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)

It is generally considered that a patient with myeloma who also has established renal impairment is unlikely to do well. While this is sometimes the case, analysis of recent data shows: (a) of 2768 patients in the MRC database for the fourth to the sixth trials, 10/163 with serum creatinine 300-600 microm/l and 20/89 with serum creatinine 600 micro/l at presentation had renal failure as a recorded presenting feature, whatever the renal function, the most common presenting feature was bone pain; (b) that many patients have persisting evidence of reduced renal function yet survive for more than the median time of 36 months which applies to myeloma generally. Patients with renal impairment, especially those whose myeloma is brought to plateau by chemotherapy, should be assessed thoroughly for evidence of other than myeloma induced renal damage as both renovascular disease and prostatic obstruction in males are common in the elderly population at risk.
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PMID:Renal impairment in myeloma: time for a reappraisal? 987 Apr 34

The economic impact of using prophylactic clodronate as an adjunct to chemotherapy in the management of multiple myeloma for the first 4 years following diagnosis was established from the perspective of the National Health Service (NHS). A state-transition model of the course of multiple myeloma was constructed using the MRC VI myelomatosis trial results and information on patient management obtained retrospectively from clinical trialists. Data were collected on resource use and corresponding costs for standard management and managing severe hypercalcaemia, vertebral and non-vertebral fractures. Managing patients with prophylactic clodronate cost the NHS a mean 22 934 pound silver per patient; comprising 16 697 pounds silver for standard management, 4862 pound silver for clodronate therapy and 1376 pound silver for adverse events. Managing patients without prophylactic clodronate cost a mean 19 557 pound silver (16 697 pound silver and 2860 pound silver for standard management and adverse events respectively). Therefore prophylactic clodronate therapy increased the cost by 3377 pound silver, or 17% per patient. Hospitalization accounted for 32% of the total cost, whereas chemotherapy accounted for 5%. The results were robust to sensitivity analyses (range 2605 pound silver-4150 pound silver). Further studies are required to assess the impact of prophylactic clodronate on quality of life to enable the clinical benefits and additional cost of this treatment to be compared with other healthcare interventions.
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PMID:Economic impact of using clodronate in the management of patients with multiple myeloma. 1005 Jul 20

Survival for myeloma has improved from a median of 7 months in the 1950s to about 30 months today. Progress in chemotherapy has contributed a great deal to this improvement, although it may also, in part, reflect the improved treatment of infections, renal failure and hypercalcaemia as well as earlier diagnosis. For over 30 years, the gold standard of treatment has been oral melphalan and prednisolone, producing a clinical response in approximately 60% of patients and a median survival of around 36 months. Relapse is unfortunately inevitable in all but a handful and, for the majority, treatment can only hope to produce significant periods of remission with minimal treatment-related morbidity and mortality. Recently, improved results have been seen with the introduction of aggressive chemotherapy and bone-marrow transplantation. Marrow ablative therapies produce remissions in virtually all patients, with complete remissions in approximately 1/3. The best response is seen in those with a lower tumour burden, which will reduce the development of secondary resistance. Current treatment is moving towards an approach using sequential therapy. This involves induction chemotherapy with VAD or a similar regimen such as VAMP (vincristine, adriamycin and methylprednisolone), proceeding to high-dose therapy, often with some form of stem-cell rescue. This ensures minimal tumour burden prior to high-dose treatment as well as reducing graft infiltration, improving general performance status and allowing recovery of renal function. Relapse remains a problem, although the use of IFN may reduce this by prolonging the plateau phase. High-dose therapy should be given early, before prolonged use of alkylating agents induces stem-cell dysplasia, before significant complications arise from the myeloma, and before drug resistance is significant. Unfortunately, these treatments come at a price, in terms of increased treatment-related toxicity. There also remains uncertainty as to the extra benefits of high-dose treatment with marrow rescue over high-dose chemotherapy alone. We await the current MRC trial with interest. For a very few, there is the tantalising possibility of cure with allografting. For those in complete remission after first-line induction therapy, allogeneic bone-marrow transplantation offers the best hope of survival, but comes at a greatly increased risk of toxicity, and it is uncertain if it is superior to autografting for the majority of patients. It may soon be possible to identify those poor prognosis patients in whom an allogeneic transplant should be offered at an early stage. Candidate biochemical markers include serum beta 2 microglobulin, neopterin, IL-6, plasma cell labelling index, CRP or LDH and prognostic clinical features include IgD myeloma or stage III disease at presentation. Many patients will have primary refractory of relapsing disease in whom survival is short despite all current therapeutic modalities. They should therefore be considered for trials of newer agents, drug combinations and therapeutic interventions such as cytokine manipulation or gene therapy. The lack of effective, curative treatment options for patients with myeloma places great importance on effective palliation. While improving survival duration remains elusive in this condition, all possible efforts must be made to ensure quality of life is maximized.
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PMID:Treatment of myeloma. 1020 67

We previously reported the isolation of the novel human DENN gene, which is differentially expressed in normal and neoplastic cells. DENN is identical to MADD (mitogen-activated protein kinase-activating death domain), which interacts with tumor necrosis factor receptor 1 through their death domains. DENN is also homologous to Rab3 GEP, a rat Rab3 GDP/GTP exchange protein. Real-time reverse transcription-polymerase chain reaction analysis showed that DENN expression in cancer cell lines was 26-50 times that in normal cells. The Jurkat human leukemia, PLC/PRF/5 human hepatoma, and NS-1 mouse myeloma cell lines as well as the MRC-5 human fetal lung and Vero monkey kidney cell lines were treated successfully with four separate DENN-targeted antisense oligodeoxynucleotides (ODNs) to abrogate DENN expression. Quantitative assessment of cell viability and apoptosis by flow cytometry via fluorescein diacetate and propidium iodide membrane-integrity tests, terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick end-labeling, and annexin V assays showed that antisense silencing of DENN resulted in markedly more pronounced cell death in cancer cells compared with nonmalignant cells. Antisense-treated cell lines exhibited extensive loss of DNA content, forming distinct sub-G(1) peaks, while cell proliferation diminished significantly. Ultrastructural features of programmed cell death in cells subjected to antisense ODNs were authenticated by electron microscopy. In contrast, transfection of cell lines with a plasmid construct to achieve DENN overexpression augmented cellular proliferation and could reverse the apoptotic effect of antisense and staurosporine treatment. Our findings suggest that DENN is intimately involved in anti-apoptotic and cell-survival processes.
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PMID:Induction of marked apoptosis in mammalian cancer cell lines by antisense DNA treatment to abolish expression of DENN (differentially expressed in normal and neoplastic cells). 1241 May 63

Future therapy options for multiple myeloma may be directed at asymptomatic disease, as only symptomatic myeloma is treated currently. Additional genetic information from gene array analysis will mean that the identification of cases with poor prognosis will become more sophisticated. New markers are being discovered constantly, and these continuously change the picture regarding prognostic factors. More intensive treatment options increase the depth of remissions, thereby improving outcomes. In pilot studies, cyclophosphamide, thalidomide and dexamethasone (CTD) was a highly effective, well-tolerated regimen for patients refractory to initial therapy with VAD or with relapsed disease. It is being further evaluated as induction therapy in the current MRC Myeloma IX trial. Also under investigation is a small molecule derivative of thalidomide, CC-4047 (Actimid). It has between 1,000 and 10,000 times more potent antitumour necrosis factor alpha activity, with an additional immunomodulatory effect. It has been shown to be between 50 and 2,000 times more potent in the stimulation of T-cell proliferation and 50-100 times more potent in augmenting interleukin-2 and interferon-gamma production. With many possible approaches to study and work through, future strategies will revolve around exploration of the effectiveness of combinations that incorporate new agents in various disease and treatment settings. The use of genetic profiles to further delineate groups for different treatment approaches should enable the introduction of patient-specific treatment programmes in the future.
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PMID:Future directions in multiple myeloma treatment. 1616 66

The large MRC/ECOG Adult Acute Lymphoblastic Leukemia Study establishes the value of sibling donor allogeneic transplantation in patients with standard risk, demonstrating superior outcome to conventional chemotherapy. The small but significant number of patients having matched unrelated donor transplantations on this study protocol appear to do well and might establish the value of such an approach for those without a sibling. Reduced-intensity conditioning might begin to address the transplantation-related mortality problems of the older patients. The youngest adults might not need to undergo transplantation at all. If they are now treated on pediatric chemotherapy protocols, their outcome appears to improve significantly.
Clin Lymphoma Myeloma 2009
PMID:Transplantations in adult acute lymphoblastic leukemia--grounds for optimism? 1977 43

Preclinical and clinical evidence suggests that bisphosphonates have anticancer activities both within and outside bone. Early clinical trials of bisphosphonates provided evidence for antimyeloma effects in exploratory analyses in high-risk subsets, and recent trials of zoledronic acid (ZOL) have provided further support of antimyeloma activity The MRC Myeloma IX trial is an innovative 2 x 2 factorial trial comparing ZOL and clodronate (CLO) in patients with newly diagnosed multiple myeloma receiving either intensive or non-intensive therapy regimens. Results showed that ZOL significantly reduced skeletal morbidity and significantly improved both progression-free and overall survival versus CLO. Notably, the survival benefit with ZOL remained significant after adjustment for skeletal-related events, consistent with clinically meaningful antimyeloma activity. Further analyses of these data will provide greater insight into ZOL interactions with primary treatment regimens for multiple myeloma.
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PMID:Can bisphosphonates improve outcomes in patients with newly diagnosed multiple myeloma? 2135 77

Out-of-specification (OOS) results were reported by a contract lab in the in vitro adventitious agent assay (AVA) for two products manufactured using mouse myeloma cells in perfusion bioreactors. Cytopathic effect observed for test article-inoculated MRC-5 monolayers resembled foci seen in tissue culture cells infected with transforming viruses. All reasonable known technologies, including highly sensitive, state-of-the-art methodologies and multiple, redundant, and orthogonal methods, were deployed to screen broadly for potential viral and microbial contaminants. Due to the appearance of apparent foci, testing for murine, bovine, and human polyomavirus contamination was heavily represented in the analytical investigation. The results obtained in this extensive screening provided convincing evidence for the lack of an infectious viral or other biological agent. Although the initial investigation produced no reason to invalidate AVA yielding OOS results or to suspect an assay artifact, an extended evaluation revealed several irregularities at the contract test lab reporting the OOS results. The extended investigation also included attempts to reproduce OOS results at alternate contract testing labs and an inter-laboratory study in which methodological differences in the AVA at the three different contract labs were investigated. Only the contract lab initially reporting the OOS results reported foci during this extended evaluation. The results of the inter-laboratory study suggested that the foci artifact might be attributed to the prolonged exposure of the MRC-5 monolayer to cell debris present in the test article. Confocal immunofluorescence microscopy and transmission electron microscopy were subsequently used to provide convincing evidence that the foci observed in test article-inoculated AVA wells were composed of a core of degraded myeloma cell debris covered by one or more layers of MRC-5 cells. The observation that the foci were detected in the AVA at a contract lab where the MRC-5 monolayer is exposed to production cell line debris for a prolonged period strongly suggests that these foci form when MRC-5 grow over the cell debris present in the test article. The cumulative results of the investigation supported the conclusion that the OOS results were artifacts of the AVA test system and not a result of contamination with a virus or other biological agent. Testing was discontinued at the contract lab generating the OOS results and validated at a second contract lab. Manufacturing resumed in consultation with health authorities. The lots were retested following a standard operating procedure (SOP) already in place and ultimately dispositioned for use in normal distribution channels.
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PMID:Apparent virus contamination in biopharmaceutical product at centocor. 2150 55

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.
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PMID:Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. 2165 83

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease.
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PMID:The Medical Research Council Myeloma IX trial: the impact on treatment paradigms. 2199 38


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