Clinical Characteristics and Prognosis of MAF Deletion in Chinese Patients With Multiple Myeloma

BackgroundIn this study, we analyzed the frequency, clinical characteristics, and prognosis of MAF deletion in Chinese patients with multiple myeloma (MM).Patients and MethodsTwo hundred consecutive patients with newly diagnosed MM were analyzed. Patient samples were evaluated using a fluorescence in situ hybridization probe set, including 13q deletion, 17p deletion, and 1q21 gain, as well as immunoglobulin heavy chain gene (IgH) rearrangement, IgH/cyclin D1, IgH/fibroblast growth factor receptor 3 (FGFR3), and IgH/MAF. The frequency of MAF deletion and the clinical characteristics and overall survival of patients with MAF deletion were analyzed.ResultsThe incidence rate of MAF deletion was 15.0% (30/200) in newly diagnosed patients and all of them were monoallelic of MAF deletion. MAF deletion was associated with sex (P = .008), lactate dehydrogenase level (P = .026), 13q deletion (P = .028), FGFR3 deletion (P = .006), and IgH deletion (P = .018). Additionally, in an analysis of the overall survival rates of patients with MAF deletion who received a bortezomib-based regimen treatment, no significant differences were found in overall survival between positive and negative groups (P = .365).ConclusionMAF deletion was more frequent than MAF translocation with IgH in patients with MM and was more commonly observed in women. Moreover, MAF deletion was often combined with 13q, FGFR3, and IgH deletion. MAF deletion did not influence prognosis in patients with MM who were given a bortezomib-based chemotherapy regimen.     

Deep Sequencing Reveals Myeloma Cells in Peripheral Blood in Majority of Multiple Myeloma Patients

IntroductionThe evaluation of myeloma cells in multiple myeloma (MM) patients has generally been limited to the assessment of bone marrow involvement because of the sensitivity limitations of traditional minimal-residual-disease–detection methods.Materials and MethodsWe developed a sequencing-based method to identify myeloma cells in bone marrow (BM) and peripheral blood (PB) samples, based on their unique immunoglobulin gene rearrangements, that can detect cancer clones at levels well below 1 in 1 million leukocytes (0.0001%). In this multisite study, we used this sequencing method to determine the fraction of patients with myeloma cells in their PB at diagnosis and posttreatment time points.ResultsUsing this sequencing approach, we detected myeloma cells in the PB in the vast majority of MM patients (44/46, 96%). We demonstrated a clear correlation (R² = 0.57) between myeloma clone levels in paired BM and PB samples, and noted that PB clone levels were approximately 100-fold lower than levels in BM samples. The sequencing assay demonstrated a clear sensitivity advantage in the BM compartment and at least equivalent sensitivity in the PB compared with that of monoclonal-protein results.ConclusionThis study highlights the promise of a blood-based, sequencing minimal-residual-disease assay that can be used to measure MM disease burden at different time points and various disease stages.     

VAD Regimen in the Treatment of Resistant Multiple Myeloma: Slow or Fast Infusion?

The VAD regimen is effective in the treatment of resistant and relapsing multiple myeloma. In the original VAD regimen, vincristine (V) and doxorubicin (A) are given as continuous infusions together with peroral dexamethasone (D). For practical reasons, we have shortened the infusion times: 8 hours for vincristine and 1 hour for doxorubicin. In this retrospective analysis, we have compared the efficacy and toxicity of the original and modified VAD protocols in the treatment of myeloma patients at our institution. Of the 31 consecutive patients with myeloma, primarily or secondarily resistant to alkylating agents, 16 were treated by the original and 15 by the modified VAD protocol. We found no significant difference in the response rates (good responses 31% and 20% respectively), survival times (17 and 9 months respectively) or toxicity between the two protocols. VAD may well be modified so as to consist of short infusions of V and A. The overall efficacy of the traditional and modified regimens is, however, rather unsatisfactory in patients with advanced myeloma.     

Effect of the Choice of Primary Chemotherapy on the Cumulative Length of Stay in Hospital for Multiple Myeloma

The actual use of hospital beds for patients with multiple myeloma was calculated from a randomised trial of primary treatment with either melphalan and prednisone (MP, 66 patients) or intensive combination chemotherapy with vincristine, cyclophosphamide, lomustine, melphalan and methylprednisolone (MOCCA, 64 patients). The survival of the patients was similar in both arms, and the samples, 20 and 32 patients, respectively, were well representative for the whole arms. The average numbers of hospital days were similar fur both arms. For the first year MP 33.2 (SD 27.6) vs. MOCCA 32.1 (SD 19.0), and during the first to 4th years 78.5 (SD 45.9) vs. 67.8 (SD 34.1). For the year of death it was 50.4 (SD 33.1) vii. 36.3 (SD 27.0), respectivelly. Thus the choice of primary chemotherapy whether conventional or more aggressive had no influence on the actual number of in-patient hospital days concerned. When the combination chemotherapy schedule is well tolerated it can be administered just as well on an ambulatory basis or by using it with very short admissions. It seems that the need for inpatient care for patients with multiple myeloma is mostly related to the complications of the disease itself and to intercurrent disorders including infections.     

外周血细胞计数及其比值对初诊伴非骨相关髓外病变的多发性骨髓瘤患者预后的评估价值

 目的 探讨外周血淋巴细胞计数（ALC）、单核细胞计数（AMC）、淋巴细胞与单核细胞比值（LMR）、血小板与淋巴细胞比值（PLR）与初诊时伴非骨相关髓外病变（sEMD）的多发性骨髓瘤（MM）患者临床病理特征的相关性以及对疗效和生存的影响。方法 收集81例初诊时伴sEMD的MM患者临床病理资料，分别分析外周血ALC、AMC、LMR、PLR与血红蛋白、肌酐水平、乳酸脱氢酶水平、β2微球蛋白水平、治疗疗效、预后生存情况等指标关系。以ALC、AMC、PLR、LMR中位数为界值进行分组。Kaplan-Meier法分析ALC、AMC、PLR、LMR与生存及预后之间的关系；预后多因素分析采用Cox风险回归模型。结果 81例患者ALC、AMC、PLR、LMR中位数分别为1.38×10⁹/L、0.48×10⁹/L、134.9、3.11，多因素分析结果显示：LMR≤3.11（P=0.021）、PLR≥134.9（P=0.019）、LDH≥247U/L（P=0.041）、Hb≤110 g/L（P=0.004）是初诊伴sEMD的MM患者预后不良的影响因素。结论 对于初诊伴sEMD的MM患者，LMR≤3.11、PLR≥134.9、LDH≥247 U/L、Hb≤110 g/L可能是其影响预后不良的独立因素。     

Peripheral Blood Monoclonal B-Cells Predict the Event Free Survival in Multiple Myeloma

Reinfusion of myeloma progenitor cells may contribute to relapse of multiple myeloma after autologous stem cell transplantation. The aim of our study was to investigate whether monoclonal B-cells are present in the apheresis product and to evaluate the clinical relevance of these cells. Leukapheresis products of 55 patients were purged with anti-B-cell-Monoclonal antibodies (MoAbs) and immunobeads. Monoclonal B-cells were found in 85% of patients within the B-cell population. In one third of all myeloma patients, the majority of B-cells was represented by monoclonal myeloma progenitor B-cells, whereas in two thirds of patients monoclonal cells only represented a small part of the entire B-cell population. As shown by sequence analysis, monoclonal precursor B-cells and malignant plasma cells had the identical genetic CDR III sequence. The purging efficacy, using a negative selection system, was a median of 3 logs (range 1,5-3,5). No statistical difference in the purging efficacy was found when 3, 4 or 5 MoAbs against B-cells antigens were used. However, a tumor specific signal could be detected in the purged harvest of all patients, when the highly sensitive ASO-PCR approach was used. Furthermore, we found a direct correlation between the amount of remaining monoclonal cells after negative selection and the event free survival of myeloma patients. 10/15 patients with a median of 20 × 10³ monoclonal cells in the purged product relapsed at a median of 1,4 years, whereas only 6/24 patients with an oligoclonal pattern including a low number of remaining monoclonal cells relapsed at a median of 2,2 years. The event free survival (EFS) was statistically different between the two groups (p = 0,014).     

妇科肿瘤患者外周血淋巴细胞亚群研究

应用抗人淋巴细胞单克隆抗体免疫荧光技术检测２０９例妇科肿瘤患者的外周血淋巴细胞亚群，发现妇科恶性肿瘤患者的ＣＤ３、ＣＤ４、ＣＤ４／ＣＤ８比值明显下降，而ＣＤ８明显增加；且这些改变在早期即已出现，随肿瘤负荷的增加而愈加明显。当给予适当治疗减少肿瘤负荷后，这些变化逐渐恢复；而一旦出现复发，上述各项指标又明显改变。因而上述检测指标可考虑作为临床诊断、观察疗效、监测复发和预后的参考。     

Multiple Myeloma and Other Malignancies: A Pilot Study From the Houston VA

BackgroundThe prognosis of multiple myeloma (MM) has improved in recent years. Therefore, second malignant neoplasms (SMNs) may become an issue for longer term survivors with MM. An increased incidence of second malignancies was reported in patients who received lenalidomide for relapsed or refractory myeloma.Patients and MethodsData from the Tumor Registry of the Michael E. DeBakey VA Medical Center (1995-2010) were analyzed. Kaplan-Meier survival statistics were calculated.ResultsIn 197 patients with MM, 39 different cancers were observed in 33 patients, the large majority occurring before the diagnosis of MM, with most being early-stage or good-prognosis malignancies. Despite this, the prognosis of patients with a second or third cancer was clearly inferior to patients without other cancers. Notable was a significant number of prostate cancers as preexisting malignancies.ConclusionAt present, most other cancers (for which MM is the secondary malignancy) may not be related to the treatment for myeloma, but due to underlying immunologic, genetic, or environmental factors. Larger studies and careful follow-up, especially in good-risk patients treated with novel agents, are indicated.     

乳腺癌患者外周血T淋巴细胞AgNOR活性表达及其临床意义

目的:探讨乳腺癌患者外周血T淋巴细胞AgNOR的活性表达及其与临床病理因素的相关性.方法:利用KL型图像分析系统检测80例乳腺癌患者,40例乳腺纤维腺瘤患者,25例乳腺炎症患者和75例健康人外周血T淋巴细胞AgNOR的活性表达(T淋巴细胞核仁银染面积与细胞核面积比值,即I.S%),并与乳腺癌患者临床病理因素进行相关性分析.双抗体夹心法检测乳腺癌患者CA153和CEA.结果:发现乳腺癌患者外周血T淋巴细胞AgNOR的活性表达(5.88±6.05%)明显低于健康人(7.07±0.81%)、乳腺纤维腺瘤患者(6.58±0.72%)和乳腺炎症患者(9.58±0.68%)(P=0.000);乳腺炎症患者AgNOR的活性表达明显高于健康人、乳腺纤维腺瘤和乳腺癌患者(P=0.000);健康人与乳腺纤维腺瘤患者之间比较无显著性差异(P＞0.05).乳腺癌患者AgNOR阳性率(65.00%)明显优于CA153(17.50%)和CEA(12.50%)的阳性率(P=0.000).AgNOR表达与乳腺癌临床分期有关(P＜0.05),而与年龄、肿瘤大小、淋巴结转移状况无相关性(P＞0.05).结论:AgNOR阳性表达可作为评价乳腺癌发生、发展的客观生物学指标;在乳腺癌诊断、鉴别诊断和病情监测等方面有重要意义.     

硼替佐米和沙利度胺联合VAD方案治疗多发性骨髓瘤疗效分析

目的探讨硼替佐米、沙利度胺联合VAD方案治疗多发性骨髓瘤（MM）的临床疗效。方法 18例初诊MM患者采用硼替佐米、沙利度胺联合VAD方案治疗（A组）,硼替佐米1.3 mg/m2,沙利度胺从100 mg/d开始口服,逐渐增加剂量,至200 mg/d。单纯使用VAD方案（B组）治疗的23例初诊MM患者作为对照组。结果 A组的治疗有效率优于B组（P〈0.05）,联合治疗组的不良反应有皮疹、便秘、神经毒性、乏力、嗜睡、脱发及感染。结论硼替佐米和沙利度胺联合VAD方案治疗MM疗效明显优于VAD方案,缓解率高,对于初诊性MM是疗效较好而又较安全的方案,在选择化疗方案时可优先考虑。     

多发性骨髓瘤免疫微环境的研究进展

多发性骨髓瘤是一种以骨髓中单克隆浆细胞的恶性增殖为特征的血液系统肿瘤。骨髓微环境对骨髓瘤细胞的增殖与存活起到关键的支撑作用,其中大量免疫细胞处于免疫抑制状态是该疾病重要的发病机制之一。本文以近年来开展的骨髓瘤免疫微环境研究为基础,就目前多发性骨髓瘤免疫治疗手段、现存问题进行阐述,同时对免疫治疗未来发展方向提出思考和建议,为多发性骨髓瘤诊治研究领域的同道提供参考。     

Multi-drug Combination Therapy with Vincristine-Melphalan-Cyclophosphamide-Prednisolone Was More Effective than Cyclophosphamide-Prednisolone in Stage III Myeloma

A cooperative randomized clinical trial to compare the effectiveness of multi-drug combination chemotherapy (VMCP, vincristine-melphalan-cyclophosphamide-prednisolone) with CP (cyclophosphamide-prednisolone) for the treatment of multiple myeloma was performed. When the whole group of patients was evaluated, the choice of chemotherapy (VMCP or CP) was not a significant prognostic factor associated with response or survival by uni- or multivariate analysis, and the difference between the survival curves of the treatment groups was only marginally significant. However, when the analysis was confined to stage III patients, the choice of chemotherapy became a significant prognostic factor associated with both response rate and survival, and the statistical difference between survival curves was significant. Taking the disease characteristics of multiple myeloma into consideration, the better result obtained with multi-drug combination chemotherapy in the treatment of stage III patients is consistent with other studies supporting the superiority of multi-drug combination chemotherapy for patients with overt systemic disease.     

A Randomized Study of MOD Versus VAD in the Treatment of Relapsed and Resistant Multiple Myeloma

67 patients with relapsed or resistant multiple myeloma were randomized to receive either VAD (vincristine, doxorubicin, dexamethasone) or MOD (mitozantrone, vincristine, dexamethasone). 12/30 (40%) patients receiving VAD and 15/37 (41%) patients receiving MOD achieved plateaux. The median duration of plateaux was significantly longer on VAD (15 months) than on MOD (8 months). No significant difference in overall survival was seen between the two treatment arms. The only toxicity which was severe in more than 5% of treatment cycles on either treatment arm was myelosup-pression. No toxicity was significantly more severe on MOD than VAD. However, hair loss was significantly more severe on VAD than MOD. The frequencies of thrombocytopenia, haematuria and cutaneous toxicity were significantly greater on VAD than on MOD. Raised serum direct bilirubin levels were seen significantly more often on MOD than VAD. MOD and VAD have similar efficacy in relapsed/resistant multiple myeloma. MOD is the less toxic of the two regimens.     

Statins Reduce Mortality in Multiple Myeloma: A Population-Based US Study

BackgroundWe studied the effect of statins on mortality in a nationally representative sample of patients with multiple myeloma, and explored the benefit of statins in a subgroup of patients treated with novel agents.MethodsPatients diagnosed with multiple myeloma between 2007 and 2013 were identified in the SEER-Medicare database using International Classification of Diseases (ICD)-03 codes. ICD-9 and Healthcare Common Procedure Coding System codes were used to identify comorbidities and treatments. We assessed the association of statins with mortality in patients with multiple myeloma using multivariate Cox proportional hazards regression analysis. For subanalysis, we used the same statistical technique to investigate the effect of statins on mortality in myeloma patients treated with novel agents.ResultsA total of 5922 patients were diagnosed with multiple myeloma within the study period. Use of statins was associated with 21% reduction in risk of death (adjusted hazard ratio [aHR] 0.79; 95% confidence interval [CI] 0.74-0.84) among all patients with multiple myeloma. Among the patents treated with novel agents (n = 3603), statins reduced mortality by 10% (aHR = 0.90, 95% CI 0.83-0.98).ConclusionsUse of statins is likely associated with lower mortality in patients with multiple myeloma.     

MPV方案治疗难治性复发性多发性骨髓瘤18例临床观察

目的评估MPV方案治疗难治性复发性多发性骨髓瘤（MM）的疗效。方法18例难治性复发性MM患者,均给予MPV方案化疗,治疗4个周期观察疗效。观察项目包括血清M蛋白、肝肾功能、尿蛋白、骨髓像、血像等。结果经4个周期治疗,7例完全缓解,8例部分缓解,总有效率为83．33％。结论MPV方案是治疗难治性复发性MM较好的选择。     

Minimal Residual Disease Negativity Does Not Overcome Poor Prognosis in High-Risk Multiple Myeloma: A Single-Center Retrospective Study

BackgroundMinimal residual disease (MRD) is a standard measurement for response assessment in multiple myeloma (MM). Despite new treatments, high-risk MM patients continue to have poor prognosis. We evaluated the effect of MRD negativity in high-risk versus standard-risk patients.Patients and MethodsWe retrospectively evaluated all consecutive MM patients who underwent routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10⁻⁵ at our center from 2015 to 2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups.ResultsOne hundred thirty-six patients with MRD testing after initial therapy or autologous stem-cell transplantation were identified. At a median follow-up of 14 months (range, 1-36 months), progression-free survival and overall survival were significantly worse in high-risk versus standard-risk patients. During the study period, 50% of high-risk group had experienced disease progression (relapse and/or death) versus 20% in the standard-risk group (P = .0006). No patients with standard-risk died, but 4 (14%) in the high-risk group did (P = .0007). Regardless of MRD status, high-risk patients had statistically significant worse progression-free survival than standard-risk patients. At median follow-up, those with disease 10% standard-risk/MRD negative; 20% standard-risk/MRD positive; 40% high-risk/MRD negative; and 45% high-risk/MRD positive had either experienced relapse or died (P = .0041). MRD status did not significantly affect overall survival in either group (P = .0914); however, longer follow-up is needed to assess survival.ConclusionGenetic abnormalities remain a powerful prognostic indicator for MM, regardless of MRD status. For newly diagnosed MM patients treated with novel triple-drug initial therapy and frontline autologous stem-cell transplantation, MRD-negative status did not mitigate the poor-prognosis outcomes of high-risk MM patients.     

多发性骨髓瘤患者血清血管生成素水平的测定及意义

目的研究血管生成素（Angs）与多发性骨髓瘤（MM）的关系并探讨其临床意义。方法用双抗体夹心酶联免疫吸附测定法检测60例MM患者不同时期的Angs血清浓度,观察其与MM临床分期、肿瘤量分级和治疗效果的关系。结果MM患者血清中Ang-2较正常对照组明显升高;血清Ang-1含量与正常对照组差异无统计学意义。MM患者Ⅱ期的Ang-2血清水平显著低于Ⅲ期。不同肿瘤量分级的MM患者血清Ang-2含量差异有统计学意义。MM治疗有效者,血清Ang-2水平比治疗前明显降低,血清Ang-1水平与治疗前差异无统计学意义;治疗无效者,其血清Ang-1、Ang-2含量与治疗前比较差异均无统计学意义。结论MM患者血清Ang-2水平测定对MM的发病机制研究、病情评价、疗效监测、预后预测有一定意义。     

外周血Th17及T淋巴细胞亚群指标与小儿白血病的关系研究

目的 研究与分析外周血Th17及T淋巴细胞亚群指标与小儿白血病的关系.方法 选取60例白血病患儿为观察组,60例健康儿童为对照组,然后检测并比较两组的外周血Th17及T淋巴细胞亚群指标水平,同时将观察组中不同分期与类型白血病患儿的外周血Th17及T淋巴细胞亚群指标水平进行比较,并以Logistic分析上述外周血Th17及T淋巴细胞亚群指标与小儿白血病的关系.结果 观察组的外周血IL-6及CD8+水平高于对照组,其他外周血Th17及T淋巴细胞亚群指标水平则均低于对照组,且不同分期与不同类型白血病患儿其表达水平也存在显著性差异,以Lo-gistic分析显示,外周血Th17及T淋巴细胞亚群指标水平均与小儿白血病有密切的关系.结论 外周血Th17及T淋巴细胞亚群指标在白血病患儿中呈现异常表达的状态,且与本病有密切的关系,可作为疾病的重要监测指标.     

Relapse of Aggressive Myeloma after Complete Remission in Secondary Acute Leukemia: Coincidence or Consequence?

We describe a patient with multiple myeloma who developed secondary acute myelomonocytic leukemia after long-term melphalan treatment. Following two courses of low-dose cytarabine, complete remission of the A.M.L. was achieved. Shortly thereafter an aggressive relapse of the quiescent myeloma occurred with acute renal failure and massive infiltration of bone marrow with multinucleated giant plasma cells. Although it is well known that administration of melphalan to patients with multiple myeloma increases the likelihood of A.M.L., this case demonstrates that treatment of A.M.L. in a patient with multiple myeloma may perhaps influence the course of multiple myeloma.