多发性骨髓瘤分子细胞遗传学异常的研究

目的探讨多发性骨髓瘤（MM）的分子细胞遗传学异常。方法应用CD138单克隆抗体磁珠分选系统纯化23例初治MM患者的骨髓浆细胞，结合一组探针和间期荧光原位杂交技术检测MM患者13q14缺失、p53缺失以及IgH基因重排的发生率。结果23例MM患者中，10例（43．5％）13q14缺失。阳性率为79％-96％；11例（47．8％）IgH基因重排；7例（30．4％）有13q14缺失和IgH基因重排；所有病例均未检测到p53基因缺失。结论13q14缺失及IgH基因重排在MM患者中的发生率较高；13q14的缺失和IgH基因重排的发生率同疾病进展、预后的关系有待进一步研究。     

伴有多种FISH异常多发性骨髓瘤患者的预后分析

目的分析同时伴有2种及2种以上的荧光原位杂交(FISH)结果异常的多发性骨髓瘤(MM)患者的预后情况,筛选预后较差的MM者。方法共计纳入2011年7月至2017年2月期间767例在长征医院就诊的初诊MM患者,所有患者初诊时均进行FISH检测,所检测的FISH异常包括IgH易位、t(4;14)、t(11;14)、t(14;16)、17p-、1q扩增、-13/13q-,分析所有FISH异常对预后的影响。结果多因素COX回归分析结果示1q扩增、17p-、t(4;14)是MM患者的独立不良预后因素,进一步将1q扩增、17p-、t(4;14)3种预后因素按不同组合将患者分为7组,仅伴有1q扩增患者295例(38%),仅伴有17p-患者37例(4.8%),仅伴有t(4;14)的患者38例(4.9%),同时伴有1q扩增和17p-的患者42例(5.4%),同时伴有1q扩增和t(4;14)的患者77例(10.0%),同时伴有t(4;14)和17p-的患者为6例(0.7%),同时伴有1q扩增、t(4;14)和17p-3种FISH异常的患者为13例(1.7%)。因最后2种情况患者例数较少,未纳入生存分析。前5组MM患者的3年无进展生存(PFS)率分别为:32.6%、27.0%、60.4%、27.3%、25.7%,3年总生存(OS)率分别为:63.0%、52.8%、86%、59.0%、55.2%。仅伴有1q扩增或仅伴有17p-的患者和同时伴有1q扩增及17p-患者比较,其OS差异无统计学意义(P=0.651,P=0.339)。结论 17p-和1q扩增为MM的高危预后因素,但同时伴有17p-和1q扩增的患者相较于仅单独伴有17p-或1q扩增的患者其不良预后风险并不增加。     

间期荧光原位杂交技术检测多发性骨髓瘤基因组异常的临床意义

目的 探讨I-FISH技术检测MM基因组异常的临床意义.方法 应用CC技术(常规R显带)和I-FISH技术[包括GLP13q14(RB1基因)、GLP17p13.1(P53基因)、GLP13q14.3(D13S319)、GLP1q21及GLP14q32(IgH基因)DNA序列探针]分别对20例初治的MM患者(按Bataille分期,Ⅰ期7例、Ⅱ期5例、Ⅲ期8例)进行基因组检测;比较两种方法对MM染色体和基因组异常的检出率;并分析基因组异常与Bataille分期的关系.结果 CC技术从20例MM患者中检出1例[5%(1/20)]染色体异常,且为复杂核型--46,XX,-2,del(3)(p21),add(6)(q26),der(10)(q26),der(14)(32),+mar,inc[6].I-FISH检出12例[60%(12/20)]基因组异常,其中基因组异常发生频率在RB1、D13S319和P53均为30%(6/20),IgH和1q21均为20%(4/20);经配对χ2检验,I-FISH的检出率高于CC技术(χ2=9.09,P=0.001).在20例MM患者中,RB1基因异常的6例,Ⅰ期占1/20,Ⅱ期占1/20,Ⅲ期占4/20;D13S319异常的6例,Ⅰ期占2/20,Ⅱ期占1/20,Ⅲ期占3/20;P53基因异常的6例,Ⅰ期占2/20,Ⅲ期占4/20;1q21异常的4例,Ⅰ期和Ⅲ期占2/20;IgH基因异常的4例,Ⅰ期占1/20,Ⅲ期占3/20.结论 I-FISH对MM患者基因组异常检出率较高,其可检出不同Bataille分期的MM患者.

Abstract：

Objective To investigate the clinical significance of I-FISH for detection of genomic abnormalities in MM. Methods Twenty newly diagnosed MM patients(seven cases at stage Ⅰ , five cases at stage Ⅱ and eight cases at stage Ⅲ according to Bataille staging) were analyzed by combining the technique of CC (R-binding stain) and I-FISH [ including GLP13q14 (RBI gene), GLP17p13. 1 (P53 gene),GLP13q14. 3(D13S319) ,GLP1q21 ,GLP14q32(IgH gene) DNA sequence probes]. These two methods were compared for the detection rates of chromosomal and genomic abnormalities in MM and the association between genomic abnormalities and Bataille stages was also analyzed. Results CC examination showed only 1 case [5% (1/20) ] was found complex chromosomal abnormalities--46,XX,-2,del(3) (p21) ,add(6)(q26) ,der(10)(q26),der(14)(q32), + mar, inc[6]. While I-FISH assay showed that 12 cases [60%(12/20) ] were found genomic abnormalities. The frequencies of RB1, D13S319 and P53 were all 30%(6/20), and the frequencies of IgH gene and 1q21 were both 20% (4/20). The detection rate of the I-FISH was much higher than CC (χ2 = 9. 09, P = 0. 001) according to paired χ2 test. Of 20 patients,6 cases had RB1 gene abnormality, 1 case at stage Ⅰ , 2 cases at stage Ⅱ and 4 cases at stage Ⅲ. Of 20 patients, 6 cases had D13S319 gene abnormality, 2 cases at stage Ⅰ , 1 case at stage Ⅱ and 3 cases at stage Ⅲ. Of 20 patients, 6 cases in 20 had P53 gene abnormality, 2 cases at stage Ⅰ and 4 cases at stage Ⅲ. Of 20 patients, 4 cases had 1q21 gene abnormality, 2 cases at stage Ⅰ and 2 cases at stage Ⅲ. Of 20 patients, 4 cases had IGH gene abnormality, 1 case at stage Ⅰ and 3 cases at stage Ⅲ. Conclusion Ⅰ-FISH has higher detection rate for the genomic abnormalities in MM and can be used in detection of MM patients in different Bataille stages.     

Phagocytic myeloma cells in asymptomatic multiple myeloma

A newly observed case of asymptomatic multiple myeloma in which phagocytic myeloma cells were observed is described. Bone marrow aspirates contained 16% myeloma cells, 2% of which engulfed red blood cells, lymphocytes, and platelets. The possibility is discussed that phagocytizing ability may be one of the markers for malignant plasma cells. Nothing is so far known of the phagocytosis by plasma cells in benign monoclonal gammopathy which is strictly defined.     

多发性骨髓瘤与新生血管形成

尽管大剂量化疗和和造血干细胞移植提高了多发性骨髓瘤(MM)的完全缓解率,但其复发率高,是一种不可治愈的疾病。目前,研究新生血管形成尤其是血管内皮生长因子(VEGF)已经成为生物医学的焦点,由此产生的单克隆抗VEGF抗体bevazicumab等各类靶向药物,显示出显著的临床前和临床的抗肿瘤活性。已知浆细胞的累积可以诱导骨髓层面的基础血管形成,支持肿瘤细胞的生长,加速疾病的进展。这里,我们讨论肿瘤血管生成的机制,并总结现有的和潜在的抗MM血管生成剂,以寻求MM新的治疗方案。     

Velcade in multiple myeloma

AIM: To study efficacy of velcade therapy in patients with progressive or refractory multiple myeloma (MM). MATERIAL AND METHODS: From April 2005 to November 2006 velcade was used in therapy of 18 patients (11 females and 7 males) with progressive or refractory to prior standard therapy MM course. The patients' age median was 55 years (36 to 76 years). Velcade was injected intravenously on the course days 1, 4, 8 and 11 with interval 10 days between the courses. A total of 77 courses were made (median 4.5). RESULTS: Overall efficacy was assessed according to EBMT criteria in 16 (68%) patients. Partial remission (PR) was achieved in 9 patients, complete remission (CR)--in 1, minimal response (MR)--in 1 patient. Five patients failed the treatment. In 5 of 11 patients with confirmed efficacy of velcade the drug was used in induction of remission before high-dose chemotherapy (HDC) and autotransplantation of hemopoietic stem cells (HSC), in 3--as monotherapy, in 1--in combination with high-dose dexamethasone, in--with high dose dexamethasone and doxorubicin. Four patients achieved PR, one--MR. HSC were obtained before velcade therapy in one patient, in 4--after its conduction. After HDC there were one CR and 4 PR. Recovery of hemopoiesis after HDC took the same time as after standard induction therapy. In 6 of 11 patients HDC was not performed. Velcade therapy is continued in 2 patients, in 1 case with CR the treatment was stopped. In 3 cases PR for 2 to 6 months was followed by the disease progression. CONCLUSION: Velcade as a new effective antitumor drug can be used for treatment of progressive and refractory forms of MM.     

Anemia in multiple myeloma

Anemia is a common complication in patients with multiple myeloma (MM) and occurs in more than two thirds of all patients. The most frequent underlying pathophysiological mechanism is anemia of chronic disease (ACD), relative erythropoietin (EPO) deficiency (due partly to renal impairment) and myelosuppressive effects of chemotherapy, but many other factors may account for or contribute to anemia in myeloma. In patients who achieve complete remission after chemotherapy, anemia usually normalizes. Nonresponders and relapsing myeloma patients often continue to suffer from anemia. Treatment options for anemic myeloma patients include red blood cell (RBC) transfusions and recombinant human erythropoietin (rHuEPO). Red blood cell transfusions convey an immediate effect and rapidly increase the patient's hemoglobin level. Unfortunately, effects of RBC transfusions are only transient and can be associated with several risks, including infections and mild to even life-threatening immunologic reactions. rHuEPO is biologically equivalent to the human endogenous hormone EPO, and its application leads to an increase of hemoglobin levels over an extended time without the risks of blood transfusions. Several studies reported a significant improvement of erythropoiesis, reduction in transfusion need, and improved quality of life by using rHuEPO as long-term treatment of myeloma-associated anemia. Recently, an international expert panel recommended the use of rHuEPO for anemic myeloma patients where other possible causes of anemia have been eliminated.     

初治多发性骨髓瘤患者细胞遗传学异常流行病学的多中心回顾性研究

目的了解我国初诊多发性骨髓瘤(MM)患者细胞遗传学异常(CA)的构成和频率,基于2018年更新的危险分层标准(mSMART3.0)分析双打击MM(DHMM)及三打击MM(THMM)的发生率。方法纳入全国5个中心的初诊MM患者,磁珠分选CD138细胞或浆细胞比例≥50%的骨髓标本行初诊间期FISH(iFISH)检测CA的基线结果,分析原发CA(pCA)、继发CA(sCA)、高危(HR)CA和DHMM/THMM的发生率,并分析不同CA组合的情况。结果共纳入初诊MM患者1015例,IgH重排、del(13q)/13q14、1q21扩增、del(17p)发生率分别为54.0%、46.4%、46.1%、9.9%。其中,1q21扩增拷贝数=3、≥4的发生率分别为35.8%、12.7%。454例患者具有完整CA基线结果,pCA中t(4;14)、t(11;14)和t(14;16)发生率分别为14.1%、11.2%和4.8%;44.3%患者携带≥2种CA,包括2种CA(28.0%)、3种CA(13.4%)和≥4种CA(2.9%);83.3%的1q扩增患者伴其他CA,以del(13q)/13q14最常见(61.1%),IgH重排次之(31.5%);95.0%的del(17p)患者伴其他CA,以del(13q)/13q14最常见(75.2%),1q21扩增次之(49.5%);68.6%的IgH重排患者伴其他CA,以del(13q)/13q14和1q21扩增最常见(均为61.9%);根据2016年国际骨髓瘤工作组的定义,57.7%患者携带HRCA;依据2018年mSMART 3.0的定义,DHMM(HRCA=2)和THMM(HRCA≥3)患者分别占14.3%和2.9%。结论更新了我国初诊MM患者的CA谱,发现基于CA的HR MM占初诊MM患者的比例近58%,并首次报道DHMM和THMM的发生率约为17%。     

Carfilzomib in multiple myeloma

Introduction: Advances in drug therapy for multiple myeloma (MM) during the previous decade have improved survival outcomes; however, the disease remains incurable as patients eventually relapse or become refractory to all available therapies. Therefore, there is a clear need for more effective and well-tolerated treatments.

Areas covered: We review preclinical and clinical data regarding the use of carfilzomib, a proteasome inhibitor that is structurally and mechanistically distinct from bortezomib, for the treatment of MM patients. Carfilzomib pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are summarized, based on Phase I/II trial data.

Expert opinion: Carfilzomib represents a significant advance in the management of relapsed and/or refractory MM patients, including those intolerant or resistant to bortezomib. High response rates have been demonstrated with carfilzomib as a single agent or in combination with alkylating agents, immunomodulators and corticosteroids, even among patients who have failed multiple prior therapies. Carfilzomib also has significant potential in the frontline setting, with encouraging response and survival rates observed for combination regimens. Further evaluation of carfilzomib-containing regimens is ongoing in Phase III trials and investigator-sponsored studies, which include combinations with novel investigational agents. These findings will shape the future role of carfilzomib for MM patients across multiple settings.     

Nonsecretory multiple myeloma

Nonsecretory multiple myeloma (NSMM) is a rare variant of the classic form of multiple myeloma (MM) and accounts for 1% to 5% of all cases of MM. The clinical presentation and radiographic findings of NSMM and MM are the same. The diagnosis of MM requires the detection of a monoclonal gammopathy in the serum or urine. In NSMM, however, no such gammopathy can be demonstrated, making the diagnosis more difficult. We describe a 43-year-old African American woman who initially had back pain and pathologic vertebral compression fractures that were thought to be due to osteoporosis. Five months later, hypercalcemia developed and NSMM was diagnosed. No monoclonal gammopathy was found in the serum or urine, but skeletal survey showed diffuse osteolytic lesions, and bone marrow biopsy revealed marked plasmacytosis. The immunohistochemical techniques and chromosomal analysis methods that are currently available are discussed.     

多发性骨髓瘤的免疫治疗

多发性骨髓瘤(MM)的发生、发展与机体免疫功能缺陷密切相关.传统的化疗多注重于直接杀伤MM细胞,患者接受化疗后不良反应较大,生活质量较低.更为重要的是,绝大多数MM患者接受化疗后,疾病进展或复发.免疫治疗因其导致的不良反应少,靶向性强,而有望成为治愈MM的新型治疗手段.笔者拟就有关MM免疫治疗的细胞免疫治疗、体液免疫治疗、放射免疫治疗及免疫调节剂4个方面的现状及进展进行综述.     

多发性骨髓瘤骨病的发病机制

多发性骨髓瘤(multiple myeloma,MM)是常见的血液系统恶性肿瘤,进行性的骨质破坏是其突出的临床特点之一,约90%的患者伴有不同程度的骨损害[1].与其他实体瘤骨转移所致的骨质破坏不同,60%的MM患者在确诊时就伴有明显的骨痛,并逐渐发展为病理性骨折[2].     

Epidemiology of multiple myeloma

Death rates due to multiple myeloma are increasing by every year in Japan since 1970. 1,896 men and 1,889 women were died, during 2005. Crude mortality rates are also rising since 1970 and reach 3.04 per 100,000 and 2.89 per 100,000 among men and women, respectively in 2005. Age-adjusted mortality rates (using the 1985 Japan Standard) reach 1.5-1.6 per 100,000 in 1995 and persist its value till now.     

Bone lesion in multiple myeloma

Bone destruction is a hallmark of multiple myeloma(MM). Almost all MM patients develop osteolytic bone lesions that can cause pathologic fractures and severe bone pain. Osteolytic lesions result from increased bone resorption due to osteoclast stimulation and decreased bone formation due to osteoblast inhibition. Plain radiography, CT, and MRI are established imaging techniques in MM. FDG-PET imaging is promising newer scanning technique under current evaluation. The aggressive features of MM bone lesions have significantly contributed to poor prognosis. Therefore, a systemic approach to analgesia, which includes radiotherapy and orthopedic intervention, must be applied as a part of the comprehensive care plan of MM patient. Bisphosphonates have been shown to reduce vertebral fractures and bone pain.     

Thalidomide in multiple myeloma.

Thalidomide--removed from widespread clinical use by 1962 because of severe teratogenicity--has anti-angiogenic and immunomodulatory effects, including the inhibition of TNF alpha. It has returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was FDA-approved in 1998, and more recently certain malignancies, including multiple myeloma. Whilst the mechanism of action of thalidomide remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials both as a single agent and in combination have confirmed benefit in relapsed and refractory disease. Thalidomide's role in treating newly diagnosed patients is currently under study and it is now established as an important therapeutic option in the treatment of multiple myeloma.