The 474th case: anemia, ostealgia, proteinuria / 中华内科杂志

A 49-year-old woman was admitted to hospital with intermittent dizziness and fatigue for 7 years. The symptoms were aggravated and accompanied by bone pain for more than 4 months. She was referred to our hospital. Laboratory tests and imaging findings suggested that acquired Fanconi Syndrome (FS) was associated with smoldering multiple myeloma (MM). Renal biopsy and electron microscopy confirmed the diagnosis of proximal light chain tubular disease (LCPT). LCPT causes proximal tubular dysfunction, which is characterized by the cytoplasmic crystal deposition usually kappa monoclonal light chain in the proximal tubule. MM with FS and LCPT is less common in clinical practice because it is difficult to diagnose. This is a typical case focusing on the differential diagnosis of monoclonal gammopathy of renal significance(MGRS) such as LCPT and plasma cells diseases.

The 474th case: anemia, ostealgia, proteinuria / 中华内科杂志

A 49-year-old woman was admitted to hospital with intermittent dizziness and fatigue for 7 years. The symptoms were aggravated and accompanied by bone pain for more than 4 months. She was referred to our hospital. Laboratory tests and imaging findings suggested that acquired Fanconi Syndrome (FS) was associated with smoldering multiple myeloma (MM). Renal biopsy and electron microscopy confirmed the diagnosis of proximal light chain tubular disease (LCPT). LCPT causes proximal tubular dysfunction, which is characterized by the cytoplasmic crystal deposition usually kappa monoclonal light chain in the proximal tubule. MM with FS and LCPT is less common in clinical practice because it is difficult to diagnose. This is a typical case focusing on the differential diagnosis of monoclonal gammopathy of renal significance(MGRS) such as LCPT and plasma cells diseases.

Clinical analysis of early death in multiple myeloma / 中国肿瘤临床

Objective:This study investigated the clinical characteristics of multiple myeloma with early death in the era of novel drugs. Methods:Medical records from 188 patients diagnosed from January 2009 to December 2015 were retrospectively reviewed, showing that early death occurred in 19 patients. Early death was defined as death by any cause within the first year after diagnosis. Results:(1) Early mortality was 10.1%, and the median age was 67 years old (range:40-84 years). Eight cases presented IgG type, and 11 cases were non-IgG type. All 19 patients were diagnosed to be at stageⅢin accordance with the Durie–Salmon staging system, and renal insufficiency occurred in 10 patients. In accordance with the International Staging System (ISS), four patients were diagnosed to be at stageⅡ, whereas 15 other patients were at stageⅢ. Extramedullary plasmacytoma (EMP) occurred in six cases, whereas 10 cases pre-sented high-risk patients with cytogenetic abnormalities. Elevated lactate dehydrogenase (LDH) was found in five cases, amyloidosis was detected in three patients, and secondary plasma cell leukemia was observed in two cases. The median score of performance sta-tus (KPS) was 70 (range: 20-80). A total of 16 patients were treated with bortezomib, and 3 patients were treated with CADT. (2) Among the 13 patients who were evaluated, the overall response rate was 46.2%(6/13), and the complete response (CR) and near-CR rate was 7.7%(1/13). (3) The median overall survival was 3 (1-11.5) months, although the two patients with secondary plasma cell leu-kemia survived for less than 2 months. (4) Eight patients died of disease progression (42.1%), eight patients died of severe infections (42.1%), and three patients died of thrombotic events. Conclusion:The important causes of early death include the following:high-risk cytogenetics, elevated LDH, EMP, amyloidosis, advanced age, poor performance status, and serious complications during treat-ment. In the era of novel drugs, we should improve early diagnosis rates and explore individualized treatment for high-risk multiple my-eloma for the benefit of a wide range of patients.

A clinical analysis of 69 newly diagnosed multiple myeloma patients with renal insufficiency / 中华内科杂志

Objective To investigate the efficacy and outcome in newly diagnosed multiple myeloma (MM) patients with renal insufficiency using bortezomib-or thalidomide-based regimens as front line treatment.Method Sixty-nine newly diagnosed MM patients with renal insufficiency were retrospectively analyzed from August 2006 to August 2014.Results ① Among thirty-nine patients with bortezomib based regimens (the bortezomib group),the overall response rate (ORR) was 89.7％ and complete response (CR) plus near CR(nCR) rate was 41.0％.By contrast,among thirty patients with thalidomide based regimens (the thalidomide group),the ORR was 83.3％ and CR + nCR rate was 26.7％.There was no significant difference of either ORR or CR + nCR rate between bortezomib and thalidomide groups.② The improvement rate of renal function in bortezomib group and thalidomide group were 87.2％ and 60.0％respectively (P =0.012).The median duration time of renal injury was 45 days in 52 patients with renal function improved,which was significantly shorter compared with 222 days in 17 patients without improvement (P ＜ 0.05).There was no difference of median serum creatinine and creatinine clearance rate between the two groups.③ The median progression-free survival (PFS) and the overall survival (OS) were 18 and 33.5 months,respectively in all patients.The three-year and five-year OS rates were 57％ and 17％,respectively.The median PFS was 19 months in bortezomib group,while it was only 12 months in thalidomide group (P =0.023).The median OS were 36.5 months and 25.5 months respectively,which was no difference (P =0.285).Conclusions The newly diagnosed MM patients with renal insufficiency could get higher ORR and the longer PFS using bortezomib-containing regimens as initial therapy.Meanwhile the improvement rate of renal function and the living quality in patients with bortezomib are better compared with those with thalidomide based treatment.

Impact of 1q21 amplification on prognosis and treatment effect of multiple myeloma / 白血病·淋巴瘤

Objective To investigate the value of 1q21 amplification in newly diagnosed myeloma patients.Methods Fifty-two cases of newly diagnosed multiple myeloma from June 2008 to June 2010 were enrolled.Fluorescence in situ hybridization (FISH) was used to detect the 1q21 amplification,and the clinical characteristics and treatment response were analyzed.Results 1q21 amplification was discovered in 30 of 52 patients (57.7 ％),Clinical characteristics such as gender,malignant pleural effusion,extramedullary plasmacytoma,bone destruction,β2 microglobulin,ALB,hemoglobin,blood calcium,plasma cell proportion,clinical stage seemed to have no correlation with 1q21 amplification.The 52 patients all received bortezomibbased regimens.The response rates were not significant difference between patients with and without 1q21 amplification,the OS was also not significant difference [26 months (6-30 months) vs 30 months (12-85 months),P =0.409],but the patients with presence of 1q21 gain resulted in significantly shorter PFS [8 months (1-30 months) vs 20 months (3--48 months),P=0.019].Multivariate analysis showed 1q21 with more than two additional genetic abnormalities was an independent prognostic predictor (P =0.031).Conclusion 1q21 amplification is one of the adverse prognostic predictors,the response rate is not significant difference between patients with and without 1q21 amplification in bortezomib-based group,but the 1q21 amplification could result in significantly shortened PFS.

A few questions deserved special attention in diagnosis and treatment of multiple myeloma / 白血病·淋巴瘤

The key point of the diagnosis and therapeutic principle of the multiple myeloma (MM) have been well established due to the past decades of research and clinical practice.But the higher heterogeneity of the MM including the extramedullary plasmacytomas,systemic amyloidosis,venous thrombus and osteopathy that have made the disease more complicated and cause a lot of attention.

Effects of bortezomib combined with ifosfamide, methylprednisolone and thalidomide for the treatment of multiple myeloma / 白血病·淋巴瘤

Objective To investigate the efficacy and toxicity of bortezomib in combination with ifosfamide, methylprednisolone, thalidomide (V-CMPT) for the treatment of multiple myeloma (MM). Methods Twenty-four patients with newly diagnosed or relapsed/refractory MM were treated with V-CMPT. This regimen was repeated every three weeks as one cycle, and each case received two cycles. We adopted the examination of bone marrow and M protein and other hematological markers to evaluate the condition of disease and the therapeutic response. Results Of the nine patients with newly diagnosed MM, three achieved a complete remission (CR), five of a partial response (PR), and 1 of a minor response (MR). Of the patients with relapsed/refractory MM, two achieved a CR, two had a near CR (nCR), three had a PR, six had a MR, and two were no chang (NC). There was no obvious difference in the two groups (P = 0.511, P = 1.000). The overall response rate (ORR) was 91.7 %, and the CR/nCR rate was 29.2 %. After two cycles, the levels of hemoglobin, the serum albumin and the serum β2-microglobulin were obviously improved. The main adverse events were transient, including gastrointestinal reaction, thrombocytopenia, neuropathy, which could be controlled during the interval of chemotherapy or by symptomatic treatment and had no influence on the chemotherapy.Conclusion V-CMPT regiman was effective against the newly diagnosed and relapsed/refractory MM and could improve the related hematological markers with high response rate and tolerable toxicities.

Study on SDF-1α and CD44v6 expression in multiple myeloma patients / 白血病·淋巴瘤

Objective To explore the relationship of stromal derived factor 1α (SDF-1α) and CD44variant isoforms (CD44v6) with progress of multiple myeloma (MM). Methods Bone marrow mononuclear cells(MNCs) and bone marrow stromal cells (BMSCs) from 24 cases of MM patients (14 cases of untreated and relapsed and 10 cases of stable MM patients) and 15 cases of subjects were investigated as potential SDF-1αand CD44v6 product. The level of SDF-1α and CD44v6 of the conditioned media from MM patients and subjects were analyzed by ELISA. Results The level of SDF-1α and CD44v6 from MNCs in untreated and relapsed MM patients [(7232.41 ± 2644.97) pg/ml and (34.34 ± 13.20) ng/ml] were significantly higher than stable MM patients [(2315.49 ± 748.29) pg/ml and (15.69 ± 5.28) ng/ml] (t =6.25, t= 7.82, P ＜0.05) and 15 subjects [(1149.52 ± 636.06) pg/ml and (4.85 ± 3.62) ng/ml] (t= 4.60, t = 7.61, P＜ 0.05). The level of SDF-1α in stable MM patients was different from healthy subjects (P ＜0.05), but the level of CD44v6 in stable MM patients was not different from controls. The level of SDF-1α and CD44v6 in stable MM patients were significantly higher than health subjects (t = 2.99, t= 4.87, P ＜0.05). The level of SDF-1α was also detected from BMSCs of MM patients. When human MM cell lines U266 were adhered to BMSCs of 9 untreated and relapsed MM patients,and added rhIL-6 to it, there was significant increase of SDF-1α, compared with BMSCs in subjects and MM patients. The expression level of SDF-lα was correlated with the level of CD44v6 (r =0.51, P =0.03). Conclusion The increase of SDF-1α (may be produced by myeloma cells and BMSCs) and CD44v6 (may be produced by myeloma cells) activity is associated with the progress or pathogenesis of MM, and may be involved with tumor invasion. The completion of these processes in vivo may need participation of myeloma cells, BMSCs, IL-6,SDF-lα and CD44v6.

Current treatment at multiple myeloma / 白血病·淋巴瘤

The breakthrough progress has been made in the treatment of multiple myeloma.Since 1990 s,autologous stem-cell transplantation (ASCT) has resulted in high response rate of MM,and the median overall survival was 5 years.The recent introduction of the novel agents including thalidomide,bortezomib,and lenalidomide further increase the response rate of MM.It is reported that the median overall survival was increased by 50 ％.The latest estimates of the median overall survival was about 10 years in under 65 years old patients,and 5-6 years in the elderly patients.The novel agents under investigation will further prolong the overall survival rate and progression free survival in the near future.

The efficacy and safety of bortezomib plus thalidomide in treatment of newly diagnosed multiple myeloma / 中华内科杂志

Objective The aim of this phase Ⅱ study was to determine the efficacy and safety of combined bortezomib and thalidomide (VT) regime as initial treatment for newly diagnosed multiple myeloma (MM) in China. Methods Thirty-four patients were enrolled in this study and received VT regime up to 21-day cycles. Bortezomib (1.3 mg/m2) was administered intravenously on days 1, 4, 8, and 11, while oral thalidomide ( 100 mg/day) was given from days 1 to 21. The primary end point was clinical response.The secondary end point was safety. Results Among the 34 patients, 20 were male, 14 were female, with a median age of 59 years, and 15 in international stage system (ISS) Ⅲ ,18 in ISS Ⅱ , 1 in ISS Ⅰ . Among them, 28 completed 2 cycles' treatment and achieved an overall response rate (ORR) of 92.9%; 26 were able to complete the planned 8 cycles of therapy. After 8 cycles, the ORR was 100% ( complete response 30. 8%, near-complete response 23.1%, partial response 42. 3%, minimal response 3.8% ). After followed up with a median time of 12 months, the estimated rate without progress of disease was 62%, and the estimated continous remission rate of 12 months was 62%. The median survival time was not achieved. The most common adverse events were mild to moderate ( grades 1, 2). The main toxicities were hematologic (53. 3% ), gastrointestinal ( 40. 0% ), peripheral neuropathy ( 38.0% ), fatigue ( 36. 6% ) and fever (32. 0% ). Conclusions VT regime provides a very high ORR and complete response rate in the treatment of newly diagnosed MM patients. No patients experienced deep venous thrombosis. In conclusion,bortezomib in combination with thalidomide is a very effective regimen for newly diagnosed MM patients and the toxicities are manageable.

Bortezomib causes hepatic impairement in four patients with multiple myeloma / 白血病·淋巴瘤

Objective To obserue that bortezomib lead to hepatic impairment and even hepatic insufficiency. Methods Four multiple myeloma patients with hepatic impairment in velcade therapy were analyzed. All of 4 patients ranged from 46 to 60-year-old were relapsed and refractory, including 3 cases of male and 1 of female; 2 of K light chain type, 1 of non secretion type and 1 of IgGλλ biclonal type; 3 in stage ⅢB and 1 in stage ⅢA. Results Four patients had normal hepatic function before bortezomib therapy, but all appeared hepatic impairment during therapy. ALT and aspartate aminotransferase were increased by 2-80 and 1.5-70 times compared with before the chemotherapy, respectively, and bilirubin and alkaline phosphatase in 2 patients and glutamyltranspeptidase in 1 patient were increased. Hepatic function restored normally after patients were given liver securing drug and discontinued bortezomib therapy. Conclusion It isn't rare that bortezomib causing hepatic impairment in the patients with multiple myeloma.

Clinical analysis of 4 patients with POEMS syndrome / 白血病·淋巴瘤

Objective To evaluate the clinical features of POEMS syndrome. Methods The clinical materials of 4 patients with POEMS syndrome were analysed retrospectively. Results All 4 patients presented polyneuropathy, abnormal globulinemia and endocrinopathy. All were treated with corticoid, cyclophosphamide and thalidomide. Some patients were treated with human immunoglobulin. Conclusion POEMS syndrome was a rare disease with involvement of multiorgan which result in difficult diagnosis. So for suspected cases, a necessary examination to avoid misdiagnosis should be given.

Malignant pleural effusion of multiple myeloma / 白血病·淋巴瘤

Objective To investigate the clinical characteristics, prognosis and treatment of pleural effusion of multiple myeloma. Methods From Jun 2005 to March 2010, of 162 patients with multiple myeloma treated in our department were complicated with pleural effusion, whose the proportion male to female was 8:7 and the median age was 56.8 (37-68) years. The diagnosis of malignant pleural effusion was dependent on physical examination, chest X ray, pleural aspiration and pleural fluid cytology. According to internatinal system stages and Durie-Salmon stages, the patients were staged. Results The results of pleural fluid cytology showed that the myeloma cells were positive in 13 patients and was negative in the other 2 patients. All patients received the chemotherapy regimen including bortezomib, large dose of glucocorticoids and cisplatin, cyclophosphamide, etoposide or prednisone (DECP). Although pleural effusion was controlled in some degrees, but were quickly relapsed. Eleven patients died, 2 of steady disease and 2 follow-up. Conclusion Multiple myeloma with myelomatous pleural effusion was very poor in the prognosis. Myelomatous pleural effusion was taken as a late manifestation in multiple myeloma or prediction of the aggressive behavior of the disease.

Pay attention to the clinical study of plasma cell disorders / 白血病·淋巴瘤

Plasma cell dyscrasia including multiple myeloma, monoelonal gammopathy of undetermined significance(MGUS), Waldenstrom s macroglobulinemia, amyloidosis and POEMS syndrome is a common malignant disease of hematological system and its incidence is increased by year. Deeply study the clinical process of this kind of disease and make reasonable therapies is an important approach for extending the life span and improving the prognosis of patients.

A clinical analysis of 25 cases of multiple myeloma compficated by extramedullary plasmacytomas / 中华内科杂志

Objective To investigate the clinical features of multiple myeloma (MM) complicated by extramedullary plasmacytomas(EM). Methods Twenty five patients were enrolled into the study. The proportion male to famale was 15:10 and the median age 55. 2 years. The distribution of different isotypes was IgA ten, IgG nine and light chain λ five. The sites of complicating plasmacytoma included muscle, bone, skin, rectum, and testicles. The most common site was muscle. Results Patients with complicated extramedullary plasmacytomas at the time of diagnosis received traditional treatment, including vincristiuum, adriamycin, dexamethasonum, mephalan, presnisone, thalidomide and bortezomib. Rates of overall response (ORR) were 80%. Plasmacytomas occurring after the diagnosis of MM received cisplatin, etoposide, cyclophosphamide, presnisone, or bortezomib ORR were 66. 7% ,50. 0%. Conclusion These results lend support to the efficacy of bortezomib in the treatment of plasmacytoma. MM cases with unconventional disease recurrence are likely to be seen due to sub-clinical seeding of turnout cells suggestive of the presence of an EM clone of plasma cells with a high degree of chemoresistance. Available data in the literature concerning the optimal therapy for patients with EM relapse were reviewed.

Relationship of expression of osteopontin and CD44 variant isoforms in multiple myeloma patients with progress of multiple myeloma / 中国癌症杂志

Background and purpose: Osteopontin (OPN) is a glycophosphoprotein that is expressed by numerous human cancer cells. The function of OPN in skeletal modeling and remodeling, bone resorption, angiogenesis and tumor cell metastasis and progression through binding with integrin and CD44 receptors were studied. Our purpose of the study was to detect the level of osteopontin(OPN) and CD44 variant isoforms(CD44v6) in multiple myeloma (MM) patients, and to explore the relationship between OPN and CD44v6 with the progress of MM. Methods: 32 MM patients were admitted to our hospital from Sep. 2007 to Dec. 2008. The patients were divided into two groups, group A (untreated and relapsed MM patients) and B (stable MM patients), and the control group including 15 subjects were the benign anemia patients or healthy people who suffered bone fracture. Bone marrow mononuclear cells (MNCs) and bone marrow stromal cells (BMSCs) from MM patients and subjects were investigated as potential OPN and CD44v6 producers. The level of OPN and CD44v6 of the conditioned media from MM patients and subjects were analyzed by ELISA. Results: The OPN level in group A (19 cases) was significantly higher than group B (13 cases) and control group (P<0.05). The CD44v6 level of 14 patients in group A was significantly higher than that of 10 cases in group B and control group (P<0.05); The OPN level of MM patients was correlated with the level of CD44v6 (r=0.52, P=0.000), the percentage of plasma cells in the bone marrow (r=0.74, P=0.000), M protein (r=0.53, P=0.014), and β2-microglubin (r=0.62, P=0.002). Conclusion: The increase of OPN and CD44v6 is associated with progress and pathogenesis of MM,and may be involved with tumor burden, stage and tumor invasion.

Clinical analysis of 15 patients with Waldenstrom macroglobulinemia / 中华内科杂志

Objective To explore the clinical characteristics of Waldenstrom macroglobulinemia (WM) and enhance the level of diagnosis and treatment. Method The data of 15 patients with WM in our 68.5(60-79) years, male/female =2.75/1. Main clinical manifestations were fatigue, loss of weight, splenomegaly and lymphadenopathy. All the patients accepted the treatment of alkylating agents, purine nucleoside analogs, bortezomib or thalidomide respectively. The follow-up period for the patients was 4 months to 10 years and the median follow-up time was 82 months. Conclusion WM may often be seen in old male patients with varied clinical manifestations. The primary treatment is chemotherapy, but the disease is incurable. Bortezomib and thalidomide may improve the therapeutic effect.

A report of 9 multiple myeloma patients with extramedullary and extraosseous plasmocytoma and literature review / 白血病·淋巴瘤

Objective Extramedullary plagmocytoma at diagnose or during the course of multiple myeloma is rare.In order to know this entity better and explore new therapy for it,by combining with literature review,we conducted a retrospective study to describe the clinical and laboratory features of this entity and the outcome of these manirestation.Methods From January 2001 to July 2007,123 multiple myeloma patients were treated in our hospital.We analysed the clinical features of patients with extramedullary plagmocytoma at diagnose or during the course of multiple myeloma.The response to therapy was evaluated according to the EBMT criteria.Results 9 eligible patients out of 123 with MM were retrieved from the hematology department of Beijing Chaoyang hospital.The median age was 55(range:48～66)with a female/male ratio of 1/8.One patients was found to have Extramedullary and extraosseous tumor at the time of MM diagnose,and eight patients developed Extramedullary tumor during the course of the disease.Multiple sites were usually involved.Resistance to traditional chemotherapy wag frequent.With a median follow-up of 19 months(range:3～47),2 patients are alive.Median time from progression of disease to diagnose of Extramedullary disease was 4 and a half months.The median interval from diagnosis of Extramedullary disease to death was 2 months and OS was 23 months.Conclusion Extramedullary plasmocytoma is a rare manifestation of MM,with a cumulative incidence of 7.3% of MM in our department.Multiple sites are usually involved.The resistance to the traditional chemotherapy is frequent and the prognosis is very poor.The new therapy is necessarily explored.

Expression and clinical significance of cyclooxygenase-2 in multiple myeloma / 白血病·淋巴瘤

Objective To investigate the expression of COX-2 in multiple myeloma(MM)and the relationship between myeloma cells proliferation and apoptosis.To provide a new prognosis factor and therapeutic target.Methods COX-2 from the 22 newly diagnosed MM,14 relapsed MM and PCNA,HSP70 of the newly diagnosed patients were detected by immunohistochemistry method.Results All the newly diagnosed MM exhibited positive COX-2 immunoreactivity.50% had strong COX-2 and 50% showed weak COX-2.Relapsed MM exhibited strong COX-2.COX-2 was related with serum β2 microglobulin,marrow plasma cells,hemoglobin,PCNA,HSP70(P=0.019,0.003,0.048,0.006,0.034).Conclusion COX-2 was overexpressed in MM.Prognosis of patients with strong COX-2 is poorer than those with weak COX-2.COX-2 may promote the proliferation and inhibit the apoptosis of myeloma cells.

Core treatment strategy for multiple myeloma in China / 白血病·淋巴瘤

The incidence of multiple myeloma(MM)has increased each year with the improving medical diagnostic technology and ageing population.The MM is still an incurable disease at present.Following the improving diagnostic technology,serious study of the therapeutic regimen,combination therapy of new drugs with conditional drugs,risk-adapted therapy in MM and individualized treatment,it is an important strategy to prolong the survival,reduce the complication and improve the prognosis.