Global cancer statistics [J]. CA Cancer J Clin,2011, 61(7):69-90
[77]王吉耀,廖二元,胡品津等.内科学.第1版[M].北京：人民卫生出版社,2005.834
[78]邹外一,李娟.造血干细胞移植治疗多发性骨髓瘤[J].临床血液学杂志,2012,25(7)410-413
[79]Barlogie B, Hall R, Zander A, et al. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma [J]. Blood,1986,67(9):1298-1301
[80]Femand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years:long-term results of a randomized control trial from the Group Myeloma-Autogreffe [J]. J Clin Oncol,2005;23(36):9227-9233
[81]Anderson K C, Alsina M, Bensinger W, et al. NCCN clinical practice guidelines in oncology:multiple myeloma [J]. J Natl Compr Canc Netw,2009,7(10):908-942
[82]Giralt S. Stem cell transplantation for multiple myeloma:Current and future status[J]. Hematology Am Sol Hematol Educ program,2011(5):191-196
[83]Lahuerta J J, Mateos M V, Martinez L J, et al. Influence of pre-and post-transplantation responses on outcome of patients with multiple myeloma:sequential improvement of response and achievement of complete response are associated with longer survival [J]. J Clin Oncol,2008,26(3):5775-5782
[84]Harousseau JL. Ten Years of improvement in the management of multiple myeloma:2000-2010 [J]. Clin Lymphoma Myeloma Leuk.2010(8);10(6):424-442
[85]刘俊茹,李娟,陈媚,等.大剂量环磷酰胺联合粒细胞集落刺激因子动员多发性骨髓瘤造血干细胞的价值研究[J].中国实用内科杂志,2011,31(7)：530-532
[86]Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma:a phase 2 study of the Intergroup Francophone du Myeloma(IFM) [J]. Blood,2010,115(1):32-37
[87]Nishihori T, Alekshun T J, Sullivan D M, et al. Bortezomib followed by a phase I study of bortezomib in combination with high-dose melphalan as a preparative regimen for hematopoietic cell transplants in patients with primary refractory multiple myeloma or plasma cell leukemia[J]. Biol Blood Marrow Transplant,2011,7(5):S200-S201
[88]Barlogie B, Tricot G J, Van Rhee F, et al. Longterm outcome results of the first tandom auto-transplant trial for multiple myeloma[J]. Br Haematol,2006,135(6):158-164
[89]Bensinger W, Bucker C, Anasettic, et al. Allogeneic marrow transplantation for multiple myelomaranalysis of risk factors on outcome[J]. Blood,1996,88(10):2787-2793
[90]Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced intensity allogenetic transplantation for multiple myeloma:an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT [J]. Blood,2005,105(11):4532-4539
[91]Gahrton G. Progress in allogenetic transplantation for multiple myeloma [J]. Eur J Haematol,2010;85(4):279-289
[92]Lokhorst H,Einsele H,Vesoled,et al. International Myeloma working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma[J]. J Clin Oncol,2010,28(6):4521-4530
[93]Brinker BT, Waller EK, Leong T, et al. Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma [J]. Cancer,2006,106(10):2171-2180
[94]Vesole D H, Zhang L, Flomenderg N,et al. A phase Ⅱ trial of autologous stem cell transplantation followed by mini-allogenenic stem cell transplantation for the treatment of multiple myoloma:an analysis of Eastern Cooperation Oncology Group ECOG E4A98 and E1A97 [J].Biol Blood Marrow Transplant,2009,15(3):83-91
[2]Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma[J]. J Clin Oncol,2005,23(15):3412-3420
[3]Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma[J].Leukemia,2006,20(9):1467-1473
[4]Raab MS, Podar K, Breitkreutz I et al.Multiple myeloma[J].Lancet,2009,374(9686):324-39
[5]胡豫,孙春艳.多发性骨髓瘤的诊断进展[J].临床血液学杂志,2012,25(7)：406-410
[6]王吉耀,廖二元,黄从新等.内科学.第2版[M].北京：人民卫生出版社,2010.825
[7]中国多发性骨髓瘤工作组.中国多发性性骨髓瘤诊治指南(2011年修订)[J].中华内科杂志,2011,50(10)：892-896
[8]Zervas K, Mihou D, Katodritou E, et al. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma:results of a multicenter randomized trial of the Greek myeloma study group[J]. Ann Oncol,2007,18 (4):1369-1375
[9]王惠君,刘传方.T-VAD与T-VD方案治疗多发性骨髓瘤的临床分析[J].临床血液学杂志,2012,25(5)：311-313
[10]Lane SW,Gill D,Mollee PN, et al. Role of VAD in the initial treatment of multiple myeloma[J].Blood,2005,106(10):3674; author reply 3674-3675
[11]Myeloma trialist collaboration Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma:an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists'Collaborative Group[J].J Clin Oncol,1998,16(12): 3832-3842
[12]Blade J, Rosinol L, Cibeira MT, et al. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010[J]. Blood,2010,115(18):3655-3663
[13]Jimenez-Zepeda VH,Reece DE, Trudel S, et al. Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for heavily pretreated relapsed or refractory multiple myeloma[J]. Leuk Lymphoma,2013,54(3):555-560
[14]Held LA, Rizzieri D, Long GD, et al. A Phase I Study of Arsenic Trioxide (Trisenox), Ascorbic Acid, and Bortezomib (Velcade) Combination Therapy in Patients With Relapsed/Refractory Multiple Myeloma[J].Cancer Invest,2013,(Epub ahead of print)
[15]Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma[J]. Br J Haematol,2013, 160(5):649-659
[16]Lancaster S.Bortezomib:the evidence of its clinical impact in multiple myeloma[J]. Core Evid,2006,1(4):265-277
[17]廖爱军,王晓彬,王慧涵等.硼替佐米联合地塞米松治疗初诊多发性骨髓瘤的初步观察[J].中华肿瘤防治杂志,2009,16(6)：466-469
[18]黄月华.硼替佐米的作用机制、临床应用及其疗效进展[J].使用诊断与治疗杂志,2008,22(4)：280-282
[19]黄红铭,侯健,周帆,等.硼替佐米对多发性骨髓瘤患者破骨细胞分化和功能的影响[J].首都医科大学学报,2008,29(2)：124-127
[20]Eda H, Aoki K, Kato S, et al. The proteasome inhibitor bortezomib inhibits FGE-2-induced reduction of TAZ levels in osteoblast-like cells [J]. Eur J Haematol,2010,85 (3):68-75
[21]Hideshima T, Ikeda H, Chauhan D,et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells [J]. Blood,2009,114 (10):1046-1052
[22]Roccaro AM, Hideshima T, Raje N, et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells [J]. Cancer Res, 2006,66(1):184-191
[23]Meister S,Schubert U,Neubert K, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition [J]. Cancer Res,2007,67(4):1783-1792
[24]Manochakian R, Miller KC, Chanan-Khan AA. Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma [J]. Oncologist,2007,12(8):978-990
[25]刘爱军,李利红,黄仲夏,等.硼替佐米、地塞米松加或不加沙利度胺治疗多发性骨髓瘤67例疗效分析[J].中华血液学杂志,2010,31(7)：486-488
[26]Rosinol L,Oriol A, Mateos MV, et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma:efficacy and clinical implications of tumor response kinetics[J]. J Clin Oncol,2007,25 (8):4452-4458
[27]Gasparetto C, Gockerman JP, Diehl LF et al. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma [J]. Biol Blood Marrow Transplant,2010,16(1):70-77
[28]钟玉萍,陈世伦,李新,等.硼替佐米为主的化疗方案治疗60例多发性骨髓瘤患者的临床分析[J].中国实验血液学杂志,2009,17(1)：214-217.
[29]何群,赵谢兰,贺艳娟,等.硼替佐米联合地塞米松治疗多发性骨髓瘤的临床分析[J].中南大学学报(医学版),2010,35(8)：864-867
[30]纪春岩,陈晨,赵川莉,等.硼替佐米为主方案治疗多发性骨髓瘤患者的临床研究[J].中华血液学杂志,2011,32(4)：265-267
[31]Moumas E, Hanf W, Desport E, et al. New insights in the treatment of myeloma with renal failure. Nephrol Ther,2011,7(8):457-466
[32]Chanan-Khan A A, Kaufman J L, Mehtaj, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failures multi-center retrospective study[J]. Blood,2007,109(5):2604-2606
[33]高大,肖镇.大剂量地塞米松联合硼替佐米及沙利度胺治疗多发性骨髓瘤合并肾衰竭的临床研究[J].白血病·淋巴瘤,2012,21(10)：604-606
[34]San-Miguel JF, Richardson PG, Sonneveld P, et al. Efficacy and safety of bortezomib in patients with renal impairment:results from the APEX phase 3 study[J]. Leukemia,2008, 22(4):842-849
[35]Drayson M, Begum G, Basu S, et al. Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma:an analysis of patients receiving conventional dose chemotherapy in Medical Research Council UK multiple myeloma trials [J]. Blood, 2006,108(6):2013-2019
[36]Ohguchi H, Sugawara T, Ishikawa I, et al. A retrospective analysis of bortezomib therapy for Japanese patients with relapsed or refractory multiple myeloma:beta2-microglobulin associated with time to progression [J]. Int J Hematol,2009,89(3):342-347
[37]Kastritis E, Zervas K, Symeonidis A, et al. Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS):an analysis of the Greek Myeloma Study Group (GMSG)[J]. Leukemia,2009,23(6):1152-1157
[38]Yang GZ, Chen WM. Bortezomib-based regimen for the treatment of 110 multiple myeloma patients [J]. Zhonghua Yi Xue Za Zhi,2010,90(38):2671-2674
[39]Field-Smith A, Morgan GJ, Davies FE. Bortezomib (Velcade trade mark) in the treatment of multiple myeloma [J]. Ther Clin Risk Manag,2006,2(3):271-279
[40]Giralt S, Aleman A, Anagnostopoulos A, et al. Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma [J]. Bone Marrow Transplant, 2002,30(6):367-373
[41]李彩霞,吴德沛,孙爱宁,等.硼替佐米治疗多发性骨髓瘤的初步临床研究.白血病·淋巴瘤,2006,15(3)：349-350
[42]Corso A, Mangiacavalli S, Varettoni M, et al. Bortezomib-induced peripheral neuropathy in multiple myeloma:a comparison between previously treated and untreated patients [J]. Leuk Res,2010,34(4):471-474
[43]Corthals SL, Kuiper R, Johnson DC, et al.Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients[J]. Haematologica,2011,96 (11):1728-1732
[44]Topp KS, Tanner KD, Levine JD. Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat[J]. J Comp Neurol,2000,424(4):563-576
[45]Kruczynski A, Barret JM, Etievant C, et al. Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid[J].Biochem Pharmacol,1998,55(5):635-648
[46]Dyke RW, Nelson RL. Phase I Anti-cancer agents Vindesine [J].Cancer Treat REV,1977; 4 (5):135
[47]王洪涛,刘卓刚,杨伟,等.硼替佐米致周围神经病变的机制及还原型谷胱甘肽逆转神经毒性的研究[J].中华血液学杂志,2011,32(2)：107-111
[48]王建芳,王洪涛,刘卓刚.硼替佐米致周围神经病变的研究进展[J].中华血液学杂志,2012,33(2)：157-159
[49]Mateos MV, Richardson PG,Schlag R et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial [J]. J Clin Oncol.2010,28(13):2259-66
[50]Basler M, Lauer C, Beck U, et al. The proteasome inhibitor bortezomib enhances the susceptibility to viral infection [J]. J Immunol,2009,183(10):6145-6150
[51]Jung SH, Bae SY, Ahn JS, et al. Lymphocytopenia is associated with an increased risk of severe infections in patients with multiple myeloma treated with bortezomib-based regimens[J]. Int J Hematol,2013,(Epub ahead of print)
[52]崔秀珍,高秀珍.吡喃阿霉素和阿霉素临床观察对比[J].中国肿瘤临床,1994,21(9)：642-644
[1]Rajkumar SV.Treatment of multiple myeloma [J]. Nat Rev Clin Oncol,2011,8(8):479-491
[2]Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma:a clash of philosophies [J]. Blood,2011,118(12):3205-3211
[3]Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/Latinos,2012 [J]. CA Cancer J Clin,2012,62(5):283-298
[4]Kyle RA, Therneau TM, Rajkumar SV, et al. Incidence of multiple myeloma in Olmsted County, Minnesota:Trend over 6 decades [J]. Cancer,2004,101(11):2667-2674
[5]Ludwig H, Viterbo L, Greil R, et al. Randomized phase Ⅱ study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma [J]. J Clin Oncol,2013,31(2):247-255
[6]胡豫,孙春艳.多发性骨髓瘤的诊断进展[J].临床血液学杂志,2012,25(7)：406-410
[7]耿传营,陈文明.新诊断多发性骨髓瘤的危险分层治疗：来自2012年美国临床肿瘤学会年会的报道[J].白血病·淋巴瘤,2012,21(7)：390-392
[8]Barlogie B, Jagannath S, Deaikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma [J]. Blood,1999,93(1):55-56
[9]Myeloma trialist collaboration Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma:an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists'Collaborative Group [J]. J Clin Oncol,1998,16(12): 3832-3842
[10]Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma [J].Br J Haematol, 2013,160(5):649-659
[11]Roccaro AM, Hideshima T, Raje N, et al.Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells [J]. Cancer Res,2006,66(1): 184-191
[12]Meister S, Schubert U, Neubert K, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition [J].Cancer Res,2007,67(4):1783-1792
[13]Manochakian R, Miller KC, Chanan-Khan AA. Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma [J]. Oncologist,2007,12(8):978-990
[14]NCCN Multiple Myeloma Panel. NCCN clinical practice guideline in oncology:multiple myeloma national comprehensive cancer[M].Net-work,2009:2
[15]刘爱军,李利红,黄仲夏,等.硼替佐米、地塞米松加或不加沙利度胺治疗多发性骨髓瘤67例疗效分析[J].中国血液学杂志,2010,31(7)：484-486
[16]Rosinol L,Oriol A, Mateos MV, et al. Phase ⅡPETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma:efficacy and clinical implications of tumor response kinetics[J]. J Clin Oncol,2007,25(12):4452-4458
[17]Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma:results of the IFM 2005-01 phase III trial [J]. J Clin Oncol,2010,28(30):4621-4629
[18]Richardson PQ Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma [J]. Blood,2010, 116(5):679-686
[19]Cavo M,Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma:a randomised phase 3 study [J]. Lancet,2010,376(9758):2075-2085
[20]Moreau P, Avet-Loiseau H, Facon T,et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma [J]:Blood,2011, 118(22):5752-5758
[21]Reeder CB, Reece DE, Kukreti V, et al.Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma:high response rates in a phase II clinical trial [J]. Leukemia,2009,23(7):1337-1341
[22]Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma[J]. Blood,2012,119(19):4375-4382
[23]Fayers PM, Palumbo A, Hulin C, et al. Thalidomide for previously untreated elderly patients with multiple myeloma:meta-analysis of 1685 individual patient data from 6 randomized clinical trials [J]. Blood,2011,118(5):1239-1247
[24]San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma [J].N Engl J Med,2008,359(9):906-917
[25]Mateos MV, Richardson PQ Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial[J]. J Clin Oncol,2010,28(13):2259-2266
[26]Mateos MV, Oriol A, Martinez-Lopez J. Bortezomib/melphalan/prednisone (BMP) versus bortezomib/thalidomide/prednisone (BTP) as induction therapy followed by maintenance treatment with bortezomib/thalidomide(BT) versus bortezomib/prednisone(BP):A randomised trial in elderly untreated patients with multiple myeloma older than 65 years[J]. Lancet Oncol,2010,11(10):934-941
[27]Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib- melphalan-prednisone for initial treatment of multiple myeloma:a randomized controlled trial[J]. J Clin Oncol,2010,28(34):5101-5109
[28]Moreau P, Karamanesht II, Domnikova N, et al. Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma [J]. Clin Pharmacokinet,2012,51(12):823-829
[29]Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma:a randomised, phase 3, non-inferiority study [J]. Lancet Oncol,2011,12(5):431-440
[30]Morabito F, Gentile M, Mazzone C, et al. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment[J]. Blood,2011,118(22):5759-5766
[31]Moreau P, Hulin C, Marit G, et al. Stem cell collection in patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation according to IFM 2005-01 trial [J]. Leukemia,2010, 24(6):1233-1235
[32]Mukherjee S, Raje N, Schoonmaker JA, et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice [J].J Clin Invest, 2008,118(2):491-504
[33]Zonder J A, Barlogie B, Durie B G,et al. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone:benefit of aspirin prophylaxis [J]. Blood,2006,108(1):403-403
[34]Kumar S, Rajkumar SV, Thalidomide and lenalidomide in the treatment of multiple myeloma [J]. Eur J Cancer,2006,42(5):1612-1622
[35]Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological maligancies[J]. J Hematol Oncol,2009,2(7):36
[36]Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia[J]. Blood,2008,111(12):5291-5297
[37]Verhelle D, Corral LG, Wong K, et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+progenitor cells [J]. Cancer Res, 2007,67(6):746-755
[38]Spina F, Montefusco V, Crippa C, et al. Lenalidomide can induce long-term responses in patients with multiple myeloma relapsing after multiple chemotherapy lines, in particular after allogeneic transplant [J]. Leuk Lymphoma,2011;52(7):1262-1270
[39]Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma:an open-label randomized controlled trial [J]. Lancet Oncol,2010, 11(4):29-37
[40]Kumar S, Giralt S, Stadtmauer EA, et al. Mobilization in myeloma revisited:IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens [J].Blood,2009,114(9):1729-1735
[41]Giralt S, Stadtmauer EA, Harousseau JL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100)[J].Leukemia,2009,23(10):1904-1912
[42]Palumbo A, Cavo M,Bringhen s, et al.Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide:a phase III, open-label, randomized trial[J]. Clin Oncol,2011,29(8):986-993
[43]Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide [J]. Blood,2012, 119(4):933-939
[44]Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide-and lenalidomide-associated thrombosis in myeloma [J]. Leukemia,2008,22(2):414-423
[45]Alexander M, Teoh KC, Lingaratnam S, et al. Thromboprophylaxis prescribing and thrombotic event rates in multiple myeloma patients treated with lenalidomide or thalidomide at a specialist cancer hospital [J]. Asia Pac J Clin Oncol,2012,(Epub ahead of print)
[46]Palumbo A,Cavo M,Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide:a phase Ⅲ,open-label, randomized trial[J]. J Clin Oncol,2011,29(8):986-993
[47]Breitkrutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma [J].Leukermia,2008,22(7): 1925-1932
[48]中曼,王晶,阳光中,等.雷利度胺为主方案治疗多发性骨髓瘤25例疗效分析[J].白血病·淋巴瘤,2010,19(7)：401-403
[49]侯健,李荣.多发性骨髓瘤的化疗进展[J].临床血液学杂志,2012,25(7)：403-405
[50]Podar K, Gouil SL, Zhang J, et al. A pivotal role for Mcl-1 in bortezomib-induced apoptosis [J].Oncogene,2008,27(6):721-731
[51]欧阳桂芳,林茂芳.三氧化二砷增强硼替佐米、地塞米松对多发性骨髓瘤细胞的作用[J].中华血液学杂志,2010,31(4)：240-243
[52]Scroggins BT, Bobzyk K, Wang D, et al. An acetylation site in the middle domain of HSP90 regulates chaperone function [J].Mol cell,2007,25(1):151
[53]Hayden PT, Mitsiades CS, Anderson KS, et al. Novel therapies in myeloma [J]. curr opin hematol,2007,14(6):609
[54]Richardson PG, Chanan-khan AA, Lonial S, et al. Tanespimycin (T)+bortezomib(BZ) in multiple myeloma(MM):confirrmation of the recommended dose using a novel formulation [J].Blood,2007,110(abstr):1165
[55]罗云,娄世锋,王导新.单克隆抗体治疗多发性骨髓瘤研究进展[J].中国免疫学杂志,2012；28(1)：94-96
[56]Di Bemardo A, Macor P, Guarnotta C, et al. Humoral immunotherapy of multiple myeloma: perspectives and perplexities[J]. Expert Opin Biol Ther,2010;10(6):863-873
[57]Jagannath S, Chanan-Khan AA, Heffner LT, et al. BTO62, an antibody-drug conjugate direct against CD138, shows clinical activity in a phase I study in patients with relapsed or replased/refractory multiple myeloma [J]. Blood,2010;116(21):3060-3061
[58]Rosenblatt J, Vasir B, Uhl L, et al. Vaccination with dendritic cell/tumor fusion cells in cellular and humoral antitumor immune responses in patients with multiple myeloma [J]. Blood,2011,17(12):393-402
[59]Rosenblatt J, Avigan D. Cellular immunotherapy for multiple myeloma [J]. Best Pract Res Clin Haematol,2008,21(11):559-577
[60]钟国成,颜斌,孙薏,等.DC-CIK过继免疫联合化疗治疗多发性骨髓瘤的疗效分析[J].中华血液学杂志,2012,33(12)：1000-1003
[61]Mahindra A, Laubach J, Raje N, et al. Latest advances and current challenges in the treatment of multiple myeloma [J]. Nat Rev Clin Oncol,2012,9(3):135-143
[62]Mastyi W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma cells [J]. Blood,2004,103(7):2332-2336
[63]Pilarski LM, Seeberger K, Coupland RW, et al. Leukemiac B cells clonally identical to myeloma plasma cells are myeloma genic in NOD/SCID mice [J]. Exp Hematol,2002,30(5): 221-228
[64]Mastui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance [J].Cancer Res,2008,68(6):190-197
[65]Ghosh N, Matsui W. Cancer stem cells in multiple myeloma [J].Cancer Lett,2009,277:1-7
[66]姜鸾,陈文明.多发性骨髓瘤干细胞的研究现状[J].中华血液学杂志,2012,33(4)：343-346
[67]Tircot G, Yang Y, Xu CY, et al. Targeting myeloma stem cells through simultaneous inhibition of Wnt and Hedgehog (Hh) signaling pathways [J]. Blood (ASH Annual Meeting Abstracts),2010,116(11):Abstract 615
[68]Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains atumor stem cell compartment in multiple myeloma [J]. Proc Natl Acad Sci USA,2007,104:4048-4053
[69]谢振卿,李斯丹,徐燕,等.多发性骨髓瘤骨病的发生机制和靶向治疗研究进展[J].中华血液学杂志,2012,33(3)：247-249
[70]中华医学血液学分会.多发性骨髓瘤骨病诊治指南[J].中华血液学杂志,2011,32(10)：721-723
[71]Anderson KC. Oncogenomics to target myeloma in the bone marrow microenvironment[J]. Clin Caner Res,2011,17(6):1225-1233
[72]Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma [J]. J Clin Oncol,2011, 29(11):1125-1132
[73]Fulciniti M, Tassone P, Hideshima T, et al. Anti-DKKl mAb(BHQ880) as a potential therapeutic agent for multiple myeloma[J]. Blood,2009,114(2):371-379
[74]Breitkrutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma [J]. Leukermia,2008,22(6): 1925-1932
[75]Vallet S, Smith MR, Raje N. Novel bone-targeted strategies in oncology [J]. Clin Cancer Res,2010,16(3):4084-4093
[76]Jemal A, Bray F, Center M M, et al. Global cancer statistics [J]. CA Cancer J Clin,2011, 61(7):69-90
[77]王吉耀,廖二元,胡品津等.内科学.第1版[M].北京：人民卫生出版社,2005.834
[78]邹外一,李娟.造血干细胞移植治疗多发性骨髓瘤[J].临床血液学杂志,2012,25(7)410-413
[79]Barlogie B, Hall R, Zander A, et al. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma [J]. Blood,1986,67(9):1298-1301
[80]Femand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years:long-term results of a randomized control trial from the Group Myeloma-Autogreffe [J]. J Clin Oncol,2005;23(36):9227-9233
[81]Anderson K C, Alsina M, Bensinger W, et al. NCCN clinical practice guidelines in oncology:multiple myeloma [J]. J Natl Compr Canc Netw,2009,7(10):908-942
[82]Giralt S. Stem cell transplantation for multiple myeloma:Current and future status[J]. Hematology Am Sol Hematol Educ program,2011(5):191-196
[83]Lahuerta J J, Mateos M V, Martinez L J, et al. Influence of pre-and post-transplantation responses on outcome of patients with multiple myeloma:sequential improvement of response and achievement of complete response are associated with longer survival [J]. J Clin Oncol,2008,26(3):5775-5782
[84]Harousseau JL. Ten Years of improvement in the management of multiple myeloma:2000-2010 [J]. Clin Lymphoma Myeloma Leuk.2010(8);10(6):424-442
[85]刘俊茹,李娟,陈媚,等.大剂量环磷酰胺联合粒细胞集落刺激因子动员多发性骨髓瘤造血干细胞的价值研究[J].中国实用内科杂志,2011,31(7)：530-532
[86]Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma:a phase 2 study of the Intergroup Francophone du Myeloma(IFM) [J]. Blood,2010,115(1):32-37
[87]Nishihori T, Alekshun T J, Sullivan D M, et al. Bortezomib followed by a phase I study of bortezomib in combination with high-dose melphalan as a preparative regimen for hematopoietic cell transplants in patients with primary refractory multiple myeloma or plasma cell leukemia[J]. Biol Blood Marrow Transplant,2011,7(5):S200-S201
[88]Barlogie B, Tricot G J, Van Rhee F, et al. Longterm outcome results of the first tandom auto-transplant trial for multiple myeloma[J]. Br Haematol,2006,135(6):158-164
[89]Bensinger W, Bucker C, Anasettic, et al. Allogeneic marrow transplantation for multiple myelomaranalysis of risk factors on outcome[J]. Blood,1996,88(10):2787-2793
[90]Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced intensity allogenetic transplantation for multiple myeloma:an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT [J]. Blood,2005,105(11):4532-4539
[91]Gahrton G. Progress in allogenetic transplantation for multiple myeloma [J]. Eur J Haematol,2010;85(4):279-289
[92]Lokhorst H,Einsele H,Vesoled,et al. International Myeloma working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma[J]. J Clin Oncol,2010,28(6):4521-4530
[93]Brinker BT, Waller EK, Leong T, et al. Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma [J]. Cancer,2006,106(10):2171-2180
[94]Vesole D H, Zhang L, Flomenderg N,et al. A phase Ⅱ trial of autologous stem cell transplantation followed by mini-allogenenic stem cell transplantation for the treatment of multiple myoloma:an analysis of Eastern Cooperation Oncology Group ECOG E4A98 and E1A97 [J].Biol Blood Marrow Transplant,2009,15(3):83-91
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