Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Palliative therapy is often a major objective for clinicians while treating advanced cancer. This is particularly true in multiple myeloma (MM), where bone involvement markedly influences the quality of life of patients. Bisphosphonates (BP) are a new class of drugs regulating bone turnover, which exert their activity mainly by inhibiting osteoclast bone resorption. Three BP (etidronate, ETD; clodronate, CDN; pamidronate, PMD) have so far been investigated in the clinical setting for treating bone disease in patients with MM. The results of these trials, including our own experience, are reviewed here. Although all three BP were effective in lowering hypercalcemia of MM patients, PMD, a second generation BP, clearly had the most substantial long term clinical benefits regarding bony complications, pain and quality of life. CDN also showed some activity in reducing the development of new lytic lesions, while no significant beneficial effect was seen in patients using ETD. Interestingly, some studies have reported an improved survival in subsets of MM patients receiving BP and this is in agreement with recent evidence of possible direct anti-neoplastic activities of these drugs mediated through reduction of IL-6 production and stimulation of neoplastic cell apoptosis.
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PMID:The role of bisphosphonates for the treatment of bone disease in multiple myeloma. 992 36

We report on an in vivo model of human myeloma producing bone disease in irradiated severe combined immunodeficiency disease mice using the human myeloma cell line JJN-3 and its subline JJN-3 T1. The cell lines are not Epstein-Barr virus transformed and produce large amounts of hepatocyte growth factor (HGF). Mice had radiological signs of osteolysis and mild hypercalcemia. Xenografted cells were predominantly found in bone marrow and brown adipose tissue, but also in meninges and liver. Take was documented by histopathological examination, immunophenotyping of cultured bone marrow, and radiography. HGF was detected in serum and bone marrow plasma. Disease generally occurred within 45 days of intravenous inoculation and was signaled by paraparesis or signs of intracranial neoplasia. More than 90% of the mice had take of xenografts. The subline JJN-3 T1 gave more reproducible bone marrow take than the native cell line. Bone histomorphometric examination revealed a 99% reduction in osteoblast counts and a 33% reduction in osteoclast counts in areas of tumor growth. Bone formation rates were reduced by 53%. The results suggest that osteoblastopenia and reduced bone formation is of importance for the occurrence of osteolytic lesions in this model.
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PMID:Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. 993 80

We determined the effects of the potent bisphosphonate ibandronate in a murine model of human myeloma bone disease. In this model, bone lesions typical of the human disease develop in mice following inoculation of myeloma cells via the tail vein. Treatment with ibandronate (4 micrograms per mouse per day) significantly reduced the occurrence of osteolytic bone lesions in myeloma-bearing mice. However, ibandronate did not prevent the mice from developing hindlimb paralysis and did not produce a detectable effect on survival. There was no significant effect of ibandronate on total myeloma cell burden, as assessed by morphometric measurements of myeloma cells in the bone marrow, liver, and spleen, or by measurement of serum IgG2b levels. These results support clinical findings that bisphosphonates may be useful for the treatment of myeloma-associated bone destruction, but suggest that other therapies are also required to reduce tumor growth.
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PMID:Ibandronate reduces osteolytic lesions but not tumor burden in a murine model of myeloma bone disease. 1002 99

The net impact of malignancy and anti-tumor therapy on bone resorption in myeloma is poorly understood because conventional skeletal radiographs are relatively insensitive for the diagnosis and monitoring of bone disease. We performed determinations of bone mineral density (BMD) at the lumbar spine, femoral neck and radial diaphysis by dual energy X ray absorptiometry (DEXA) in 168 consecutive patients with myeloma seen at our institution. Follow up studies were performed in 41 of these patients. A detailed analysis of patient and disease characteristics was performed to identify the determinants of BMD. Compared to normal age and sex matched controls, mean (+/- SE) BMD was significantly decreased at the lumbar spine (Z score -0.4 +/- 0.10) and femoral neck (Z score -1.0 +/- 0.10), but was surprisingly above normal at the radial diaphysis (Z score +0.35 +/- 0.10), a cortical bone site devoid of hematopoietic marrow, suggesting a differential bone preserving effect at this site. Lack of correlation between the BMD findings and the presence or extent of radiographically evident osteolytic lesions suggested the presence of a systemic bone disease. On multivariate analysis, duration of disease >12 months (p = 0.003) and female sex (p = 0.01) were independently associated with a lower BMD at the femoral neck/lumbar spine. On follow up DEXA (n = 41), BMD increased at > or = 1 site in 9 of 20 patients receiving bisphosphonates and in only 2 of 21 patients not receiving such therapy (p = 0.02). Similarly a decline in BMD at > or = 1 site was seen in 9 of 21 patients not receiving bisphosphonates, irrespective of the disease response status. Interval pamidronate therapy (p = 0.0007) and a low serum beta-2-microglobulin (< 2.5 mg/l) (p = 0.04) were the two most significant variables associated with an increase in BMD on multivariate analysis. These data suggest that myeloma is associated with a systemic bone disease with progressive generalized cancellous bone loss and a bone preserving effect on the radial cortical bone. The early use of bisphosphonates may improve myeloma related bone disease.
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PMID:Biologic and therapeutic determinants of bone mineral density in multiple myeloma. 1003 7

Multiple myeloma is a haematological malignancy characterized by an expansion of malignant plasma cells within the bone marrow and is frequently associated with bone disease involving the development of osteolytic bone lesions, pathological fractures, osteoporosis and hypercalcaemia. A class of anti-resorptive drugs known as bisphosphonates have been in use to treat osteoclast-mediated bone diseases for the past 3 decades, and are currently proving effective in the treatment of the bone disease associated with multiple myeloma. Recent studies have suggested that bisphosphonate treatment may also result in an improvement in survival in some patients with multiple myeloma. These effects on survival may reflect an indirect effect of the bisphosphonates on tumour growth, via inhibition of osteoclast activity and hence a reduction in the release of tumour growth factors. However, it is also possible that bisphosphonates may have a direct effect on myeloma cells. In support of this we have demonstrated that bisphosphonates can decrease cell proliferation and induce apoptosis in human myeloma cells in vitro, and this review discusses the possibility that bisphosphonates may have not only an anti-resorptive action, but may also have a direct anti-tumour activity.
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PMID:Anti-tumour activity of bisphosphonates in human myeloma cells. 1003 8

Interleukin-1beta(IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) are potent bone resorbing cytokines that may contribute to the development of the osteolytic bone disease observed in patients with multiple myeloma (MM). Although these factors have been identified in cultures of bone marrow mononuclear cells isolated from patients, the identity of the cells responsible for producing IL-1beta and TNFalpha remains unclear. Using a sensitive dual-colour fluorescence in situ hybridization (FISH) technique and a two-colour immunofluorescence method we have investigated the expression of the mRNA and protein, for IL-1beta and TNFalpha, by individual bone marrow plasma cells from patients with MM and monoclonal gammopathy of undetermined significance (MGUS). The mRNA for IL-1beta and TNFalpha was identified in all cells expressing the immunoglobulin light chain from all patients with MM and MGUS. However, the IL-1beta protein could not be detected in cytoplasmic light chain positive cells in any of the patients examined. In contrast, the TNFalpha protein was detected in clonal plasma cells from patients with both MM and MGUS. Interestingly, the IL-1beta and TNFalpha mRNA and proteins were readily detected within a small proportion of the non-plasma cells from patients with both MM and MGUS. These data suggest that myeloma cells in vivo are able to produce TNFalpha but not IL-1beta. In addition, a small proportion of accessory cells are likely to be able to contribute to the production of both ILbeta and TNFalpha.
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PMID:Expression of interleukin-1beta and tumour necrosis factor-alpha in plasma cells from patients with multiple myeloma. 1005 Jul 19

This paper traces the lack of progress, until recently, in the treatment of multiple myeloma (MM) to having ignored the principles that led to cure in acute leukemia more than 2 decades ago. Only in the mid-1980s did investigation begin to consider complete remission (CR) a research objective, representing a necessary first step toward cure. The experience with autologous and allogeneic stem cell-supported high-dose therapy is reviewed, demonstrating, in both historically controlled and randomized studies, the validity of the dose-response concept in MM in terms of increased CR rates as well as extended event-free (EFS) and overall survival (OS). Avoidance of hematopoietic stem cell-damaging agents, especially melphalan, nitrosoureas, and ionizing radiation to marrow-containing sites, assures the ability of peripheral stem cell collection of high quality and quantity, providing rapid engraftment so that mortality is well under 5% following high-dose melphalan (200 mg/m2). This treatment can be applied safely to patients even >70 years of age and in the presence of renal failure. Tandem autotransplants after multiregimen induction have yielded CR rates in the 40% range with median durations of EFS and OS of 43 and 62 months, respectively. Certain chromosomal abnormalities (11 and 13; and translocations) represent the dominant adverse prognosticator for EFS and OS, confirmed in over 500 patients including those with prior therapy. Allogeneic transplants, possible in less than 10% of MM patients, are associated with a 50% mortality during the first year and, unfortunately, late relapses; thus, this approach should be reserved for patients with high-risk disease early in their management. A risk-based treatment algorithm that matches a patient's disease risk with the risk of intervention is presently used, followed by bisphosphonate therapy, not only to delay the onset of MM-related bone disease but also to induce tumor cell apoptosis, indirectly or directly, by down-regulation of cytokines with antiapoptotic activities. Although many patients relapse, this author subscribes to his mentor's motto: "Be Prepared for Success!".
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PMID:Advances in therapy of multiple myeloma: lessons from acute leukemia. 1006 62

Tumor-induced osteolysis or lytic bone disease is mediated by osteoclast activation. Osteoclasts can be activated directly by products produced by tumors or indirectly through other nonmalignant cells. By reducing osteoclastic activity, bisphosphonates inhibit bone resorption. Since these agents were shown effective in treating other diseases associated with increased bone resorption, including cancer-related hypercalcemia and Paget's disease of bone, studies have been initiated to explore the use of bisphosphonates in patients with osteolytic bone metastases. Recent large randomized double-blind studies show the efficacy of these agents in reducing skeletal complications in patients with bone metastases from both breast cancer and multiple myeloma.
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PMID:Bisphosphonates in the treatment of malignant bone disease. 1007 75

Although a variable proportion of multiple myeloma patients can achieve response with conventional chemotherapy, residual tumor cells, which are refractory, finally reemerge leading to disease progression. The expression of the multidrug resistance protein (MDR1) has been one of the most extensively explored mechanisms of drug resistance and has been related to a poor response to chemotherapy in several human tumors. Nevertheless, a careful analysis of the literature on MDR1 expression in multiple myeloma (MM) shows the existence of disturbing discrepancies as regards both the incidence of MDR1 over-expression and its clinical value. A prerequisite for the assessment of MDR1 in tumor cells should be the identification of the neoplastic cells present in the sample. This is particularly important in MM, where the percentage of tumor cells in bone marrow (BM) is relatively low. In the present study we have analyzed the functional expression of MDR1 in BM plasma cells (PC), from a group of 40 untreated MM patients. For that purpose, the rhodamine 123 efflux assay was used in combination with specific staining for plasma cells (CD38 strong+). The mean fluorescence channel (MFC) of rhodamine 123 in myelomatous PC from MM patients was 311 and 110 after incubating cells with this fluorochrome for 15 and 60 min, respectively. The median percentage of rhodamine 123 elimination by BM PC was of 61% (range: 0.29 to 88%). Upon analyzing the relationship between the ability of myelomatous PC to eliminate rhodamine 123 and other clinical and biological disease characteristics we found that, within the group of patients displaying high MDR1 expression (>61% rhodamine efflux), there was a higher incidence of cases with bone disease (P = 0.014) and advanced clinical stages (P = 0.031), greater calcium (P = 0.007) and creatinine serum levels (P = 0.061), and lower levels of albumin in serum (P = 0.015). All these parameters are usually associated with a poor prognosis. When we analyzed the possible relationship between the ability of BM PC to eliminate rhodamine 123 and the presence of numerical chromosome abnormalities we observed that a low MDR1 expression was related to a higher incidence of trisomies of chromosomes 6 and 17, although these differences did not reach statistical significance (P = 0.06). In spite of these associations, from the prognostic point of view, MDR1 expression did not correlate with other relevant prognostic factors, response to treatment (P = 0.38) or overall survival (P = 0.12).
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PMID:Correlation of rhodamine 123 efflux by neoplastic plasma cells with clinical and biological characteristics of multiple myeloma. 1008 73

Bone disease is a frequent manifestation of multiple myeloma, and results in considerable morbidity. In this review we summarise the current theories as to the mechanism of bony destruction in this disease and discuss the interrelationships between the malignant plasma cells and those cells responsible for bone remodelling, i.e. the osteoclasts and osteoblasts. The bisphosphonates are a long established group of drugs known to have inhibitory effects on osteoclast activity, and in common use for osteoporosis and Paget's disease. Their role in myeloma is less clear. Several clinical studies, including phase III randomised placebo controlled trials, have been reported in recent years. Although these have tended to show a benefit for bisphosphonate treatment, we have not yet identified the most appropriate use of these agents. Two of the clinical trials have suggested that bisphosphonates may also have a beneficial effect on the underlying disease, a tantalizing theory which has been supported with some early laboratory data.
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PMID:Bisphosphonates in multiple myeloma. 1019 85


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