A review of the proteasome inhibitor bortezomib in multiple myeloma

Multiple myeloma (MM) represented 14% of new haematological malignancies in the US in 2003 and almost 19% of anticipated deaths. Treatment with standard chemotherapy has resulted in a median survival of about 3 years and despite the improvements in survival seen with the use of intensive therapy supported by autologous stem cell transplantation, MM remains incurable; hence, new therapeutic strategies are urgently needed. One novel approach to the treatment of MM is the use of proteasome inhibitors. Proteasomes are ubiquitous protease complexes involved in diverse aspects of cell biology, such as protein homeostasis, cell cycle progression, apoptosis and inflammation, as well as resistance to antineoplastic therapy. The first-in-class proteasome inhibitor, bortezomib was recently approved in the US for the treatment of patients with MM who have received at least two prior therapies and are progressing on their last therapy. Its use in earlier-stage MM, other haematological malignancies and in solid tumours as monotherapy and in combination therapy is currently under investigation.     

Monoclonal Gammopathy–Associated Proliferative Glomerulonephritis

Monoclonal gammopathy is characterized by circulating monoclonal immunoglobulin owing to clonal proliferation of immunoglobulin-producing B lymphocytes or plasma cells. Clonal proliferation of B lymphocytes is seen in B-cell lymphoma/leukemia, and clonal plasma cell proliferation is seen in multiple myeloma and monoclonal gammopathy of undetermined significance. The monoclonal immunoglobulin in the setting of a B-cell or plasma cell disorder can cause a proliferative glomerulonephritis via 2 mechanisms: (1) glomerular deposition of the monoclonal immunoglobulin with activation of the classical pathway of complement (direct mechanism), resulting in an immunoglobulin-positive C3-positive glomerulonephritis, and (2) glomerular deposition of complement factors of the alternative and terminal pathway via inhibition of alternative pathway–regulating proteins by the monoclonal immunoglobulin (indirect mechanism), resulting in immunoglobulin-negative C3-positive glomerulonephritis (C3 glomerulopathy). Evaluation should include serum and urine electrophoresis and immunofixation as well as serum-free light-chain assay. If a monoclonal immunoglobulin is detected on these tests, bone marrow biopsy or imaging is needed to exclude more advanced plasma cell dyscrasia. Evaluation of alternative pathway of complement should be done in patients with Ig-negative C3-positive glomerulonephritis. If monoclonal gammopathy is due to an underlying malignant disease such as myeloma, lymphoma, or chronic lymphocytic leukemia, then specific treatment should be aimed at treating the malignant disease, with the goal of eradicating the clonal cells producing the immunoglobulin. In contrast, if monoclonal gammopathy is due to a monoclonal gammopathy of undetermined significance, treatment options include bortezomib, cyclophosphamide, and dexamethasone for a non-IgM monoclonal immunoglobulin and rituximab alone or in combination with cyclophosphamide and dexamethasone for an IgM monoclonal immunoglobulin.     

硼替佐米联合地塞米松与沙利度胺治疗多发性骨髓瘤的效果

目的比较硼替佐米＋地塞米松＋沙利度胺（BDT）方案与长春地辛＋表柔比星＋地塞米松＋沙利度胺（VADT）方案治疗多发性骨髓瘤（MM）的临床效果。方法MM病人67例,应用BDT方案治疗30例,VADT方案治疗37例,均治疗4个疗程,比较两组治疗前、治疗后β2-微球蛋白、免疫球蛋白、骨髓瘤细胞的变化,并比较两组疗效。结果BDT组及VADT组化疗后β2-微球蛋白、免疫球蛋白、骨髓瘤细胞均低于化疗前,差异有显著性（t=2．837～7．562,P％0．05）。BDT组完全缓解（CR）占13．0％,接近完全缓解（ncR）占20．0％,部分缓解（PR）占53．0％,微小反应（MR）占6．7％,总有效率93．3％;VADT组CR占3．0％,nCR占10．8％,PR占40．5％,MR占16．2％,总有效率70．3％,两组疗效比较,差异有显著性（Hc=51．67,P〈0．05）。结论BDT方案治疗MM效果优于VADT方案,且起效快,可改善病人的预后。     

糖皮质激素和硼替佐米体外干预多发性骨髓瘤细胞BAFF/APRIL mRNA表达的初步探索

本研究观察糖皮质激素和硼替佐米对U266骨髓瘤细胞株和多发性骨髓瘤(MM)患者骨髓单个核细胞(BMMNC)BAFF/APRIL mRNA表达的影响。分离MM患者BMMNC,对U266骨髓瘤细胞株和BMMNC进行药物干预(单用地塞米松100、200μg/ml,甲基强的松龙100、200μg/ml,硼替佐米0.1μg/ml,以及地塞米松或甲基强的松龙与硼替佐米联用)48小时,收集细胞,进行荧光定量实时PCR检测BAFF/APRIL mRNA表达的水平。采用SPSS 17.0进行统计学分析。结果表明,U266细胞及7例初治的MM患者BMMNC均高表达BAFF/APRIL基因。地塞米松,甲基强的松龙,硼替佐米单独作用于U266细胞或MM患者BMMNC后,BAFF/APRIL基因表达较未干预前降低(p<0.01),其中硼替佐米干预后BAFF/APRIL表达最低(p<0.05)。地塞米松或甲基强的松龙和硼替佐米联用后BAFF/APRIL基因表达较单独干预时低(p<0.01);地塞米松联用硼替佐米时BAFF/APRIL基因表达的抑制强度大于甲基强的松龙和硼替佐米联用的抑制强度(p<0.05)。结论:糖皮质激素和硼替佐米干预后的骨髓瘤细胞BAFF/APRIL基因表达下降,提示糖皮质激素和硼替佐米除了存在已知的糖皮质激素受体和蛋白酶体作用靶点外,可能还存在BAFF/APRIL及其受体这种新的作用靶点。     

调控组织因子基因表达的药物筛选研究

本研究建立TF启动子转录活性的荧光素酶基因稳定细胞株,应用该细胞模型筛选调控TF基因表达的药物,并为深入研究其分子机制打下基础。构建TF启动子的一系列5′端截短型的荧光素酶报告基因质粒(包括-2174 bp~+128 bp,-684 bp~+128 bp,-247 bp~+128 bp,-201 bp~+128 bp),将质粒电转染至U937细胞中,建立表达荧光素酶报告基因的稳定细胞株。应用ATRA验证该细胞株的功能;应用bortezomib、尿多酸肽(CDA-II)等药物处理该细胞株24小时,分析荧光素酶基因活性,筛选出能够调控TF基因表达的药物。结果发现,5 nmol/L bortezomib能激活其转录活性,上调TF转录本表达水平;1 mg/ml CDA-Ⅱ抑制TF启动子的转录活性,下调TF转录本的表达水平。TF启动子逐步截短功能分析发现,bortezomib及CDA-ⅡII调控TF启动子转录活性的区域位于-201 bp—0 bp之间。结论:本研究建立了表达TF启动子荧光素酶活性的U937稳定细胞株,并筛选出能够调控TF基因转录的药物CDA-II及bortezomib,为将来筛选新药物及深入研究其分子机...     

Clinical impact of chromosomal aberrations in multiple myeloma

Chromosomal aberrations are frequently found in multiple myeloma cells and play a major role in patient outcome and management of the disease. The most important chromosomal aberrations associated with poor outcome are del(17p), t(4;14), t(14;16) and t(14;20). Others that may be associated with adverse prognosis include amp(1)(q21), del(1p32), del(13), del(8p21) and hypodiploidy. Many chromosomal aberrations have no or uncertain impact; for example, t(11;14), t(8;14) and hyperdiploidy. Attempts have been made to overcome the negative prognostic impact of chromosomal aberrations using autologous or allogeneic transplantation or new immunomodulatory drugs such as thalidomide, lenalidomide and the proteasome inhibitor bortezomib, but the results are controversial. Data suggest that allogeneic transplantation and treatment with bortezomib or lenalidomide may help to overcome the negative effect of del(13) on prognosis, whereas bortezomib may have some influence on reducing the impact of del(17p), t(4;14) and t(14;16). Chromosome analysis should always be performed at diagnosis of multiple myeloma to improve the prediction of outcome and to aid treatment decision-making.     

国内硼替佐米联合化疗方案治疗多发性骨髓瘤的Meta分析

目的评价国内硼替佐米治疗多发性骨髓瘤的疗效与安全性。方法计算机检索中国知识资源总库CNKI,万方数据库,中国科技期刊数据库(重庆维普),检索年限从硼替佐米开始在中国临床应用至今(2005～2010年)。手工检索所有纳入文献的相关参考文献,筛选硼替佐米治疗多发性骨髓瘤的随机对照试验,进行资料提取后,采用STATA11软件进行Meta分析。结果共纳入7个随机对照临床试验(RCT),包括301例患者。Meta分析结果显示,硼替佐米联合化疗方案与单用MP(马法兰、泼尼松),M2(卡氮芥、环磷酰胺、长春新碱)和VAD(马法兰或长春新碱、阿霉素、地塞米松)方案比较,其治疗缓解率[RR=1.40,95%CI(1.08,1.81)]和总有效率[RR=1.29,95%CI(1.03,1.61)]差异均有统计学意义。结论目前国内的有限证据表明,与单用MP、M2或VAD方案相比,硼替佐米联合化疗方案能增加多发性骨髓瘤治疗的总有效率和缓解率,但由于纳入研究样本量小且质量较低,上述结论尚需要高质量、大样本的随机双盲对照试验加以证实。     

Bortezomib plus EPOCH is effective as frontline treatment in patients with plasmablastic lymphoma

Acute myeloid leukaemia (AML) is a lethal haematological malignancy characterized by an immunosuppressive milieu in the tumour microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation, resulting in increased AML susceptibility to T cell-mediated killing. Exposure to HMA results in the activation of the endogenous retroviral pathway with concomitant downstream amplification of critical mediators of inflammation. In an immunocompetent murine leukaemia model, guadecitabine negatively regulates inhibitory accessory cells in the TME by decreasing PD-1 (also termed PDCD1) expressing T cells and reducing AML-mediated expansion of myeloid-derived suppressor cells. Therapy with guadecitabine results in enhanced leukaemia-specific immunity, as manifested by increased CD4 and CD8 cells targeting syngeneic leukaemia cells. We have previously reported that vaccination with AML/dendritic cell fusions elicits the expansion of leukaemia-specific T cells and protects against disease relapse. In the present study, we demonstrate that vaccination in conjunction with HMA therapy results in enhanced anti-leukaemia immunity and survival. The combination of a novel personalized dendritic cell/AML fusion vaccine and an HMA has therapeutic potential, and a clinical trial investigating this combination is planned.     

Frontline treatment of elderly non transplant-eligible multiple myeloma patients using CyBorD with or without thalidomide-based consolidation: a retrospective multi-centre analysis of real-world data

Bortezomib in combination with cyclophosphamide and dexamethasone (CyBorD, is a well-established frontline chemotherapy regimen for patients with multiple myeloma, but prospective data on elderly non-transplant eligible patients is limited. A total of 155 patients aged 70 years or older with newly diagnosed multiple myeloma who received at least one cycle of CyBorD chemotherapy in three centres across New Zealand were evaluated. Partial response or better was achieved in 79·4%, of whom 52·9% achieved at least a very good partial response. After a median follow-up of 31·9 months, the median event-free survival (EFS) was 17·0 months (age 70–80 years, 17·7 months; age above 80 years, 8·6 months; P = 0·002). The median overall survival was 45·1 months (age 70–80, 49·8 months; above 80, 33·3 months; P = 0·003). Amongst those who had seven or more cycles of treatment, those who had a pre-planned switch to bortezomib-thalidomide-dexamethasone (VTD) consolidation had a superior median EFS of 25·4 months, compared with 20·3 months in the CyBorD only group (P = 0·028). This is the largest real-world dataset on the efficacy of CyBorD in the elderly population, and pre-planned switch to VTD was associated with better outcomes.