The adverse prognostic impact of advanced age in multiple myeloma

The adverse prognostic impact of advanced age in multiple myeloma is multi-factorial. In this review we explore the various contributory factors to this phenomenon. These include general biological and psychosocial factors, which impact on cancer in the elderly population such as the presence of multiple co morbidities and poor performance status at diagnosis and variation in patient's expectations of treatment. Factors specific to myeloma include the ability to deliver optimum therapy in older patients and the impact of this on disease response, possible biological differences of myeloma in older patients, and how these various factors impact on the efficacy of conventional-dose, high-dose (HDT) and newer disease modifying therapies. Selected elderly patients can gain equal benefit to younger patients from effective therapies such as HDT. However, the use of specific assessment tools for the elderly, apart from chronological age, should be used to select elderly patients who will benefit. Future testing of newer therapies in patients with myeloma must include older patients, who will make up an increasing proportion of the myeloma population in the future and should incorporate assessment of effect of these therapies on quality of life.     

Clinical significance of cytogenetics and interphase fluorescence in situ hybridization analysis in newly diagnosed multiple myeloma in Taiwan.

BACKGROUND: The incidence of multiple myeloma (MM) is lower in Asia than in Western countries. However, it is not known whether cytogenetic abnormalities (CA) characteristic of MM in Asia differ from those documented in the West. PATIENTS AND METHODS: We analyzed CA by conventional cytogenetics (CG) and/or fluorescence in situ hybridization (FISH), assessed their clinical significance in 150 Chinese MM patients and compared our data with that derived from Western countries. RESULTS: CA were detected by CG (CG_CA) in 44 (29.3%) of the 150 patients and by FISH (FISH_CA) in 59 (67%) of the 88 patients studied. Presence of either CG_CA or FISH_CA was associated with a poor prognosis. Patients with CG_CA and hyperdiploid chromosomes, always associated with several trisomies, had a longer survival (median 25 months versus 12 months; P=0.025) in comparison with those with non-hyperdiploid chromosomes, usually associated with a monosomy 13/partial deletion of 13q (Delta13) and a rearrangement of 14q32. A novel recurrent CG_CA, add(19)(p13), was found in four patients: all males with immunoglobulin G/lambda isotypes, extramedullary myeloma at diagnosis and a poor prognosis. Three groups of patients with significantly different survival, CG_Delta13, FISH_Delta13 but without CG_Delta13, and neither CG_Delta13 nor FISH_Delta13 (median 9 versus 15 versus 32 months; P=0.013) were identified. CONCLUSIONS: We conclude that MM CA in our patients are similar to those noted in Western countries, and that combined CG and FISH analysis can predict prognosis. The clinical significance of add(19)(p13) needs to be further investigated.     

多发性骨髓瘤细胞遗传学异常研究进展

 随着细胞遗传学和分子生物学技术的迅速发展,人们对多发性骨髓瘤（MM）中细胞遗传学异常的认识逐渐加深。MM细胞遗传学异常以非整倍体核型、13号染色体异常、Ig易位等为主,具有独特的分子生物学改变,与疾病的临床特点密切相关。对此领域进行深入探讨,将有助于我们了解MM的发生、发展机制,建立更合理有效的诊治策略。     

The clinical significance of cereblon expression in multiple myeloma

Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). We demonstrate here that no patient with very low CRBN expression responded to IMiD plus dexamethasone therapy. In 53 refractory MM patients treated with pomalidomide and dexamethasone, CRBN levels predict for decreased response rates and significant differences in PFS (3.0 vs. 8.9 months, p < 0.001) and OS (9.1 vs. 27.2 months, p = 0.01) (lowest quartile vs. highest three quartiles). While higher CRBN levels can serve as a surrogate for low risk disease, our study demonstrates that low CRBN expression can predict resistance to IMiD monotherapy and is a predictive biomarker for survival outcomes.     

Relevant prognostic features of multiple myeloma and the new International Staging System

The new International Staging System should be reported in all future studies of multiple myeloma. However, the system fails to account for recent research findings pertaining to mechanisms of disease progression. This review describes development of the International Staging System and details prognostic factors that may further our understanding of the biology of multiple myeloma.     

TGFβR2 aberrant methylation is a potential prognostic marker and therapeutic target in multiple myeloma

Multiple myeloma (MM) is an incurable hematological malignancy. Different studies demonstrated the occurrence of genetic and epigenetic alterations in MM. The aberrant methylation is one of the most frequent epigenetic alterations in human genome. This study evaluated the aberrant methylation status of 20 genes in 51 MM samples by quantitative methylation‐specific PCR (QMSP) and compared the methylation profile with clinicopathological characteristics of the patients. The QMSP analyses showed that PTGS2 (100.0%), SFN (100.0%), CDKN2B (90.2%), CDH1 (88.2%), ESR1 (72.5%), HIC1 (70.5%), CCND2 (62.7%), DCC (45.1%) and TGFβR2 (39.2%) are frequently hypermethylated in MM while aberrant methylation of RARβ (16.6%), MGMT (12.5%), AIM1 (12.5%), CDKN2A (8.3%), SOCS1 (8.3%), CCNA1 (8.3%) and THBS1 (4.1%) are rare events. There was no methylation of GSTP1, MINT31, p14ARF and RB1 in the samples tested. Hypermethylation of ESR1 was correlated positively with isotype IgA, while aberrant methylation of THBS1 correlated negatively with isotype IgG. Furthermore, hypermethylation of DCC and TGFβR2 were correlated with poor survival. The multivariate analysis showed ISS and TGFβR2 hypermethylation strongly correlated with poor outcome. This study represents the first quantitative evaluation of promoter methylation in MM and our data provide evidence that TGFβR2 hypermethylation, besides ISS, may be useful as prognostic indicator in this disease. © 2009 UICC     

microRNA-32在多发性骨髓瘤中的表达及临床意义

目的 探讨microRNA-32（miR-32）在多发性骨髓瘤（MM）骨髓单个核细胞（BMMNC）中的表达水平及意义。方法 收集43例MM患者及20例正常对照的骨髓标本,采用实时荧光定量PCR法检测BMMNC中miR-32的表达,并分析其与Durie-Salmon（D-S）分期和β2-微球蛋白（β2-MG）水平的关系。结果 miR-32在MM中的表达水平（5.29±0.31）明显高于正常对照组（相对值为1）,复发／难治组miR-32表达水平（6.86±0.24）明显高于初治组（4.15±0.29）,差异均有统计学意义（P＜0.05）。MM患者化疗后miR-32表达水平较化疗前明显降低（5.29±0.31 vs.3.43±0.45）,化疗有效组降低十分显著（4.57±0.41 vs.1.92±0.15）,差异均有统计学意义（P＜0.05）;无效／进展组miR-32表达水平化疗前后无明显改变。miR-32表达与MM D-S分期和β2-MG水平有关。结论 miR-32表达在MM的发生、发展中发挥着重要作用,有望成为MM疾病进展和疗效的预测指标。     

18FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation

The aim of this study was to investigate the prognostic value of 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pretreated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed.Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p<0.01). Presence of >10 focal lesions correlated with both TTP (p<0.01) and OS (p<0.05). Interestingly, presence of >10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p<0.01, respectively). PET resulted in a change of management in 30% of patients.Our data underline the prognostic value of 18F-FDG-PET/CT in MM patients also in the setting of post-SCT relapse. PET/CT has a significant impact on patient management.     

Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance

The conflicting data are reported on the clinical significance of VEGF deregulation and intensity of angiogenesis in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of VEGF expression and microvessel density (MVD) in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of VEGF and MVD was analyzed using standard immunohistochemical method (antibodies against VEGF and CD34, respectively) on B5-fixed and routinely processed paraffin-embedded bone marrow specimens. MVD was estimated by counting the number of microvessels in three “hot spots” at 400× magnification. VEGF immunoreactivity was estimated on the basis of intensity and percentage of positive plasma cells. VEGF was expressed in 47/59 (79.7%) specimens. There was no significant correlation between VEGF overexpression and age, clinical stage, the extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, and albumins, the extent of bone marrow infiltration, histological grade, and proliferative activity index (measured with Ki-67 immunoreactivity). No significant difference was observed regarding the overall survival between VEGF-positive and VEGF-negative patients (29 vs. 34 months, P = 0.8). Median MVD was 15, ranging from 1 to 89 microvessels per three “hot spots”. There was significant correlation between MVD and histological grade, the extent of bone marrow infiltration, and proliferative activity. Significant difference was observed regarding the overall survival between patients with low MVD (<15) and patients with high MVD (≥15) (46 vs. 22 months, P = 0.009; univariate analysis). The results of this study did not reveal clinical significance of VEGF overexpression in multiple myeloma. On the contrary, the extent of bone marrow angiogenesis is an indicator of biological potency of malignant clone and a predictor of poor survival in newly diagnosed myeloma.     

Expression, adverse prognostic significance and therapeutic small molecule inhibition of Polo-like kinase 1 in multiple myeloma

The amplified myeloma centrosome has been identified as a therapeutic target. The present study explored the expression and prognostic significance of the centrosome-associated protein PLK1 in myeloma and the effect of BI 2536, a potent and selective inhibitor of PLK1, on myeloma cells. High plasma cell expression of PLK1 protein in myeloma patient bone marrow biopsies is an independent adverse prognostic factor (HR = 2.3, p = 0.003 unadjusted; HR = 1.9, p = 0.03 in multivariable model). BI 2536 inhibits myeloma cell lines at nanomolar concentrations, and is therapeutic for xenografts in NOD/SCID mice. PLK1 inhibition is a potential new strategy for the treatment of multiple myeloma.     

多发性骨髓瘤患者血清胆固醇水平的临床意义

 目的　探讨多发性骨髓瘤（MM）患者血清胆固醇水平变化及其与分型、分期的关系。方法　回顾分析65例MM患者诊断时血脂水平,包括总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白A1（Apo-A1）和载脂蛋白B（Apo-B）,探讨血脂参数与MM患者免疫球蛋白类型和临床分期关系。以健康体检者30例作为对照组。结果　65例MM患者中IgG型35例（53.85 %）,Ⅲ期41例（63.1 %）,MM患者血清TC、HDL-C、 LDL-C、Apo-A1和Apo-B明显低于对照组 （P＜0.05）,两组TG差异无统计学意义（P＞0.05）;除1例IgD型外,其余64例患者中,IgG和IgA型患者血清TC、HDL-C、LDL-C、Apo-A1和Apo-B均显著低于轻链型（P＜0.05）,TG水平在不同Ig类型患者间无差别;Ⅲ期患者血清TC、HDL-C、LDL-C和Apo-A1均显著低于Ⅰ期患者和对照组（P均＜0.05）,且Ⅱ期患者血清LDL-C 也显著低于Ⅰ期患者（P＜0.05）。结论　MM患者存在低胆固醇血症,且血清胆固醇水平与疾病分期有关。     

血清胱抑素C在多发性骨髓瘤预后中的意义

目的 探讨血清胱抑素C（Cys-C）在多发性骨髓瘤（MM）预后中的意义.方法 收集初诊MM患者160例,平均年龄61.38岁,治疗前检测Cys-C、血清肌酐、β2-微球蛋白（β2-MG）、乳酸脱氢酶（LDH）及血红蛋白水平;中位随访38个月,观察Cys-C与总生存（OS）、无事件生存（EFS）的关系.结果 160例MM患者Cys-C水平为（0.96±0.32） mg/L,高于80例健康对照组的（0.71±0.16）mg/L（P＜0.000）;按ISS分期,Ⅰ期患者Cys-C水平为（0.70±0.13）mg/L,Ⅱ期为（0.87±0.16）mg/L,Ⅲ期为（1.23±0.33）mg/L,各期间Cys-C水平差异均有统计学意义（均P＜0.05）;Cys-C与血清肌酐、β2-MG、LDH呈正相关（r=0.669,r=0.672,r=0.521;均P＜ 0.000）,与血红蛋白呈负相关（r=-0.436,P＜ 0.000）.用ROC分析,Cys-C水平＞0.95 mg/L的患者和Cys-C≤0.95 mg/L的患者相比有较短的EFS和OS（中位EFS分别为30、57个月,P＜0.05;中位OS分别为43、68个月,P＜0.05）.结论 对于MM患者,Cys-C不仅是反应肾损害的敏感指标,也是反应肿瘤负荷及判断预后的指标之一.     

多发性骨髓瘤患者的手术治疗与预后分析

目的：总结32例经手术治疗的多发性骨髓瘤（multiplemyeloma,MM）骨相关事件患者的术后效果,并进行术后生存分析。方法2004年11月至2010年11月,手术治疗32例（手术共计40次）多发性骨髓瘤患者：脊柱手术24例次;长骨及骨盆手术11例次;软组织肿物切除术4例次;颅骨手术1例。术后平均随访14.0个月,术后应用VAS评分评价患者疼痛缓解情况,采用（ Kaplan-Meier,K-M ）法进行生存评估,采用单因素Cox模型分析预后风险因素。结果术前26例以疼痛为主的患者术后24例缓解（92.3%,24/26）,术前、术后1个月与术后6个月VAS平均评分分别为7.2、3.4、0.8;19例脊髓神经功能受损的患者,术后12例好转（63.2%,12/19）,具体为5例由Frankel C至D,2例由Frankel B至D,2例由Frankel B至C,A至B、A至C、D至E各1例。K-M法估计术后中位生存期为22个月,估计术后1、3年的总体生存率分别为70%和38%。单因素Cox模型分析显示术前病程≥12个月（ RR 11.199,P＝0.023）、手术次数一次（RR5.273,P＝0.045）及贫血（RR5.171,P＝0.034）是具有意义的术后生存危险因素。结论手术干预是缓解多发性骨髓瘤骨相关事件症状的有效措施之一。术前病程、手术次数及贫血可能是具有意义的术后生存危险因素,对此仍需进一步研究。     

多发性骨髓瘤完全缓解后微小残留病变的检测进展及意义

 已经证实传统意义上完全缓解（CR）的患者体内仍残留约1010 个肿瘤细胞,是疾病进展和复发的根源。为进一步了解体内残存的肿瘤细胞,聚合酶链反应（polymerase chain reaction,PCR）检测IgH基因单克隆重排、流式细胞术（flow cytometic,FCM）检查细胞表面抗原及染色体异常倍体和荧光原位杂交（flurescence in situ hybridizztion,FISH）分析染色体异常核型可用于临床以监测微小残留病的动态变化,判断预后并指导治疗。     

Hepcidin-25在多发性骨髓瘤中的表达及其临床意义

目的 探讨Hepcidin-25在多发性骨髓瘤（MM）患者不同疾病过程中的动态变化及其与疗效、预后的关系.方法 在临床诊疗的不同阶段分别采用实时定量聚合酶链反应（RT-PCR）、酶联免疫吸附法（ELISA）分析54例MM患者Hepcidin-25的mRNA及蛋白表达水平,研究Hepcidin-25的动态变化与患者临床表现的相关性及其对患者预后的临床预测价值.结果 MM患者Hepcidin-25 mRNA表达量明显高于健康对照组（0.58±0.19比0.08±0.03,P=0.001）,其蛋白质水平也明显高于健康对照组[（5.2±11.9）ng/ml比（22.5±7.1）ng/ml,P=0.019）].对MM患者随访发现,治疗后缓解患者（17例）的Hepcidin-25水平为（26.4±7.3） ng/ml,较其治疗前的（33.4±7.4） ng/ ml降低（t=5.312,P=0.021）.而治疗无效病情加重患者（37例）的Hepcidin-25水平为（55.9±12.7）ng/ml,较治疗前的（39.1 ±9.9）ng/ml增高（t=2.811,P=0.037）.治疗缓解组与治疗无效病情加重组患者生存率差异有统计学意义（P＜0.01）.治疗后缓解患者的血红蛋白（Hh）水平为124g/L,较治疗前的102 g/L升高（t=2.113,P=0.035）,与Hepcidin-25具有很好的相关性（r=-0.535,P=0.002）.而治疗无效病情加重患者的Hb水平为46 g/L,较治疗前的73 g/L降低（t=2.730,P=0.036）,与Hepcidin-25呈负相关（r=-0.642,P=0.001）.结论 MM患者的Hepcidin-25表达量较高,与慢性病贫血密切相关.较高水平的Hepcidin-25表达量对临床复发有一定的预测价值,与MM患者疗效、预后有密切关系.     

International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with total therapy 2 and 3 protocols

BACKGROUND:

Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling‐based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies.

METHODS:

The authors examined overall survival (OS), event‐free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling‐derived risk and delTP53 status, in the context of the 3 Total Therapy regimens.

RESULTS:

Whereas gene expression profiling risk segregated outcomes within all 3 International Staging System stages, International Staging System 3 conferred inferior prognosis only in low‐risk myeloma, whereas the grave prognosis of high‐risk disease was International Staging System‐independent. After adjusting for gene expression profiling‐defined high risk and delTP53 in multivariate analysis, International Staging System 3 and cytogenetic abnormalities both retained independent adverse implications for OS, EFS, and CRD. Among the 86% with low‐risk disease, cytogenetic abnormalities and delTP53 both affected all 3 endpoints negatively, whereas the International Staging System 3 effect was limited to OS. Total Therapy 3 improved survival outcomes beyond results obtained with Total Therapy 2.

CONCLUSIONS:

In the genomic era, standard laboratory variables, such as International Staging System stage and presence of cytogenetic abnormalities, continue to impact survival after adjusting for gene expression profiling risk and delTP53 status, providing a basis for stratification in our current practice of gene expression profiling risk‐based treatment assignment. Cancer 2011. © 2010 American Cancer Society.     

淋巴细胞绝对计数与多发性骨髓预后的相关性分析

  目的  探讨淋巴细胞绝对计数与多发性骨髓瘤患者疾病进展和预后的相关性。  方法  收集102例初发多发性骨髓瘤患者的淋巴细胞绝对计数及各项临床指标,分析淋巴细胞绝对计数与多发性骨髓瘤患者疾病进展和预后的相关性。  结果  根据中位淋巴细胞绝对计数分组后得出,组1（淋巴细胞绝对计数＞1.51×109/L）发病年龄、血清乳酸脱氢酶和β2-微球蛋白明显低于组2（淋巴细胞绝对计数 < 1.51×109/L）,组1患者中位总生存期大于组2（P < 0.05）。但两组患者性别、白蛋白、D-S分期、ISS分期、分组和疗效差异无统计学意义（P>0.05）。  结论  初发时淋巴细胞绝对计数高的患者预后较好,淋巴细胞绝对计数低的患者预后较差。推测淋巴细胞绝对计数可能成为多发性骨髓瘤的独立预后因素之一。      

多发性骨髓瘤的治疗进展

目的 多发性骨髓瘤(mutciple myelome,MM)是血液系统恶性肿瘤,近年来,MM的治疗已经取得了显著的进展.一些新药沙利度胺、硼替佐米、雷利度胺的应用扩大了MM患者的治疗选择并改善了预后.大量的Ⅲ期临床实验已经表明了新药联合治疗移植和非移植患者的有效性,基于这些研究结果,标准的诱导方案已经受到挑战、甚至被取代.对于适合移植的患者,一些新的诱导缓解方案的有效性优于长春新碱+多柔比星+地塞米松(VAD)方案.同样,对于不适合移植的患者,联合这些新药的一线治疗也被证明优于传统的马法兰+泼尼松(MP)方案.现基于新药的联合治疗策略就MM的治疗进展进行综述.     

The biological and clinical significance of the KI-67 growth fraction in multiple myeloma

We tested the significance of the Ki-67 plasma cell growth fraction in 49 bone marrow samples from 42 patients with multiple myeloma (MM). As a new approach to study myeloma cell proliferation, strong positivity of the CD38 antigen as plasma cell related feature was simultaneously evaluated with nuclear Ki-67 expression in a flow cytometric double immunofluorescence assay. Mean Ki-67 values were significantly higher in MM at relapse (22·4 per cent ± 10·4) as compared with MM at diagnosis (11·9 per cent ± 8·4, p < 0·005) and plateau-phase (10·0 per cent ± 5·5, p < 0·001), respectively. Serial observations in six patients confirmed this change in cell kinetic behaviour during the course of the disease. Elevated Ki-67 values correlated significantly with stage III (versus stage I, p < 0·05), beta-2-microglobulin serum levels > 6 (p < 0·001), plasmablastic morphology (p < 0·001), and diploid myeloma cell DNA-content (p < 0·005). No correlation was found between Ki-67 and immunoglobulin isotypes as well as immunophenotypic features (expression of CD10, CD33, and CD56) of myeloma cells. Clinically, six of seven patients with Ki-67 > 14 per cent at diagnosis had an unfavourable course (primary resistant disease or early relapse), and three of four patients with elevated Ki-67 values at plateau-phase relapsed within 3 months. Our results demonstrate the usefulness of Ki-67 in determining proliferative activity in MM and emphasize its value in the evaluation of the risk profile of MM patients.     

Cytogenetics and molecular cytogenetics in multiple myeloma

Multiple myeloma (MM) is characterized by frequent and complex genomic abnormalities that not only essentially contribute to the pathogenesis of this disease but also reflect its prognostic heterogeneity. There is evidence for two more or less mutually exclusive oncogenic pathways in the early development of clonal plasma cell disorders. Approximately half the tumours are non-hyperdiploid and carry translocations of the immunoglobulin heavy-chain (IgH) locus and various oncogenes, for example Cyclin D1, Cyclin D3, and FGFR3. The remaining hyperdiploid tumours exhibit recurrent trisomies - typically of chromosomes 5, 7, 9, 11, 15, 19, and 21 - but infrequently exhibit IgH translocations. While some chromosomal aberrations, such as deletion of chromosome arm 13q, deliver independent prognostic information that is already utilized for risk stratification within clinical trials, the prognostic significance of most other genetic aberrations in MM is undetermined.