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)

Expression of the lung resistance protein (LRP) is associated with resistance to various anticancer drugs including melphalan and, therefore, may affect the clinical outcome in multiple myeloma (MM). To determine the clinical significance of LRP, we have compared LRP expression in bone marrow plasma cells with clinical parameters including response to chemotherapy and survival of previously untreated patients with MM (n = 72). LRP expression immunocytochemically assessed by means of the LRP-56 monoclonal antibody was positive (> or =10% staining plasma cells) in 44 (61%) samples. There was no correlation between LRP expression and age, sex, type of the paraprotein, serum creatinine, stage, beta2-microglobulin, serum lactate dehydrogenase, or C-reactive protein. However, LRP expression was more frequently observed in patients with a p53 deletion than in those without such a deletion (P = 0.01). The overall response rate for all of the patients evaluable for response to induction chemotherapy (n = 58) was 67%. The response rate was 87% for patients without LRP expression but only 54% for patients with LRP expression (P = 0.01). Kaplan-Meier analysis revealed that patients with LRP expression had a shorter overall survival (median, 33 months) than those without LRP expression (median not reached; P = 0.04). These data show that LRP expression is an important marker for clinical drug resistance and predicts a poor outcome in MM.
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PMID:Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma. 1049 14

We evaluated possible prognostic factors just before salvage therapy with vincristine, doxorubicin, and dexamethasone (VAD) for 36 patients with refractory multiple myeloma. The median duration from diagnosis to the first VAD salvage was 14 months (range 2-76 months). Among parameters that have been shown to be associated with poor survival, a high serum lactate dehydrogenase (LDH) level was the sole significant predictor of survival. The median survival of patients with high LDH levels was 4 months, whereas that of patients with low LDH levels was 20 months. A multivariate analysis identified high LDH and high age as independent prognostic factors. More aggressive therapies might be indicated for high-LDH patients with refractory myeloma.
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PMID:High serum lactate dehydrogenase level predicts short survival after vincristine-doxorubicin-dexamethasone (VAD) salvage for refractory multiple myeloma. 1099 30

We evaluated the effect of eight species of light chains on cultured human kidney proximal tubule cell proliferation. Exposure to light chains for 48 hours caused dose-dependent inhibition in tritium ((3)H)-thymidine incorporation by simian virus 40 immortalized human proximal tubule cells, although the effect was variable among different species of light chains. We studied cytotoxic effects of selected toxic light chains in further detail. Two of these light chains caused significant DNA degradation. A lambda-light chain caused lactate dehydrogenase release from exposed cells at 48 hours, but not at 24 hours. Cytomorphological and electron microscopic examination of cells exposed to light chains for 24 hours showed condensed nuclei, cell detachment, paucity of mitotic activity, and apoptosis, and at 48 hours of exposure, changes consistent with necrosis. Apoptosis assay by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method showed a sixfold increase in the number of apoptotic cells exposed to the same lambda-light chain for 24 hours. Rhodamine-phalloidin staining showed variable but significant disruptions in the actin cytoskeleton. These studies show that some myeloma light chains are toxic to cultured human proximal tubule cells and induce cytoskeletal injury and DNA damage consistent with apoptosis followed by secondary necrosis. Direct proximal tubule cell toxicity may be an important mechanism of renal involvement in multiple myeloma.
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PMID:Cytotoxicity of myeloma light chains in cultured human kidney proximal tubule cells. 1100 75

Aggressive multiple myeloma with high serum lactate dehydrogenase (LDH) often has unusual clinical features and is considered to be a distinct clinical entity of multiple myeloma. A myeloma cell line, designated Maska-98, was established from the bone marrow of a patient with aggressive myeloma with extremely high serum LDH that was resistant to conventional chemotherapy. Maska-98 cells had morphological features of immature plasma cells, and immunophenotypic analysis showed that the cells expressed the plasma cell-associated surface antigens including CD38, 49d, and 56, but no T- or B-cell antigens, such as CD2, 3, 4, 8, 19, and 20. Maska-98 cells contained cytoplasmic immunoglobulin (IgG lambda). By utilizing this cell line we demonstrated that the myeloma cells produce and release a large amount of LDH, since (i) abundant LDH was found in the culture supernatant of Maska-98, (ii) immunocytochemical analysis showed that cytoplasm of the cells was strongly stained with anti-LDH monoclonal antibody, and (iii) Maska-98 cells expressed a greater amount of LDH mRNA than the T-cell line TALL-1, as shown by reverse transcription-polymerase chain reaction. As far as we know, there is no report of a myeloma cell line producing excess LDH. Therefore, Maska-98 would provide a novel source for further studies of the pathogenesis of aggressive multiple myeloma with high serum LDH.
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PMID:Lactate dehydrogenase production and release in a newly established human myeloma cell line. 1127 38

Technetium 99m-2-methoxyisobutylisonitrile (Tc-99m MIBI) is a lipophilic agent that accumulates preferentially within living malignant cells due to the higher transmembrane electrical potential as a consequence of the higher metabolic rate than in the surrounding normal cells. It has been effectively used to detect malignant tumors at diagnosis and follow-up and has been reported to be useful in detecting disease lesions in multiple myeloma. We studied 28 consecutive patients with multiple myeloma at diagnosis to determine the value of Tc-99m MIBI in comparison with Tc-99m methylene diphosphonate (MDP), conventional X-rays, computed tomography (CT) scan, and magnetic resonance imaging (MRI). We found 26 patients with obvious osteolytic lesions in X-rays, 22 patients with positive Tc-99m MIBI scans, and 15 patients with positive Tc-99m MDP scans. There was no coincidence of the positive lesions in the two scans, while in two patients the osteolytic areas were positive in the Tc-99m MDP scans, and in one case the osteolytic area was positive in the Tc-99m MIBI scan. The intensity of Tc-99m MIBI scans correlated with disease activity as determined by lactate dehydrogenase (LDH) (p<0.05), C-reactive protein (CRP) (p<0.01), beta2-microglobulin (p<0.05), and serum ferritin (p<0.01). We believe that Tc-99m MIBI scintigraphy can detect bone marrow lesions in myeloma patients that cannot be detected by other imaging methods and that it can be useful especially in solitary myeloma to exclude other involved sites. In addition, it could be a prognostic factor related to disease activity and multidrug resistance. We believe that a multicenter study is needed to evaluate the usefulness of this agent.
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PMID:Value of Tc-99m sestamibi scintigraphy in the detection of bone lesions in multiple myeloma: comparison with Tc-99m methylene diphosphonate. 1147 49

Primary plasma cell leukemia (PPCL) is a rare form of disease accounting for 1-2 percent of myelomas. Between September 1990 and November 2000, among 540 patients with myeloma studied, 24 fulfilled the criteria of PPCL (4.4 percent). We found high frequencies of female patients (62 percent), Bence Jones proteinuria (79 percent), anemia (88 percent), bleeding (54 percent), confusional syndrome (42 percent), weight loss (71 percent), hepatomegaly (25 percent), splenomegaly (21 percent), leukocytosis (62 percent), and thrombocytopenia (71 percent). High serum levels of creatinine, calcium, lactate dehydrogenase (LDH), and beta(2)-microglobulin were detected in 50 percent, 37 percent, 58 percent, and 71 percent, respectively. Four patients were treated with vincristine, melphalan, cyclophosphamide, prednisone, and adriamycin (VMCPA), 12 with vincristine, adriamycin, and dexamethasone (VAD), and 8 with M-80 (oral melphalan 80 mg/m(2) plus dexamethasone 40 mg/m(2)). There was a trend toward lower values of Karnofsky score (P=0.07) and higher values of LDH (P=0.2) in the VAD group. Other clinical characteristics were comparable among the three groups. Complete plus partial responses were achieved in one and six patients treated with VMCPA and M-80, respectively. All patients treated with VAD failed to respond to treatment. Patients receiving the M-80 regimen experienced higher platelet toxicity (P=0.05), vomiting (P<0.0003), and mucositis. Also, the need for red blood cell transfusions was higher in the M-80 group. Median overall survival was 60 days. Overall survival was better in patients achieving complete or partial response. In conclusion, our study illustrates that intermediate doses of melphalan plus dexamethasone are an effective chemotherapy regimen for this aggressive disease. Response to treatment is the only prognostic factor for survival in these patients.
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PMID:Intermediate doses of melphalan and dexamethasone are better than vincristine, adriamycin, and dexamethasone (VAD) and polychemotherapy for the treatment of primary plasma cell leukemia. 1218 4

Tumor necrosis factor-alpha (TNF-alpha) is important for function, differentiation, and transformation of B-lymphocytes in multiple myeloma (MM) but can also induce apoptosis of myeloma cells. Based on this opposite effect, it is very crucial to analyze the correlation of the serum level of TNF-alpha with clinical parameters of the patients. In this article, we analyzed 18 MM patients, 48% male and 52% female, with a mean age of 52 yr (range: 35-81 yr), clinical stage I in 21.4%, stage II in 26.4%, and stage III in 52.2% of patients. Patients with advanced clinical stage, presence of osteolysis, and elevated lactate dehydrogenase (LDH) had a significant difference (Mann-Whitney U-test, p < 0.05) in the serum level of TNF-alpha in comparison with those in the early stage, without osteolysis, and normal LDH. The correlation of individual values of TNF-alpha with the percentage of plasma cells in the bone marrow, LDH, beta2-microglobulin, fibrinogen, and sedimentation rate was significant (p < 0.05). However, we have not found a significant correlation between TNF-alpha and concentration of hemoglobin, the number of white blood cells or platelets (p > 0.05). We concluded that our data indicate determination of TNF-alpha as a good parameter for estimation of tumor mass presence, among individual patients with MM, and may by used for monitoring during application of different therapy protocols.
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PMID:Correlation of sera TNF-alpha with percentage of bone marrow plasma cells, LDH, beta2-microglobulin, and clinical stage in multiple myeloma. 1248 23

The principle of alkylating agent dose intensity, especially with melphalan-based tandem autotransplants, has been effective in increasing the rate of complete remission beyond 40% and effecting 10-year survivorship in about 40% of the three fourths of patients presenting without cytogenetic abnormalities (Total Therapy I). Further dose escalation and post-transplant consolidation therapy, as practiced with Total Therapy II, seems to further improve results in these patients, but not in those with chromosome 13 abnormalities or lactate dehydrogenase elevation. Phase III trials for post-transplant relapse indicate higher complete remission and near-complete remission rates among patients randomized to thalidomide added to dexamethasone versus dexamethasone alone. In a phase I/II study, thalidomide derivative CC-5013, with less sedative and neurotoxic effects, promoted responses in eight of 15 patients with post-transplant relapse, refractory to other salvage therapies, at dose levels of > or = 25 mg daily. Based on a profound graft-vs-myeloma effect with allografts, mini-allotransplants were evaluated in 31 high-risk patients with cytogenetic abnormalities and prior autotransplants; all nine with responsive disease and only one prior autotransplant remain disease-free and alive. Such mini-allotransplants are now offered as consolidation after one standard autotransplant to patients with cytogenetic abnormalities. The systematic application of gene expression profiling attempts to classify multiple myeloma (MM) patients according to molecular features and to dissect the genetic basis for drug sensitivity or resistance. Given the availability of an expanding treatment armamentarium (eg, thalidomide, CC-5013, the proteasome inhibitor PS-341, farnesyltransferase inhibitors, IL-6 receptor antibody, endothelial receptor inhibitor), gene expression profiling is anticipated to help in the selection of agents with the greatest probability of activity toward individualized treatment. Careful scrutiny of gene expression will also help in the identification of unrecognized targets for therapeutic intervention.
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PMID:High-dose therapy and immunomodulatory drugs in multiple myeloma. 1252 Apr 82

Relapsed or refractory multiple myeloma has a poor outlook. Some patients respond to thalidomide; however, criteria for predicting response have not been conclusively identified. We initiated a prospective multicenter phase 2 trial in patients with relapsed/refractory myeloma using thalidomide up to the maximum dose, 800 mg/d. Interferon-alpha-2B (1.5-3.0 x 10(6) U, subcutaneously, 3 times per week) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide with or without interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), and overall survival (OS) and to elucidate relevant prognostic factors. We enrolled 75 patients, with median age 64 years (range, 36-83 years). Median individual maximum-tolerated dose of thalidomide was 600 mg/d; 41% reached 800 mg/d. Overall RR was 28%, and 55% stable disease (SD). The only predictor for response was age 65 years or younger (38% versus 17%; P =.043). At 18 months median follow-up, the actuarial median PFS and OS were 5.5 and 14.6 months, respectively. Multivariate analysis for OS demonstrated age exceeding 65 years (median, 9.2 months versus longer than 26 months; P =.011), raised serum lactate dehydrogenase (P =.002), and raised serum creatinine (P =.007) predicted inferior outcomes. Nineteen patients received interferon. Ten discontinued owing to toxicity. Four of 12 patients who received interferon for longer than 4 weeks were converted from SD to partial response. Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for such patients.
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PMID:Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. 1263 29

Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone marrow stromal cells through an interaction between adhesion molecules present on myeloma plasma cells and their respective receptors that are present on bone marrow stromal cells. In addition, control over production of IL-6 may be exerted by other ILs such as IL-1beta and IL-10. Among target cells, the growth of normal and myeloma plasma cells is supported by IL-6, which also induces the differentiation of myeloma plasmablastic cells into mature plasma cells. This last action also is shared by IL-3, IL-4, and, most likely, IL-8. Evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor (sIL-6R), and soluble IL-2 receptor (sIL-2R), together with the activity exerted by IL-3 and IL-4 on some cellular subsets, may constitute an additional element in the differential diagnosis of borderline cases. However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high beta(2) microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity. Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to beta(2) microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.
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PMID:A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. 1273 43


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