多发性骨髓瘤生物靶向治疗研究进展

近年来,多发性骨髓瘤（MM）新药研发迅速,新的靶向治疗药物的临床应用进一步提高了MM患者的疗效。2016年第58届美国血液学会（ASH）年会上,多项关于MM的生物靶向治疗研究有了令人鼓舞的进展,尤其是各种新药的联合应用更是本届年会的一大亮点,同时还有很多新药的Ⅰ、Ⅱ期临床试验研究报道。对该届ASH年会上报道的关于MM的分子靶向治疗药物研究新进展进行介绍。     

多发性骨髓瘤的新药治疗方案：第57届美国血液学会年会报道

随着对多发性骨髓瘤（MM）生物学认识的加深和新药的出现，含新药的联合化疗方案加深了MM的治疗反应并延长了患者的生存期。文章总结了第57届美国血液学会年会报道的免疫调节剂、蛋白酶体抑制剂、去乙酰化转移酶抑制剂及单克隆抗体等新药联合治疗在MM中的进展。同时，微小残留病（MRD）也随之被用于评价缓解的深度。为使MM患者达到更长期缓解和更高生命质量的目标，新药组合的方案更受推荐，尤其对于复发或高危的MM患者。     

复发、难治多发性骨髓瘤诊治进展：第19届欧洲血液学会年会报道

复发、难治多发性骨髓瘤（MM）始终是MM治疗领域的一大难题.2014年第19届欧洲血液学会（EHA）年会围绕复发、难治MM,从定义、预后、治疗策略到新的药物进行了详细完整的阐述.兼顾有效性及安全性的新药在这一领域显示了良好的前景.     

多发性骨髓瘤治疗进展：第57届美国血液学会年会报道

多发性骨髓瘤（MM）是血液系统常见的恶性肿瘤之一。第57届美国血液学会年会就MM诊断和危险分层、新药时代的维持治疗、药物组合最佳方案及微小残留病检测方法和意义等热点问题进行了探讨。     

多发性骨髓瘤患者骨髓基质细胞IL-1β.IL-6.SCF.TPO表达的研究

 【摘要】　目的　研究多发性骨髓瘤 （MM） 患者骨髓基质细胞多种细胞因子在mRNA水平的表达情况，探讨不同因子在MM发生、发展中可能存在的作用。方法　采用半定量RT-PCR方法在mRNA水平上检测MM患者骨髓基质细胞白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、干细胞因子（SCF）、血小板生成素（TPO）的表达。结果　IL-1β、IL-6的表达：MM组与正常对照组和非MM组相比差异均具有统计学意义（P＜0.01）。SCF的表达：自体移植后患者组与正常对照组相比差异无统计学意义（P＞0.05），初发MM组和难治复发MM组与正常对照组和非MM组相比差异均有统计学意义（P＜0.05）。TPO的表达：MM组与正常对照组相比差异具有统计学意义（其中初发组P＜0.01，其余两组P＜0.05）。初发组与非MM组相比差异有统计学意义（P＜0.01），难治复发MM组和移植后患者组与非MM组相比差异无统计学意义。结论　体外培养的MM患者骨髓基质细胞 IL-1β、IL-6、SCF和TPO存在表达异常，这些因子在疾病进展中可能起重要作用。     

意义未明的单克隆免疫球蛋白血症的病程演变、鉴别诊断及其干预策略:第54届美国血液学会年会报道

 【摘要】　意义未明的单克隆免疫球蛋白血症（monoclonal gammopathy of undetermined significances,MGUS）被界定为癌前克隆性疾病。其在50岁以上人群中的发病率达到4.2 %,且以每年1 %的高风险向多发性骨髓瘤（multiple myeloma,MM）和相关的恶性疾病转化。确定其病程演变将指导临床诊断和治疗。大多数MGUS患者仅需随访观察。而少部分患者则经过冒烟型骨髓瘤（smoldering multiple myeloma,SMM）阶段进展为MM,或者因M蛋白导致终末器官损害,发展为轻链型疾病,如轻链型淀粉样变性、轻链沉淀病等,需要启动药物干预措施。2012年第54届美国血液学会（ASH）年会进行了这部分内容的详细报道。     

硼替佐米联合化疗治疗多发性骨髓瘤28例疗效分析

 【摘要】　目的　观察以蛋白酶体抑制剂硼替佐米为主的化疗方案治疗多发性骨髓瘤（MM）的疗效和患者不良反应。方法　28例MM患者接受以硼替佐米为主的联合方案化疗。疗效评定按照EBMT 标准进行。结果　28 例MM患者中,初治20例,复发难治8 例。25例可评估疗效,总反应率达100 %（25／25）,其中完全缓解（CR）5 例,接近完全缓解（nCR）10 例,部分缓解（PR）10 例。主要不良反应包括周围神经病变、血小板减少、消化道反应及病毒感染,经对症处理后好转,一般不影响治疗。结论　以硼替佐米为主的联合化疗治疗初治和复发难治MM 起效较快,治疗反应率高,不良反应可耐受。     

多发性骨髓瘤患者血栓形成与防治

 【摘要】 在多发性骨髓瘤（MM）患者中,静脉血栓栓塞症的发生率远高于健康人群。就MM患者中血栓形成的机制、相关危险因素、治疗、预防等方面的一些研究进展作一综述。     

IgD型多发性骨髓瘤的诊治现状及展望

IgD型多发性骨髓瘤（IgD multiple myeloma，IgD MM）是多发性骨髓瘤（multiple myeloma，MM）中一种罕见类型，以年轻男性患者居多。主要表现为高钙血症、肾衰竭、贫血、骨损害、髓外浸润和系统性淀粉样变性等，具有侵袭性高，预后较差的特点。近年来，随着免疫调节剂（沙利度胺、来那度胺）、蛋白酶抑制剂（硼替佐米）等药物以及自体造血干细胞移植（autologous stem cell transplantation，ASCT）的应用，IgD型MM的预后得到明显改善。新一代蛋白酶体抑制剂、CD38单克隆抗体、组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor,HDACI）、新型免疫治疗技术等治疗方法也为IgD型MM 的治疗提供了新的方向。目前关于IgD型MM的相关报道较少，本文就IgD型MM的临床特点、诊断、治疗、预后及新药研究现状进行如下综述。     

关注多发性骨髓瘤诊疗中的几个问题

 【摘要】　多发性骨髓瘤（MM）的诊断要点及治疗原则已被深刻认识及掌握。但是由于MM高度的异质性,有部分患者合并系统性淀粉样变性,出现明显的髓外浸润、静脉血栓形成与重度MM骨病,使疾病的诊疗复杂化,应引起注意。     

Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma

In this report, we provide a comprehensive review on the preclinical and clinical investigations conducted in development of the next-generation immunomodulatory drug (IMiD) pomalidomide for the treatment of relapsed/refractory multiple myeloma (MM). We consulted PubMed, MEDLINE, ASH, ASCO annual symposium abstracts and http://clinicaltrials.gov/ for the purpose of this literature review. Twenty-six preclinical and 11 clinical studies were examined. These studies delineate the mechanisms of action of pomalidomide and attest to the robust clinical activity in relapsed/refractory MM. MM is the second most common hematological malignancy in the US. Despite availability of several therapeutic agents, MM remains incurable. Thus, the development of new therapies remains a priority. Pomalidomide is the newest member of the IMiDs class of drugs, and in preclinical and clinical investigations, it has demonstrated an improved efficacy and toxicity profile in comparison to its sister compounds, lenalidomide and thalidomide. Importantly, recent clinical studies have demonstrated its activity in relapsed or refractory myeloma, particularly in lenalidomide and bortezomib-refractory patients. Thus, the addition of pomalidomide to the anti-myeloma armamentarium is widely anticipated to have a significant impact on the overall clinical outcome of advanced stage relapsed and refractory MM patients.     

多发性骨髓瘤的EBV、B7-1及主动免疫治疗研究

目的探讨EB病毒在多发性骨髓瘤的病因作用及新型疫苗治疗多发性骨髓瘤的作用。方法用多聚酶链反应（PCR）的方法检测21例多发性骨髓瘤（MM）患者瘤细胞的EB病毒DNA;应用间接免疫荧光法检测瘤细胞上MHCⅠ、Ⅱ类分子及共刺激分子B7-1的表达;应用细胞因子与瘤细胞制成的疫苗主动免疫治疗4例MM患者。结果发现66.7％的MM患者瘤细胞内有EB病毒DNA;瘤细胞膜多表达MHCⅠ、Ⅱ分子及B7－1。4例MM患者用疫苗治疗后3例取得明显疗效。结论EB病毒很可能是MM的病因,与B7－1阳性的细胞及细胞因子联合制成的疫苗主动免疫治疗MM具有较明显的疗效。     

Significant impact of survivin on myeloma cell growth.

Survivin is a fascinating member of the inhibitor of apoptosis protein (IAP) family with its dual roles in mitosis and apoptosis, and emerges as an attractive target for cancer therapy. Multiple myeloma (MM) is a plasma cell malignancy, characterized by deregulated proliferation, cell-death processes and fatal outcome. We thus investigated survivin expression in myeloma cells and its role in MM biology to evaluate its potential interest as a target in MM treatment. Our results describe the cancer-specific overexpression of survivin in myeloma cells and show a significant correlation between survivin expression at protein level and clinical course of MM. Moreover, survivin knockdown by RNA interference led to growth rate inhibition of myeloma cells related to apoptosis induction and deep cell-cycle disruption. Finally, survivin knockdown sensitized myeloma cells to conventional anti-myeloma agents. Altogether, these data argue for the interest to evaluate survivin antagonists in MM treatment.     

Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma

Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM.     

A unique pathway in the homing of murine multiple myeloma cells: CD44v10 mediates binding to bone marrow endothelium

Our group recently reported that multiple myeloma (MM) cells preferentially adhere to bone marrow (BM) endothelial cells and selectively home to the BM, suggesting the involvement of specific adhesive interactions in this process. The highly regulated expression of CD44 variant isoforms (CD44v) on the MM cells makes them good candidate adhesion molecules involved in this homing. We addressed this in the 5T experimental mouse model of myeloma. Fluorescence-activated cell sorting analysis demonstrated expression of CD44v6, CD44v7, and CD44v10 on the in vivo growing 5T2MM and 5T33MM myeloma lines. Antibody blocking experiments revealed the involvement of CD44v10 in the adhesion of 5T2MM and 5T33MM cells to BM endothelial cells. Coinjection of anti-CD44v10 antibodies with the myeloma cells into syngeneic mice demonstrated a selective blocking of their BM homing which resulted in a decreased BM tumor load and serum paraprotein at the end stage of the disease. The highly restricted expression of CD44v10 on MM cells, the blocking of MM adhesion to BM endothelial cells and of homing to BM by anti-CD44v10, and the decreased BM tumor load suggest that myeloma cells home to the BM via interactions mediated by this specific region of the adhesion molecule CD44.     

Homing of the myeloma cell clone

The presence of myeloma cells in the blood circulation, implicates that these cells must have the potential to extravasate and home to the bone marrow environment. Using the 5T2 MM mouse model, we could demonstrate that the restricted localization of myeloma cells in the bone marrow is the result of selective migration of myeloma cells in the bone marrow combined with a selective growth of the tumour cells in the bone marrow microenvironment. Moreover, we showed that 5T2 MM cells bind in vitro selectively to bone marrow-derived endothelial cells (EC) and not to lung-derived EC. In order to identify which chemotactic molecules mediate the transendothelial migration of myeloma cells, we examined the motility-inducing effect of different extracellular matrix proteins on myeloma cell lines. We found that laminin-1, a major component of the basement membrane, triggers the motility of both human myeloma cells and 5T2 MM cells, through the 67 kD laminin receptor. Because of the broad distribution of laminin in extracellular matrices throughout the body, it is clear that this molecule on itself can not be the only factor that determines the specificity of myeloma cell homing. In the 5T2 MM model we identified IGF-1 as a more specific bone marrow derived chemoattractant for myeloma cells. In addition we demonstrated that the marrow microenvironment can upregulate the expression of the IGF-1 receptor on 5T mouse myeloma cells. In the end phase of the disease, increasing numbers of myeloma cells are detectable in the peripheral blood and extramedullary tumour growth can occur. We found that the stroma-independent variant of the human MM5 myeloma cell line showed an increased in vitro motility as compared to the stroma-dependent variant. By representational difference analysis we demonstrated that the stroma-dependent MM5 cells show a downregulation of the motility-related protein (MRP-1/CD9) which might reflect the involvement of this molecule in the regulation of myeloma cell extravasation.     

沙利度胺与利妥昔单抗协同抗骨髓瘤细胞作用的体外研究

背景与目的：利妥昔单抗（美罗华）的疗效与细胞膜上的CD20表达密度有关,如何提高多发性骨髓瘤细胞上CD20的表达、增加美罗华对多发性骨髓瘤的疗效,是目前临床尚未解决的问题。本文探讨沙利度胺是否能增强美罗华的抗骨髓瘤细胞作用及其可能的机制。方法：用10、50、75、100、150、200、300μg/ml的沙利度胺,0.5、1、2、4、8、12、16μg/ml的美罗华,上述7种浓度的沙利度胺联合16μg/ml的美罗华以及上述7种浓度的美罗华联合75μg/ml的沙利度胺分别加入18例初治和20例复发难治的多发性骨髓瘤患者瘤细胞甲基纤维素的半固体培养体系中,观察它们对瘤细胞集落形成的影响,并用流式细胞仪测定经上述7种浓度沙利度胺处理前后瘤细胞表达CD20的表达情况。结果：初治多发性骨髓瘤患者瘤细胞集落形成的抑制现象出现于：①单用浓度大于或等于75μg/ml沙利度胺或单用16μg/ml美罗华;②75μg/ml沙利度胺加或不加16μg/ml美罗华;③浓度大于或等于75μg/ml沙利度胺加或不加16μg/ml美罗华;复发难治多性骨髓瘤患者瘤细胞集落形成的抑制现象出现于：①75μg/ml沙利度胺加16μg/ml美罗华;②浓度大于或等于100μg/ml沙利度胺加或不加16μg/ml美罗华;浓度大于75μg/ml沙利度胺可增加复发难治多发性骨髓瘤细胞CD20抗原的表达。结论：体外沙利度胺能增强美罗华对多发性骨髓瘤细胞集落形成的抑制作用,这种增强作用与沙利度胺增加瘤细胞CD20抗原表达有关。     

环氧合酶-2在多发性骨髓瘤中的表达及其临床意义

 目的　探讨环氧合酶-2（COX-2）在多发性骨髓瘤（MM）中的表达及其与骨髓瘤细胞增生和凋亡的关系,为MM病情及预后判断提供新的标志物并提供新的治疗靶点。方法　用免疫组织化学法检测22例初治MM、14例复发MM骨髓组织中COX-2及初治MM骨髓组织中增生细胞核抗原（PCNA）、热休克蛋白70（HSP70）的表达。结果　COX-2在初治MM中的阳性表达率为100 %,弱阳性和强阳性各占50 %;在复发MM中均为强阳性表达。COX-2与血β2微球蛋白、骨髓浆细胞比例、血红蛋白水平、PCNA、HSP70具有相关性（P＝0.019、P＝0.003、P＝0.048、P＝0.006、P＝0.034）。结论　COX-2在MM中呈高表达。COX-2强阳性的初治MM患者病情较重、预后较差。