Interrelationship and expression profiling of cyclooxygenase and angiogenic factors in Indian patients with multiple myeloma

Multiple myeloma (MM) is classically illustrated by a desynchronized cytokine system with rise in inflammatory cytokines. There are recent reports which emphasized the potential role of angiogenesis in the development of MM. Role of cyclooxygenase 2 (COX-2) is well documented in the pathogenesis of solid tumors, but little is known about its occurrence and function in hematologic neoplasms. Involvement of neoangiogenesis is reported in the progression of MM, and angiopoietins probably contribute to this progression by enhancing neovascularization. Circulatory and mRNA levels of angiogenic factors and cyclooxygenase were determined in 125 subjects (75 MM patients and 50 healthy controls) by using enzyme-linked immunosorbent assay and quantitative PCR. We observed significant increase for angiogenic factors (Ang-1, Ang-2, hepatocyte growth factor, and vascular endothelial growth factor) and cyclooxygenase at circulatory level, as well as at mRNA level, as compared to healthy controls except insignificant increase for Ang-1 at circulatory level. We have also observed the significant positive correlation of all angiogenic factors with cyclooxygenase. The strong association found between angiogenic factors and COX-2 in this study may lead to the development of combination therapeutic strategy to treat MM. Therefore, targeting COX-2 by using its effective inhibitors demonstrating antiangiogenic and antitumor effects could be used as a new therapeutic approach for treatment of MM.     

High levels of serum angiogenic growth factors in patients with AL amyloidosis: comparisons with normal individuals and multiple myeloma patients

Serum levels of five angiogenic cytokines were evaluated in 82 patients with primary systemic amyloidosis (AL). Angiopoietin‐1, vascular endothelial growth factor, basic fibroblast growth factor and angiogenin were higher in AL patients than in controls (n = 35) and newly‐diagnosed, symptomatic, myeloma patients (n = 35). Angiopoetin‐1/Angiopoetin‐2 ratio was lower in AL compared to controls but higher than in myeloma patients. Angiopoetin‐2 correlated with cardiac dysfunction indices; however, none of the angiogenic growth factors was prognostically significant. The increased angiogenic cytokine levels observed in AL seem to represent either a toxic effect of amyloid fibrils or light chains, or a compensatory response to organ dysfunction.     

Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma

BACKGROUND: Interleukin-17 (IL-17) is a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and regulates the production of a variety of proangiogenic factors, such as tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial cell growth factor (VEGF). Angiogenesis is implicated in the progression of multiple myeloma (MM). METHODS: We measured serum levels of IL-17, TNF-alpha, and VEGF, as well as microvessel density (MVD) in 40 untreated MM patients. RESULTS: Levels of IL-17 in the sera of patients with MM were higher than those in matched controls; however, the difference did not reach statistical significance. Serum levels of both TNF-alpha and VEGF in MM patients were significantly higher than those in controls (p<0.001 in both instances). Levels of IL-17 in MM patients, both stage II and stage III, were significantly higher than those of stage I patients (p=0.001 and p<0.001, respectively). Similarly, higher values of VEGF (p<0.001), TNF-alpha (p<0.001), and MVD (p<0.035) were associated with advanced disease stage. Serum values of IL-17 in MM patients correlated positively not only with VEGF (Spearman's rho=0.606) and TNF-alpha (r=0.552; p<0.001 in both instances), but also with MVD (r=0.385, p=0.014). In addition, a positive correlation was found between serum values of VEGF and TNF-alpha (r=0.657, p<0.001), MVD and VEGF (r=0.353, p=0.026), and between MVD and TNF-alpha (r=0.506, p=0.001) in MM patients. CONCLUSION: These results suggest that IL-17 plays a role in the promotion of angiogenesis and associated disease progression in MM.     

Serum pleiotrophin levels are elevated in multiple myeloma patients and correlate with disease status

Pleiotrophin (PTN), a tightly regulated angiogenic and mitogenic heparin-binding protein, is markedly elevated in a variety of aggressive solid tumours. The role of PTN in haematological malignancies, however, has not been previously evaluated. This study demonstrated that PTN serum levels were elevated in multiple myeloma (MM) patients when compared with healthy subjects (P < 0.0001). Serum levels of this protein significantly increased during progression of disease, and decreased during response to anti-MM therapy (P < 0.001). These results suggest that serum PTN may be a new biomarker for monitoring the disease status and therapeutic response of MM patients.     

Impaired chemiluminescence response by neutrophils in patients with multiple myeloma

Neutrophil chemiluminescence (CL) as a measure of oxygen-dependent killing activity was evaluated in 3 groups of patients: (a) 63 patients with multiple myeloma (MM); (b) 31 subjects with monoclonal gammopathy of undetermined significance (MGUS); (c) 32 healthy controls. Neutrophil CL response was shown to be significant reduced both in patients with MM (p less than 0.001) and in subjects with MGUS (p less than 0.001). A significant difference was also observed between the results obtained in MM and those of MGUS (p less than 0.001). Treated MM patients showed a more severe impairment of neutrophil chemiluminescence response than that observed in untreated patients (p less than 0.001). It is suggested that the impairment of neutrophil CL response, possibly related to decreased killing activity, may play a role, along with other known causes, in the increased susceptibility to infection observed in MM patients.     

Risk factors for early death in patients undergoing treatment for multiple myeloma

The survival time of myeloma patients improved from a few months to many years after treatment with melphalan. Perhaps chemotherapy more intensive than melphalan-prednisolone should be administered to patients at risk of early death. Therefore, early death must be accurately predicted. We analyzed 93 patients with recently diagnosed myeloma and found that 13 (14%) died within 6 months (early death). The most common cause of death was bacterial and fungal pneumonia when myeloma became uncontrollable. The response to conventional chemotherapy was poorer in patients at high risk of early death than the control group. Multivariate analysis showed that the serum level of beta-2 microglobulin was the only value that predicted early death.     

Alkaline phosphatase variation during carfilzomib treatment is associated with best response in multiple myeloma patients

The ubiquitin-proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation alkaline phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX-171-003 and 29 patients in PX-171-004 studies, for patients with relapsed/refractory myeloma, were analyzed. All patients received 20 mg/m(2) of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Sixty-seven patients from ALP data were evaluable. In PX-171-003, the ORR (>PR) was 18% and the clinical benefit response (CBR; >MR) was 26%, while in PX-171-004, the ORR was 35.5% overall and 57% in bortezomib-naive patients. ALP increment from baseline was statistically different in patients who achieved ≥ VGPR compared with all others on Days 1 (P = 0.0049) and 8 (P = 0.006) of Cycle 2. In patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline. An ALP increase over the same period of time was seen in 26%, 13% and 11% of patients achieving PR, MR, and SD, respectively. This retrospective analysis of patients with relapsed or refractory myeloma treated with single-agent carfilzomib indicates that early elevation in ALP is associated with subsequent myeloma response.     

Pneumococcal vaccination: The response of patients with multiple myeloma

Thirteen patients with multiple myeloma, one with Waldenström's macroglobulinemia and 23 age-matched normal ambulatory control subjects were immunized with 14-valent purified vaccine of pneumococcal capsular polysaccharides. Patients' serums were obtained for antibody measurement before immunization, within four to six weeks after immunization and 12 to 56 weeks after immunization. Concentrations of antibody to 12 types of polysaccharide were measured by radioimmunoassay. Concentrations of antibody to most pneumococcal types before immunization were significantly lower in the patients with myeloma when compared to those in the control subjects. Six weeks after immunization, the geometric grand mean antibody concentration for all types combined was significantly lower in the patients than in the control subjects (91 versus 820 ng of antibody nitrogen/ml, p < 0.01). No correlation was found between maximum antibody response and hematocrit value, platelet count, M protein, light chain type, immunoglobulin type or timing of chemotherapy. In patients with total white blood cell counts greater than 5,000/μl a significantly higher mean antibody concentration was achieved. When antibody concentrations were analyzed for individual patients, marked variability was observed. In four patients potentially protective antibody concentrations of 215 ng of antibody nitrogen/ml were achieved for six or more serotypes, and in six patients this level was not achieved for any serotype. Approximately 30 percent of the patients with myeloma demonstrated a significant antibody response to immunization. The modest benefits, low risk of side effects, low cost of pneumococcal polysaccharide vaccination and the emergence of pneumococci resistant to multiple antibiotics suggest it may be prudent medical practice to vaccinate patients with myeloma.     

Clinical response to the treatment of multiple myeloma

Between 1971 and 1985, 133 patients were diagnosed as symptomatic multiple myeloma. Recently the number and percentage of patients, who were older (70 years old) and type of diffuse proliferation, were remarkably increased. In 132 previously untreated patients who received chemotherapy, the 50% Survival time was 32 months; thirty-nine (29%) survived more than five years after treatment and 4 of them (3%) survived more than ten years. Among the prognostic factors related to survival time, serum albumin level, M-protein type, bone marrow plasma cell (%), clinical stage and classification according to tumor distribution were considered to be significantly important. Clinical responses were evaluated in 120 patients who received combination chemotherapy for at least 3 months. A 50% or more reduction of M-protein was obtained in 58% and a marked improvement in bone pain or motor-disturbance was found in 54%. Overall response rate evaluated by the effects of both objective and subjective symptoms was 43%. New criteria for response defined by the level of serum albumin and M-protein after treatment were proposed.     

Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma

Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)‐1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. So far, there is no study showing a significant difference in serum DKK‐1 levels in MM patients with or without lytic bone lesions. Methods: DKK‐1 serum levels were quantified in 184 untreated MM patients and 33 monoclonal gammopathy of undetermined significance (MGUS) patients by ELISA, using a monoclonal anti‐DKK‐1 antibody. Results: Serum DKK‐1 was elevated in MM as compared with MGUS (mean 11 963 pg/mL vs. 1993 pg/mL; P < 0.05). Serum DKK‐1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL vs. 15 209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK‐1 levels than patients with lytic bone disease (mean 3114 pg/mL vs. 17 915 pg/mL; P = 0.003). Of interest, serum DKK‐1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: 3114 pg/mL vs. 3559 pg/mL vs. 24 068 pg/mL; P = 0.002). Conclusion: Using a large series of myeloma patients, we could show for the first time a correlation between DKK‐1 serum concentration and the amount of lytic bone disease, indicating that DKK‐1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK‐1 as a therapeutic target in myeloma bone disease.     

Early response predicts thalidomide efficiency in patients with advanced multiple myeloma

Sixty-five patients who were primary or secondary refractory to melphalan/prednisone or other type of chemotherapy, or relapsed within 6 months after high dose chemotherapy with stem cell support, were given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median of 2 years and 22 weeks. Response was evaluated according to M-protein reduction combined with improvement of haemoglobin (Hb) concentration, renal function and pain. Altogether, 14% of patients had a minor response, 14% partial response and 6% complete response. Median survival was 12 months and 29% were alive at last contact. Decline of M protein started early and a minimum 25% reduction of M protein was detected in 14 of 20 responders (70%) after 3 weeks, and in 20 of 22 responders (91%) after 5 weeks of treatment. Reduction of M protein continued for 3 months and further decline was observed in only four patients. The Hb concentration showed a different time course, with a significant increase after 3 months and further increases continued for up to 12 months. Blood concentration levels of thalidomide from 40 patients were used to evaluate the pharmacokinetics of the drug. Rate of absorption, rate of elimination, volume of distribution, clearance and elimination half-life were calculated to be 0.200/h, 0.140/h, 0.886 l/kg, 0.126 l/h/kg and 4.98 h respectively. We found no relationship between thalidomide concentration and effect after 12 weeks.     

Bone marrow angiogenesis and plasma cell angiogenic and invasive potential in patients with active multiple myeloma

Factor VIII-related antigen-positive microvessel areas were measured by both immunohistochemistry and computerized image analysis in patients with active multiple myeloma (MM), nonactive MM and monoclonal gammopathies of undetermined significance (MGUS). A 5- to 6-fold larger area was found in patients with active MM compared to the other two groups. The conditioned medium (CM) of their bone marrow plasma cells stimulated endothelial cell proliferation and chemotaxis, monocyte chemotaxis and angiogenesis in vivo [chick embryo chorioallantoic membrane (CAM) system] more strongly and frequently than the CM of patients with nonactive MM and MGUS. An immunoassay of plasma cell lysates gave significantly higher levels of fibroblast growth factor-2 (FGF-2) in patients with active MM than in the other two groups, and a neutralizing anti-FGF-2 antibody inhibited by 54-68% the biological activity exerted by the CM in vitro and in the CAM. In situ hybridization of bone marrow plasma cells and gelatin zymography of CM showed that patients with active MM express higher levels of matrix metalloproteinase-2 (MMP-2) mRNA and protein than those with nonactive MM and MGUS, whereas MMP-9 expression and secretion overlapped in all groups. Overall data suggest that patients with active MM represent the vascular phase of plasma cell tumors that is triggered by bone marrow plasma cells, at least partly, through FGF-2 and MMP-2. Both angiogenesis and MMP-2 secretion can account for intramedullary and extramedullary spreading of plasma cells during the active MM.     

Prognostic factors in elderly multiple myeloma patients aged 65 years or older: Comparison with nonelderly patients with multiple myeloma

Background:   Although age is a prognostic factor in multiple myeloma (MM), the prognostic factors in elderly MM patients may be different to those in nonelderly MM patients due to the patient's age. The difference in the significance of prognostic factors between elderly MM patients and the nonelderly MM patients was studied.
Methods:   Forty-two elderly MM patients aged 65 years or older were compared with 68 nonelderly MM patients, who were less than 65 years of age. The characteristics of the elderly patients included: aged 65–81 years (median, 72 years); female/male ratio of 22 : 20; 24 IgG type cases, 13 IgA type cases, one non-secretory case and four cases of Bence-Jones type; one case of stage I, 12 cases at stage II and 29 cases at stage III. The prognostic factors were evaluated by means of univariate analysis and Cox's multivariate analysis.
Results:   The median survival time was significantly shorter in the elderly MM patients (24 months) than in the nonelderly patients (50 months) ( P  < 0.01). Of the univariate prognostic factors, corrected serum Ca (cCa), hemoglobin, serum P, bone marrow plasma cell and uric acid were significant prognostic factors in the elderly MM patients, while nine factors including those listed here, were significant in nonelderly controls. Multivariate analysis showed that serum cCa was the only independent prognostic factor ( P  = 0.019) in elderly MM patients, while serum P and bone lesions were significant prognostic factors in nonelderly MM patients.
Conclusion:   Corrected serum c. (cCa) was an independent prognostic factor in elderly MM patients.     

Effectiveness of propagermanium treatment in multiple myeloma patients

Interferon (IFN) is one of several drugs effective in treating multiple myeloma (MM), and propagermanium is an IFN inducer. We report on 10 MM patients who were treated with propagermanium at doses from 10 to 40 mg. Two patients achieved complete remission (CR), two patients achieved partial remission (PR), and the condition of four patients was stable (stable disease, SD). After discontinuation of propagermanium, the status of MM progressed in two patients who were in SD and in two patients who had achieved PR. The administration of propagermanium was restarted in one patient resulting in a decrease in her paraprotein.     

Frontline treatment of multiple myeloma in elderly patients

Until 2007, frontline chemotherapy with melphalan and prednisone (MP) was considered as the standard of care in the treatment of elderly patients with multiple myeloma (MM). Recently, several prospective randomized studies comparing MP with the same combination plus new agents such as thalidomide (MPT) or bortezomib (MPV) clearly showed that MPT and MPV were superior to MP in terms of progression-free and overall survival. Melphalan–prednisone–lenalidomide (MPR) is currently compared to MP in one prospective trial and will also probably be superior to MP. Lenalidomide plus low-dose dexamethasone is a promising combination. Thus, at least four highly active new treatment options are now available to treat elderly patients with MM. The goal of future trials will be to determine the best treatment strategy in this group of patients.     

多发性骨髓瘤存活期及影响因素研究

目的 探讨多发性骨髓瘤(MM)患者长期存活的相关因素.方法 统计天津医科大学总医院1983年1月至2007年9月MM患者存活期并分析其影响因素.结果 107例MM患者中位存活32个月.单因素分析显示发病年龄、髓外浸润、合并感染、外周血血小板计数、血清白蛋白、β2-微球蛋白、尿酸、骨髓浆细胞比例及形态、治疗后是否达到骨髓细胞形态学完全缓解(CR)是本组MM患者存活期的影响因素.多因素分析显示外周血血小板计数、血清β2-微球蛋白、骨髓细胞分类中浆细胞类型和治疗后是否达到骨髓细胞形态学CR是MM患者存活期的独立影响因素.结论 近20余年,MM患者中位存活近3年,其外周血血小板计数、血清β2-微球蛋白、骨髓浆细胞类型和治疗后达否骨髓细胞形态学CR是影响存活期的独立因素.     

Hypoalbuminemia in patients with multiple myeloma

Clinical data of 65 patients with myeloma were analyzed to identify factors associated with hypoalbuminemia. The serum albumin level was not affected by patient age and gender, type of myeloma, and the occurrence of Bence Jones protein, lytic bone lesions, or hypercalcemia, and it was not related to changes in body weight or in liver and renal function. The albumin level, lower in patients with proteinuria, was unrelated to severity of proteinuria. Albumin level correlated significantly with the monoclonal IgG levels, hemoglobin concentration, clinical stage of disease, and estimated body tumor burden. Further analysis indicated the disease stage or the tumor burden as the dominant factor in determining albumin level. An albumin level of 29.0 g/L or less identified unequivocally advanced disease. Practically all patients with stage III myeloma had a serum albumin level of 37.0 g/L or less. Thus, hypoalbuminemia is primarily related to the extent of myeloma proliferation and is therefore of diagnostic and prognostic importance.     

Tumour lysis syndrome complicating high-dose treatment in patients with multiple myeloma

Tumour lysis syndrome (TLS), because of its low proliferative activity, is thought to only rarely complicate the treatment of patients with multiple myeloma. However, as more aggressive therapeutic approaches are increasingly used in the management of this disease, it is conceivable that clinicians will encounter this complication more frequently. A retrospective analysis of > 800 patients with multiple myeloma treated at the University of Arkansas identified nine patients who developed a marked tumour lysis syndrome following intermediate- or high-dose chemotherapy. Evaluation of disease characteristics revealed association with high tumour mass, high proliferative activity, increased lactic dehydrogenase levels, plasmablastic morphology, and unfavourable cytogenetic abnormalities. Recognition of multiple myeloma patients at high risk for the development of tumour lysis syndrome and prompt intervention are required especially in the presence of abnormal baseline renal function frequently complicating the clinical course of these patients.