Cases Of Multiple Myeloma Patients Research Articles

Treatment Efficacy and Safety of Bortezomib Combined with Dexamethasone and Lenalidomide Chemotherapy Regimen for Multiple Myeloma

Objective: To analyze the effect of bortezomib combined with dexamethasone and lenalidomide in the treatment of multiple myeloma. Methods: 60 cases of multiple myeloma patients admitted to our hospital from January 2022 to December 2023 were selected randomly, with 30 cases in each group. Bortezomib combined with dexamethasone was administered in the control group, and bortezomib combined with dexamethasone and lenalidomide was given to the observation group, and the treatment effect was analyzed. Results: After treatment, CD3+ and CD4+ of the observation group were higher than that of the control group, CD8+ was lower than that of the control group, and the total treatment efficiency was higher, which was statistically significant (P < 0.05), and there was no difference in the total incidence of adverse reactions between the two groups (P > 0.05). Conclusion: Bortezomib combined with dexamethasone and lenalidomide is effective in the treatment of multiple myeloma as it regulates the immune function and is safe, thus it can be promoted in clinical practice.

Neutrophilic hyperleukocytosis in the multiple myeloma onset

Neutrophilic leukocytosis is not specific for multiple myeloma (MM) and is a reason for the exclusion of myeloproliferative neoplasm.A clinical case of MM patient with neutrophilic hyperleukocytosis (75 х 109/L), liver and spleen enlargement at the disease onset is presented. Examination did not reveal t(9;22), BCR/ABL gene and JAK2V617F mutation. To exclude the combination of MM with chronic neutrophilic leukemia, a study of the clinically significant part of the CSFR3R gene was performed. The absence of a CSFR3R gene mutation made it possible to exclude chronic neutrophilic leukemia and start MM treatment. After the 1st therapy course with bortezomib, cyclophosphamide and dexamethasone, blood counts returned to normal, liver and spleen size decreased. After 6 therapy courses, complete hematological remission was achieved. An attempt to mobilize peripheral blood stem cells with cyclophosphamide was unsuccessful. The effectiveness of antimyeloma therapy proved the correctness of the diagnosis and the chosen treatment tactics.Neutrophilic leukocytosis in MM is explained by the ability of plasma cells to synthesize granulocyte colony-stimulating factor in some cases. In the presence of a plasma cell tumor, the analysis of the CSFR3R gene may be of decisive importance in the differential diagnosis of reactive neutrophilic leukocytosis due to MM and the combination of MM with chronic neutrophilic leukemia.

Duration of Post-Autologous Hematopoietic Cell Transplant Anemia and Thrombocytopenia Are Associated with Prolonged Hospital Length-of-Stay for Multiple Myeloma Patients

BACKGROUND: Anemia, neutropenia, and thrombocytopenia are expected complications of autologous hematopoietic cell transplant (AHCT) for multiple myeloma (MM). However, prolonged cytopenias may predispose patients to other infectious, cardiovascular, and/or hematological toxicities. Various factors have been implicated in the length of post-AHCT cytopenias including stem cell dose, marrow microenvironment, and clonal hematopoiesis. We hypothesize that the length of post-transplant anemia, neutropenia, and thrombocytopenia may negatively impact hospital length-of-stay (LOS) and in-hospital complications. METHODS: This is a single-center observational study of MM patients who underwent AHCT. Patients were part of a larger cohort with detailed single nucleotide polymorphism (SNP) array cytogenetic data. Exclusion criteria were concurrent amyloidosis and tandem transplant. Demographic data, comorbidities, cytogenetic features (presence of TP53 deletion, and translocation status of MMSET, CCDN3, CCDN1, MAF, and MAFB), therapy line, peri-transplant laboratory values, and clinical outcome were collected retrospectively. LOS was calculated from transplant day -2 to hospital discharge. Predictive factors for LOS were calculated with multiple linear regression. Multiple logistic regression was then used to calculate associating factors for in-hospital complications. Grade III and IV post-transplant cardiovascular, infectious, and hematological complications were collected following the Common Terminology Criteria for Adverse Events (CTCAE). Post-transplant anemia was defined as sustained hemoglobin (Hb) <8 g/dL despite transfusions. The cutoffs for neutropenia and thrombocytopenia were absolute neutrophil count (ANC) <1.5 K/uL, and platelet (PLT) count <50 K/uL, respectively. RESULTS: 158 AHCT cases of MM patients were identified. 95 patients received AHCT as frontline treatment, 35 patients were transplanted in the salvage setting, and 14 patients received both frontline and subsequent-line transplant. The most commonly used conditioning regimen was melphalan 200 mg/m2 in 123 cases, followed by melphalan 140 mg/m2 in 23 patients. 50.6% (80/158) developed grade III anemia with a median onset of 9 days after transplant (IQR 5-11 days) and median length of 2 days (IQR 1-6 days). Neutropenia had higher incidence of 96.8% (153/158) with an earlier onset of 5 days (IQR 5-6 days) and median length of 5 days (IQR 2-7 days). Grade III thrombocytopenia occurred in 98.1% (155/158), with median onset of 7 days (IQR 5-7 days) and a median duration of 8 days (IQR 6-10 days). When comparing patients who received frontline transplant vs subsequent line transplants, no statistical significance was observed between onset or length of cytopenias (p=0.40). Median LOS was 16 days (IQR 15-19 days). The most frequent post-AHCT complications in our cohort were neutropenic fever (N=27), followed by engraftment syndrome (N=12), pneumonia (N=4), urinary tract infection (N=2), cellulitis (N=2), and bacteremia (N=1). Cardiovascular events were uncommon (N=3) and included pericarditis, new onset atrial fibrillation, and new onset supraventricular tachycardia. Pulmonary embolism (N=1) and deep vein thrombosis (N=3) were recorded. No major bleeding was observed. Longer LOS was independently associated with post-AHCT anemia (p=0.03) and thrombocytopenia (p=0.0005). Notably, LOS and in-hospital complication rates were not significantly associated with demographic data, pre-existing comorbidities, pre-transplant cytopenias, or cytogenetic abnormalities. CONCLUSION: In our cohort, longer duration of post-transplant anemia and thrombocytopenia were statistically associated with longer hospital LOS, but not with post-transplant complications. Prospective validation in an independent cohort is warranted. Disclosures Landgren: Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Merck: Other; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding. Chung:Genentech: Research Funding.

Hematological and Biochemical Changes in Patients with Multiple Myeloma Treated with Bortezomib Based Triple Drug Combination Chemotherapy

Background: Multiple Myeloma (MM) is a neoplastic clonal disorder and accounts for 1% of malignant tumors and 10%–15% of hematopoietic neoplasms. The prognosis of Multiple Myeloma has reversed by the advent of novel agents and triple combination therapy (Bortezomib, Thalidomide, Dexamethasone) that serve the basis of future strands of care in Multiple Myeloma patients. Objective: The aim of the study was to assess the safety, efficacy and tolerability of Bortezomib in newly diagnosed cases of Multiple Myeloma patients in Bangladesh. Materials &Methods: We undertook this clinicopathological study to assess the profile of Multiple Myeloma patients, evaluate hematological and biochemical response of 36 newly diagnosed cases of MM with or without renal impairment receiving 4 cycles of Bortezomib, Thalidomide and Dexamethasone (BTD). Results: Among the study population, 36(100%) patients had weakness. followed by anaemia (97%), bone pain (89%) and renal impairment (44%). During treatment, 8 patients (22%) suffered from somnolence, 5 patients (14%) had Peripheral neuropathy and 6 (17%) patients complained of constipation. We found 8% suffered from hyperglycaemia, 3% rash, 3% cardiac arrest, 6% electrolyte imbalance and life threatening intracranial haemorrhage occurred in 1 patient (3%). Out of 36 patients, complete response achieved in 18 patients (50%), where 6 patients (16%) showed partial response, 10 (28%) showed very good partial response and 2 (6%) patients showed no response. The overall response rate was 94% belonged to complete response(CR), Partial response(PR),very good partial response(VGPR). Conclusion: Bortezomib based combination therapy is a highly effective and safe regimen for newly diagnosed Multiple Myeloma patients. . It can be administered safely in the outpatient setting provided by clinicians.

Efficacy of Bortezomib plus dexamethasone as a first line treatment in newly diagnosed cases of Multiple Myeloma: A Single Centre Study in a Tertiary Care Hospital

Background: Multiple Myeloma (MM) accounts for 1% of malignant tumors and 10%–15% of hematopoietic neoplasms. Bortezomib, a first in class proteasome inhibitor, induces apoptosis and growth arrest and reverse chemoresistence in Myeloma cell and has demonstrated no irreversible adverse effect on haemopoietic stem cell. Dexamethasone increases the response rate. Thus, Bortezomib plus dexamethasone represent highly effective regimen for previously untreated Multiple Myeloma cases and significantly higher response rates approximately 70%– 90% have been observed.This combination thus may serve the basis of future strands of care in Multiple Myeloma patients.
 Objective: The aim of the study was to assess the efficacy , safety and tolerability of Bortezomib in newly diagnosed cases of Multiple Myeloma patients in Bangladesh.
 Materials & Methods: This prospective observational study was carried out in the Haematology department of BSMMU from June 2017 to December 2018. Patients received inj. Bortezomib (1.3mg/m2 ) 4 cycles as an intravenous bolus on days 1,4,8,11 in a three week cycle (twice weekly administration) in indoor and same patients as day care basis in outpatients department. Dexamethasone at 40 mg was given intravenously or orally on the day of and day after inj Bortezomib.A self administered questionnaire containing different set of questions regarding Multiple Myeloma were used for data collection.
 Results: Among the study population, 93% of patients had anaemia followed by bone pain (86%) and renal impairment (39%). Out of 25 patients,complete response achieved in 13 patients (52%), where 4 patients(16%) showed partial response,6 (24%) showed very good partial response and 2 (8%) patients showed no response. The overall response rate was 92% belonged to partial,very goofd partial and no respone respectively. Death occurred in 3 cases (12%). 5 patients (20%) developed Bortezomib induced peripheral neuropathy.Life threatening intracranial haemorrhage occurred in two patients (8%). Death occurred in 3 cases (12%),2 patients due to intracranial haemorrhage and another from cardiac arrest. In this study,S. creatinine, â2 microglobulin and bony lesion variables showed significant association with treatment response.
 Conclusion: Bortezomib plus dexamethasone is a highly effective and safe regimen for previously untreated multiple myeloma patients. This novel therapy in myeloma represent a new trearment paradigm targeting both tumor and microenvironment which has markedly improve overall response(OR), long progression free survival (PFS) and overall survival (OS)across in all risk groups. Moreover,it can be administered safely in the outpatient setting provided by clinicians.
 J Dhaka Medical College, Vol. 28, No.1, April, 2019, Page 34-41

Excess Serine from the Microenvironment Caused the Impaired Megakaryopoiesis and Thrombocytopia in Multiple Myeloma

Background: Thrombocytopenia is major complication in a subset of patients with multiple myeloma (MM). However, a lack of detailed studies about the megakaryopoiesis, thrombopoiesis as well as their connections with the survival of patients limits us to explore whether thrombocytopenia could be used as a reliable prognostic factor for MM. Materials and Methods: In this study, 1393 newly diagnosed MM patients were selected for investigating the potential connection between PLT counts and clinical characteristics including ISS stage, overall survival as well as progression free survival. Besides, 5T33MMvt-KaLwRij mouse model were also used to examine the megakaryopoiesis and thrombopoiesis during disease progression. The proportion and function of different subpopulations of cells including megakaryocytes, megakaryocytic-erythroid progenitors (MEPs), common myeloid progenitors (CMPs) and Lin-Sca-1+c-kit+ (LSK) cells were measured both in MM patients and mouse models. Gas chromatography-time-of-flight mass spectrometry (GC-TOFMS)-based metabolomics was used to analyze the metabolites. Results: Of the 1393 studied patients, 298 cases of MM patients are found with thrombocytopenia at the time of diagnosis. PLT counts were lower both in stage Ⅱ (P<0.01) and Ⅲ patients (P<0.001) than stageⅠpatients. Interesting, we found MM patients with thrombocytopenia had a significantly lower OS (P<0.001) and PFS (P<0.001). In mouse model, we also found PLT counts gradually decreased in peripheral blood during the disease progression (P<0.001). Further analysis demonstrated the proportion and the absolute numbers of megakaryocytes and MEPs were diminished both in mouse and MM patients with thrombocytopenia. PLT counts were negative correlated with the percentage of plasma cells or IgG2b levels (P<0.001), suggesting a potential connection of malignant cells infiltration and thrombocytopenia. In mechanism, metabolomics analysis with BM plasma identified 16 differential metabolites in MM patients with thrombopoiesis (VIP > 1.2, P < 0.05). Among them, serine was observed significantly be elevated in MM mouse and suffice to inhibit the megakaryopoieis and thrombopoiesis in vitro. Conclusion: PLT counts might be used as a reliable prognostic factor for MM patients since the thrombocytopenia was associated with poor survival in MM patients. The thrombocytopenia in MM might attribute to, at least partially, the inhibition by serine from the microenvironment. Our findings revealed novel mechanism of MM and might eventually shed light on the treatment of MM patients. Disclosures No relevant conflicts of interest to declare.

Clinical analysis of expression of CD47 in patients with multiple myeloma

Objective To investigate the expression of CD47 in multiple myeloma (MM) and its clinical significance. Methods From September 2016 to May 2018, all of 25 cases of MM patients who were diagnosed and treated in Hongqi Hospital Affiliated to Mudanjiang Medical University were selected as research subjects, and enrolled in study group. In study group, there were 15 males and 10 females with the age of (58.5±4.2) years. Twelve MM patients were treated with CTD (cyclophosphamide+ thalidomide+ dexamethasone) regimen and the rest 13 cases with VAD (vincristine+ pirarubicin+ dexamethasone) regimen. Six cases of individuals who received physical examination in the same period and the same hospital were included in control group. In control group, there were 3 males and 3 females with the age of (56.3±4.1) years. CD47 expression levels of mononuclear cells in bone marrow from MM patients and peripheral blood from healthy individuals were detected by flow cytometry. Relationships between CD47 expression in MM patients and complete remission (CR), recurrence in study group were analyzed. The positive expression rate of CD47 of subjects in two groups, and CR rates of MM patients with different treatment regimens and CD47 expressions in study group were compared by Fisher′s exact probability method. The procedure of this study is accordance with the requirement of the revised World Medical Association Declaration of Helsinki in 2013. Informed consent was obtained from all participants. Results ① CD47 positive expression rate of MM patients in study group was 40.0% (10/25), and was significantly higher than that of 0(0/6) in control group, and the difference was statistically significant (P=0.018). ② In study group, CR rate of MM patients with positive CD47 expression was 20.0% (2/10), and was significantly lower than that of 73.3% (11/15) in patients with negative CD47 expression, and the difference was statistically significant (P=0.013). CR rate of MM patients receiving CTD regimen with positive CD47 expression was 16.7% (1/6), and was significantly lower than that of 83.3% (5/6) in pactients with negative CD47 expression, and the difference was statistically significant (P=0.040). CR rate of MM patients receiving VAD regimen with positive CD47 expression was 16.7% (1/6), and was significantly lower than that of 85.7%(6/7) in patients with negative CD47 expression, and the difference was also statistically significant (P=0.029). ③ There was no statistically significant difference in CR rate between patients with positive CD47 expression who were treated with VAD and these who were treated with CTD regimen (P=0.773). And there was no statistically significant difference in CR rate between patients with negative CD47 expression who were treated with VAD and these who were treated with CTD regimen (P=0.731). ④ All 2 MM patients with positive CD47 expression who obtained CR, and 2 of 11 MM patients with negative CD47 expression had relapsed. Conclusions The expression rate of CD47 on bone marrow mononuclear cells in MM patients was significantly higher and was related to curative effect and prognosis of MM patients. CD47 may be used as a potential auxiliary evaluation indicator for efficacy and prognosis in MM. This conclusion is limited to the clinical analysis of a small sample, and it requires large sample, multi-center, randomized controlled trials for further study and verification. Key words: Multiple myeloma; Antigens, CD47; Phagocytosis; Treatment outcome; Prognosis

Treatment‐triggered onset and diagnosis of Sheehan syndrome in a multiple myeloma patient

Sheehan syndrome refers to a series of clinical symptoms resulting from avascular necrosis of anterior pituitary due to various reasons. We report a case of multiple myeloma patient after one cycle of chemotherapy consisting of bortezomib and dexamethasone diagnosis of Sheehan syndrome with obstinate diarrhea, low blood glucose, and coma symptom, especially, the fluorodeoxyglucose positron emission tomography (FDG-PET) and brain magnetic resonance imaging (MRI) revealed that the manifestations in the saddle area were in accordance with empty sella syndrome. A single administration with lenalidomide was given for both consolidative and maintenance treatment, and satisfactory efficacy was achieved. With the patient now remaining in satisfactory medical condition, the success of this therapy has been shown. This is the first report showing a patient with combined multiple myeloma and rarely seen Sheehan syndrome, in which lenalidomide was given for treatment, and satisfactory efficacy was achieved.

The correlation between findings of whole-body diffusion weighted imaging and clinical result in patients with multiple myeloma

Objective: To explore the relationship between the findings of whole body diffusion weighted imaging (WBDWI) and the clinical result in patients with multiple myeloma. Methods: A total of 43 cases of multiple myeloma patients were retrospectively collected from May 2015 to May 2017 in Tianjin First Central Hospital.Twenty-nine cases were male and 14 were female. The median age was 54 years old with a range from 36 to 73 years old. The patients were divided into two groups with and without abnormal findings pending on whole body diffusion weighted imaging. The clinical data and the ADC value were compared between the two groups, as well as comparison in patients with abnormal findings between pre-and post-treatment. Results: In 43 patients, normal findings on WBDWI were found in 10 cases, 7 males, 3 females, age (59±9) years old, and abnormal findings in 33 cases, 22 males, 11 females, age (57±10) years old.No statistical differences of age and gender were found between two groups (P>0.05) .The ratio of plasma cells and the proportion of β(2) microspheres in patients with abnormal WBDWI (50.0% (14.0%, 78.0%) , 4.8 (2.7, 7.7) mg/L)were significantly higher than those in the normal group(5.0% (2.5%, 15.0%) , 2.4 (2.0, 3.7) mg/L) (P<0.05).ADC value in different body parts of abnormal group including costal ((0.66±0.15)×10(-3) mm(2)/s), sternal bone((0.71±0.20)×10(-3) mm(2)/s), clavicles((0.67±0.17)×10(-3) mm(2)/s), thoracic vertebra((0.63±0.17)×10(-3) mm(2)/s), lumber vertebra((0.69±0.20)×10(-3) mm(2)/s), pelvic((0.83±0.36)×10(-3) mm(2)/s), proximal humerus((0.76±0.13)×10(-3) mm(2)/s), proximal femur((0.64±0.17)×10(-3) mm(2)/s), shaft of femur((0.70±0.22)×10(-3) mm(2)/s), proximal tibia((0.97±0.18)×10(-3) mm(2)/s), shaft of tibia((0.83±0.18)×10(-3) mm(2)/s) which were significantly higher than those of normal group (all P<0.05). The albumin concentration of the patients after treatment was significantly higher than those before treatment (P<0.05). Conclusion: Different imaging findings on WBDWI can reflect clinical different result in patients with multiple myeloma, and when WBDWI is normal, the clinical symptoms are mild. When abnormal findings detected on WBDWI, the clinical symptoms are still severe although albumin concentration increased after treatment.

Association of miRNA-196b-5p and miRNA-99a-5p with autophagy and apoptosis in multiple myeloma cells

目的探讨多发性骨髓瘤（MM）细胞miRNA-196b-5p和miRNA-99a-5p表达与自噬和凋亡的关系。方法以人MM细胞株U266细胞及45例MM患者瘤细胞为研究对象，以40例健康体检者为对照，采用实时定量PCR法测定细胞中miRNA-196b-5p和miRNA-99a-5p表达水平，采用Western blot法测定自噬相关蛋白（LC3-Ⅱ、LC3-Ⅰ、P62、Beclin-1）、凋亡相关分子（CL caspase3、CL caspase7、Bcl-2、Bax）和TGF-β/Smad通路相关蛋白（TGF-β1、Smad2/3、p-Smad3、Smad7）表达水平，采用流式细胞术测定细胞凋亡率，分析miRNA表达水平与MM患者临床特征的相关性。结果①与正常浆细胞比较，U266细胞、MM患者瘤细胞的miRNA-196b-5p表达显著增加（0.43±0.15对2.44±0.63、2.02±0.85，P值均<0.001），miRNA-99a-5p表达显著降低（1.87±0.61对0.62±0.15、0.80±0.33，P值均<0.001），LC3-Ⅱ/LC3-Ⅰ、Beclin-1、Bcl-2表达显著增加，P62、Bax、CL caspase3、CL caspase7表达显著降低，细胞凋亡率降低（P值均<0.05）。②正常CD138+浆细胞分别转染miRNA-196b-5p mimic或miRNA-99a-5p inhibitor 48 h后，与未转染对照组比较，LC3-Ⅱ/LC3-Ⅰ、Beclin-1、TGF-β1、p-Smad3表达显著增高，P62、Smad7表达显著降低，细胞凋亡率减少（P值均<0.05）；上述反应体系加入自噬抑制剂3-甲基腺嘌呤后，细胞凋亡率未见明显改变（P值均>0.05）。③miRNA-196b-5p和miRNA-99a-5p表达与MM患者DS分期（P值分别为0.004、0.012）、ISS分期显著相关（P值均为0.001）。结论miRNA-196b-5p和miRNA-99a-5p表达与MM患者临床特征密切相关，miRNA-196b-5p过表达和miRNA-99a-5p表达下调通过上调自噬水平抑制骨髓瘤细胞凋亡，其机制与活化TGF-β/Smad信号通路有关。

Solitary involvement of multiple myeloma in the upper thoracic spine, and anterior approach to thoracic region without full sternotomy: A case report

Multiple myeloma is cancer that starts in the plasma cells in bone marrow. Bone x- rays may show fractures or hollowed out areas of bone. The most common skeletal sites are pelvis, skull, spine, ribs and femoral and humeral shafts. The unique anatomy of thoracic spine creates challenging surgery approaches. Treatment choices of hematological malignancies of the spine are surgery, chemotherapy and radiotherapy. Unilateral L-shaped manubriotomy does not require full sternotomy for upper thoracic segment pathologies. We present a case of multiple myeloma patient in the upper thoracic area and the surgical management. We present an approach to anterior pathology of the upper thoracic spine that obviates the need for sternotomy.

Infiltration of tumor associated macrophages in multiple myeloma and its clinical significance

目的探讨肿瘤相关性巨噬细胞（TAM）在多发性骨髓瘤（MM）中的临床意义及其与肿瘤血管生成、免疫抑制的关系。方法以2015年8月至2017年6月就诊的70例MM患者为观察对象，以20例良性血液病（缺铁性贫血13例，巨幼细胞性贫血7例）患者为对照，采用免疫组化法检测骨髓标本中CD163、CD34、VEGF的表达，采用流式细胞术检测Treg细胞比例，采用ELISA法检测IL-10水平，结合临床特征进行分析。结果①70例患者中，男31例，女39例，中位年龄65（50~78）岁。MM患者组的TAM浸润密度、微血管密度（MVD）、VEGF表达水平、Treg细胞比例及IL-10水平均较对照组升高（P值均<0.05）。②在MM患者组中，疾病稳定组（15例）患者的上述指标均较初诊组（35例）和复发难治组（20例）低（P值均<0.05）；后两组差异无统计学意义（P值均>0.05）。③35例初诊MM患者中27例完成4个疗程治疗，有效组（15例）治疗后TAM浸润密度较治疗前明显下降，差异有统计学意义[（20.20±7.66）对（28.87±11.97）个/高倍，t=2.362，P=0.025]；无效组（12例）治疗前后差异无统计学意义[（42.00±13.76）对（48.25±13.59）个/高倍，t=1.119，P=0.275]。④硼替佐米方案治疗有效组患者（21例次）的TAM浸润密度较非硼替佐米方案治疗有效组（18例次）减低[（16.52±4.26）对（19.27±5.82）个/高倍，t=1.662，P=0.170]。⑤MM患者的TAM浸润密度与MVD、VEGF表达水平、Treg细胞比例及IL-10水平呈正相关（P值均<0.001）。结论骨髓微环境中浸润的TAM与MM发生、发展、疗效及治疗耐药有关，其作用机制可能与TAM促进肿瘤血管形成及抑制免疫反应有关。

Diagnostic Value of CD27 Antigen in Patients with Multiple Myeloma

To explore the expression of CD27 antigen in patients with multiple myeloma(MM), and its clinical diagnostic value, as well as the correlation of CD27 with clinical features and genetic abnormalities. Using 8 color flow cytometry, the immunophenotype of 123 MM patients' marrow cells was examined, while 51 cases of normal plasma cell reactive prolieration were used as control. Antibodies are as follows:ckappa-FITC/clambda-PE/ CD38-ECD/CD45-PERCP/CD19-PC7/ CD27-APC/CD138-BV421/ CD56-BV510. For differentiation of abnormal plasma cells from normal or reactive plasma cells, FS INT /FS PEAK with CD138/CD38 gating strategy was used to measure cell markers CD138,CD38, CD56, CD19, ckappa, clambda and CD45, then the expression rate of CD27 and mean fluorescence intensity(MFI) were analyzed for its diagnostic value in MM. At the same time, the laboratory data of 107 cases of MM patients were analyzed and the fluorescence in situ hybridization (FISH) was used to detecte 1q21 amplification, 13q14 deletion, p53 deletion and IGH rearrangement in 34 cases, then the clinical features and genetic abnormalities were compared between CD27- and CD27+ MM patients. The CD27 positive rate of abnormal plasma cells in MM patients was 48% (59/123) (percentage ≥20% as positive criterion), MFI was 31.3±35.6; while the positive rate of normal or reactive plasma cells were 100% (51/51), the MFI was 93.7±6.3. The positive rate and MFI of CD27 in MM patients were significantly lower than that in normal or reactive plasma cells (P<0.01). Laboratory examination of 58 cases of CD27 negative and 49 cases of CD27 positive MM patients indicated that no significant differences were shown on disease progress parameter, such as hemoglobin, albumin, serum calcium, serum creatinine,and no notable differences were involved in the analysis of prognostic factors between the 2 groups, such as β2-MG microglobulin and LDH levels (P<0.05). The 1q21 amplification, 13q14 deletion, p53 deletion, and IGH rearrangement results all were not significantly different between 17 cases of CD27 negative and 17 cases of CD27 positive MM patients(P<0.05). CD27 has a unique expression profile, and its negative or weak expression is highly suggestive for MM. The 8 color flow cytometry can be used to analyze the expression of multiple antigens, which can provide a reliable evidence for the diagnosis and differential diagnosis of MM disease.

Correlation Analysis Between Serum Lactate Dehydrogenase and Prognosis in Old New Diagnosed Multiple Myeloma Patients

[Abstract] Objective Multiple myeloma (MM) is a kind of plasma cell malignancy tumor with larger heterogeneity. Patient’s survival varies greatly. This study retrospectively analyzed serum lactate dehydrogenase (LDH) in 107 cases of elderly MM patients, to discuss its correlation with other clinical indicators of MM and the prognostic significance. Methods 107 cases of elderly MM patients were selected from our hospital from July 2008 to January 2016 as the research objects, all of whom were above 60 years and were newly diagnosed. OLIPAS AU5400 fully automatic biochemical analyzer was used to assay serum LDH concentration, and prognosis analysis was carried out combined with patients’ clinical data. On this basis, 73 cases of MM patients were given R-ISS staging. Results At primary diagnosis, about 9.4% patients had increased LDH (10/107), with the median follow-up time of 15 (1-88.5) months. Median overall survival (OS) was 52.5±6.9 months in normal LDH group, while 15.5±5.2 (months) in elevated LDH group, and there were statistically significant differences (p<0.001); Median progression free survival (PFS) was 24.0±3.5 months in normal LDH group, while 12.0±10.5 monthsin elevated LDH group, and there were statistically significant differences (p=0.008). Multiple factors analysis showed that LDH was an independent prognosis factor of elderly MM. Median OS of patients was 44 and 72 months (p=0.820) with stage II and stage III of ISS staging, while median PFS was 23 and 22 months (p=0.963); Median OS of patients was 44 and 22.5 months (p=0.308) with stage II and stage III of R-ISS staging, while median PFS was 24 and 14 months (p=0.105). Conclusions LDH is one of the important indicators for prognostic judgment of elderly MM patients. R-ISS staging based on LDH level is superior to the ISS staging system in prognostic judgment. DisclosuresNo relevant conflicts of interest to declare.

The significance of serum light chain ratio in the diagnosis of multiple myeloma and primary nephritic

Objective To explore the clinical value of serum κ/λ ratio in the differential diagnosis of multiple myeloma (MM) and primary nephritic, and to explore its relationship with MM other laboratory markers. Methods We obtained 88 cases of MM patients with serotyping by immunofixation and 109 cases of primary nephritic patients. In accordance with the composition of proteinMin immunofixation electrophoersis (IFE), 88 patients were divided into 4 groups: IgGκ, IgGλ, IgAκ and IgAλ. In addition, 45 serum samples of health examination were collected as control samples. The levels of serum IgG, IgA, IgM, light chain κ and λ in each group were tested by immune turbidimetry, and κ/λ ratio was calculated. The levels of serum β2-microglobin (β2-MG), albumin (ALB), serum urea (BUN), creatinine (CRE), and M protein percentage were also detected. Results ⑴ In MM group, there was no significant difference of sex and International Staging System (ISS) stages between each type(P>0.05), while there was significant difference in age distribution between each type(P 0.05). There were also significant difference of light chain, Ig, BUN and CRE levels between MM patients and primary nephritic patients(P<0.05). ⑶ The κ/λ ratio correlated with serum ALB (r=-0.264, P=0.013) and β2-MG (r=0.235, P=0.040) levels in MM. Conclusions Serum levels of light chain κ, λ, and κ/λ ratio have great significance in the differential diagnosis of multiple myeloma and primary nephritic. The κ/λ ratio correlated with several tumor markers in MM progresses, rendering it as a promising method for diagnosis and prognosis monitoring of MM. Key words: Multiple myeloma/DI; Nephrosis/DI; Immunoglobulin kappa-chains/BL; Immunoglobulin light chains/BL

Second primary malignancy in patient with multiple myeloma: a report of two cases and the review of literature

Objective: To report 2 cases of multiple myeloma (MM) with secondary malignancy and do a literature review to improve the understanding of secondary malignancy of MM.Methods: The clinical characteristics, treatment and prognosis of 2 cases of MM patients with secondary malignancy were retrospectively analyzed, and the relevant literature was reviewed.Results: The incidence rate of second primary malignancy of MM was low, and the secondary bladder cancer and the neuroendocrine carcinoma were rare.Conclusion: The pathogenesis of second primary malignancy of MM patients and the prognosis are not clear, which needs further research. DOI:10.3781/j.issn.1000-7431.2015.44.264

Exploring the Relationship Between Serum and Urinary Free Light Chain Levels During the Different Phases of Renal Damage in Multiple Myeloma Patients.

The objective was to explore the relationship between the levels of serum and urinary free light chains (FLCs) during the progression of renal damage in multiple myeloma (MM) patients. We examined 91 cases of MM patients, detected levels of serum FLCs (sFLCs), urinary FLCs (uFLCs), and serum creatinine at the same time, and then compared sFLC and uFLC levels during normal and abnormal serum creatinine phases. Among the 91 MM patients, 22 patients had abnormal serum creatinine levels (no uremia), and 69 patients had normal serum creatinine levels. The levels of sFLCs and uFLCs in patients with abnormal serum creatinine were beyond normal, namely both serum and urine positive (serum+ and urine+), and the average concentrations of κFLCs and λFLCs were 516.76 and 604.67mg/L, respectively. Of the 69 patients with normal creatinine levels, there were 39 and 30 cases of κ-type and λ-type MM, respectively. Of the κ-type patients, 11 cases were serum positive and urine negative (serum+ and urine-) with an average concentration of 55.47mg/L, and 28 cases were serum positive and urine positive (serum+ and urine+) with an average concentration of 513.09mg/L. Of the λ-type patients, 16 cases were serum positive and urine negative (serum+ and urine-) with an average concentration of 78.44mg/L, and 14 cases were serum positive and urine positive (serum+ and urine+) with an average concentration of 518.08mg/L. The levels of uFLCs did not parallel those of sFLCs. In addition to sFLC levels, renal function affected uFLC concentrations. As MM progressed, the concentration of sFLCs increased in a step-by-step manner, and the uFLCs changed from negative to positive to negative again. Therefore, the whole progression included three phases: sserum+ and urine-, serum+ and urine+, and then serum+ and urine-.

Constitutively High Expression of CD137L on Primary MM Cells Could be Inhibited By Chemotherapy but Re-Emerged after Desease Relapse

Objective: Multiple myeloma (MM) is a kind of malignant monoclonal plasma cell disorder. CD137L molecules are important member of TNFsuperfamily. Under physiological conditions, CD137L express on the surface of various active APCs and participate in keeping the balance of immune system. Under pathological conditions, CD137L could express on the surface of various tumor cells. For example, in hematologic malignancies, about 35% of AML with FAB type M4 or M5, and most CLL, B-cell lymphoma cells express CD137L. CD137L molecules play an important role in the maturation process of B cells. Active CD137L can promote proliferation, differentiation and immune response of B cells. But when B cells transform to plasma cells, the majority of B antigens will be lost, such as CD19, CD20, HLA-DR. CD137L are also lost in the process of transformation. Our previous studies showed that there is no expression of CD137L and CD137 molecular on normal plasma cells. But CD137L were highly expressed on MM cell lines U-266, KMS-11, My-5, LP-1 and 8266. CD137L signaling promoted U266 cell proliferation remarkably, which could be blocked by Bortizomib. CD137L signaling also pushed MM cells in the G1 phase to enter the S phase. To understand the expression of CD137L and CD137 on MM primary cells，We examined the bone marrow specimens of MM patients, then analyzed the relationship between the expression of CD137L and the clinical characteristics of patients.Methods: Flow cytometry was used to detect the CD137L and CD137 expression. Markers of normal plasma cell were CD45+CD38+CD138+CD19+CD56-, Markers of abnormal plasma cell were CD45-/CD45lowCD38++CD138+CD19-CD56+. bone marrow specimens from 127 cases of MM patients treated in the First Affiliated Hospital of Soochow University from 2012 to 2013 and the normal control from 10 volunteers were collected with the consent of patients and volunteers. 45 patients were newly diagnosed, 72 patients were checked after treatment, 10 patients were relapsed and refractory; 68 patients were males, 59 patients were females; The median age was 58(36-73); 3 pts were D-S staging I, 14 pts II, 59 pts III; 25 pts were ISS staging I, 65 pts II, 35 pts III.Results: Normal plasma cells didn’t express CD137L and CD137 molecular .CD137L molecular but not CD137 were expressed on primary MM cells in all 45 de novo patients. The median level was 46.7 (3.6–96.7)%, significantly higher than that on normal plasma cells (P <0.05). A retrospective analysis had been made to find no correlation between CD137L expression and patients’ age, gender, type, DS stage, ISS stage , LDH, creatinine, serum calcium, AKP, M protein and extramedullary plasmacytoma. The CD137L expression of MM cells from 12 de novo patients treated with PAD were decreased gradually with the increase of treatment courses and improvement of efficacy. The expression of CD137L on MM cells in 79 patients grouped in CR (n = 12), PR (n = 51), recurrent (n = 16) were 4.5 (0–18)%，10 (−056)% (P<0.05), 30.5 (5.3–95)% (P = 0.00) respectively.Conclusions: CD137L molecular without CD137 were constitutively highly expressed on MM cell lines and primary MM cells, but hardly on normal plasma cells. There was no relationship between the expression of CD137L with patients’ clinical and biological characteristics. But our data showed that constitutively high expression of CD137L molecular on primary MM cells could be inhibited by chemotherapy but re-emerged after desease relapse. DisclosuresNo relevant conflicts of interest to declare.

Clinical Significance of Serum Soluble Interleukin-6 Receptor Level in Multiple Myeloma

Objective To study the relationship between serum soluble interleukin 6 receptor (sIL-6R) and treatment efficacy and prognosis of multiple myeloma (MM),and explore its clinical significance of sIL-6R.Methods Form July 2006 to December 2011,67 MM patients who received treatment in Beijing Chaoyang hospital,Capital Medical University were selected into this study.According to age of patents,they were divided into the older group (＞65 years old,n=20) and young group (≤65 years old,n=47).According to Durie-Salmon (DS) staging criteria,the patients were divided into DS Ⅰ/Ⅱ stage group (n=8) and Ⅲ stage group (n=59).According to the International Staging system (ISS) criteria,the patients were divided into ISS Ⅰ stage group (n 6),stage Ⅱ stage group (n 19) and Ⅲ stage group (n=42).According to the immune classification criteria,the patients were divided into IgA group (n=19),IgG group (n=23),light chain group (n=19) and other types group (n 6).According to the median serum sIL-6R levels of patients,they were divided into sIL-6R≤500 ng/ L group (n 43) and ＞500 ng/L group (n 24).After four to six courses of treatment,there were 29 cases of MM patients could evaluate the efficacy.According to the efficacy of patients,they were divided into ≥partial remission (PR) group (n 25)and ＜PR group (n=4).(The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Beijing Chaoyang hospital.Informed consent was obtained from all participants.) The serum levels of sIL-6R were detected by enzyme-linked immunosorbent assay technique in 67 patients with MM.The serum sIL-6R levels of MM patients in different ages,immunophenotypes and clinical stages were compared.The relationship between serum levels of sIL-6R between patient outcomes and survival were analyzed.Results sIL-6R levels of MM patients in older group were (496.6±204.4) ng/L,which were similar with the young group[(494.8±260.0) ng/L)] (t=0.027,P=0.98).Patients in IgA type group had lower sIL-6R levels [(418.0±137.1) ng/L] than those of IgG type group [(590.6±285.5) ng/L] and light chain type group [(475.6±253.0) ng/L],but there were no statistical significance among these three groups (F=2.895,P＞0.05).Patients with DS stage Ⅰ/Ⅱ had higher sIL-6R levels [(598.1± 347.2) ng/L] than those of stage Ⅲ [(482.3±226.5) ng/L],and it also had no statistical significance (t=1.199,P＞0.05).Patients with ISS stage Ⅰ had lower sIL-6R levels [(469.5±271.4) ng/L] than those of stage Ⅱ [(510.9±239.9) ng/L] and stage Ⅲ [(492.1 ± 146.4) ng/L],and it also had no statistical significance (F 0.074,P＞0.05).After treatment,patients who obtained PR or more had decrease of sIL-6R levels (t=1.759,P=0.08),patients who obtained less than PR had increase of sIL-6R levels (t =0.285,P=0.78).Patients with sIL-6R ≤500 ng/L had longer overall survival time than those of ＞ 500 ng/L (32.3 months vs.19.6 months),however their had no statistical significance (P=0.18).Conclusions Serum sIL-6R levels of MM patients had no association with age,clinical stages and immunophenotype.There maybe a certain relationship among sIL 6R levels of MM patients,efficacy and survival prognosis. Key words: Multiple myeloma; Receptor,interleukin-6; Prognosis

High Incidence of Arterial Thrombosis in Young Patients Treated for Multiple Myeloma:Results of a Prospective Cohort Study.

Abstract 149▪▪This icon denotes an abstract that is clinically relevant.It is well known that patients with multiple myeloma (MM) are at high risk for venous thromboembolism (VTE). Thrombotic complications are most frequently seen in patients treated with thalidomide based regimens. Several other risk factors for VTE have been identified including abnormalities in coagulation factors, such as high factor VIII levels, APC resistance and hypofibrinolysis. Recently a few cases of MM patients and arterial thromboembolism (ATE) have been reported. Therefore we prospectively studied the risk of ATE in 195 consecutive patients aged <66 years with previously untreated MM. All patients were treated according to the HOVON 50 study protocol, a prospective randomized phase III study on the effects of 3 courses of doxorubicin and dexamethasone with thalidomide (TAD) or vincristine (VAD) followed by high dose melphalan and thalidomide or interferon-alpha2 maintenance or the HOVON 65 study protocol, a prospective randomised phase III study on the effects of 3 courses doxorubicin and dexamethasone with vincristine (VAD) or bortezomib (PAD), followed by high dose melphalan and bortezomib or thalidomide maintenance. All patients treated with TAD courses received prophylaxis for VTE with low molecular-weight heparin. During a follow-up of 522.4 patient-years 11 patients (5.6%) developed ATE. Most events occurred within one year after start of treatment (64%). Median age at onset of ATE was 59 years (range 43–65). For myocardial infarction we demonstrated an annual incidence of 0.77% in men and 0.19% in women compared to an equal age group, 55–59 years, described by Parikh et al in the Framingham Heart Study population who reported annual incidences of 0.22% in men and 0.04% in women, respectively. For cerebral ischemic events we demonstrated an annual incidence of 0.77% in men and 0.19% in women compared to 0.29% in men and 0.22% in women in the general Dutch population, aged 55–59, as described by Gijsen and Poos. Of thrombophilic factors a statistically significant higher factor VIII:C (FVIII:C) was observed in symptomatic patients, 2.93 IU/ml (1.16–6.45) versus 2.15 (0.74–6.48) (p=0.03). FVIII:C correlated significantly with age (p=0.02) and ISS stage (p=0.001). Adjustment for age and ISS stage, revealed a RR for ATE of 11.67 (95% CI: 2.23–61.18) for hypertension, a RR of 15.17 (1.78–129.54) for smoking and a RR of 1.85 (0.99–3.47) for each IU/ml increase in FVIII level, respectively. In conclusion, MM patients are at high risk for arterial thrombotic events during and following induction chemotherapy. High factor VIII levels, which may reflect disease activity, contribute to the risk of ATE especially in patients with known risk factors for cardiovascular disease. Disclosures:Sonneveld:Johnson&Johnson: Consultancy.