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)

Bisphosphonates are potent inhibitors of osteoclastic activity and reduce the disease-related skeletal complications when they are used in combination with chemotherapy in patients with multiple myeloma (MM). Pamidronate also inhibits apoptosis of primary osteoblastic cells and probably induces apoptosis on human MM cells and osteoclasts. It has been reported that interferon-alpha (IFN-alpha) decreases bone resorption and that low doses of IFN-alpha result in a significant increase in serum osteocalcin (OSC). The aim of this study was to determine the effects of pamidronate treatment on biochemical markers of bone resorption [cross-linked N-telopeptides of type I collagen (NTx)], bone formation [bone alkaline phosphatase (BAP) and OSC], disease activity [beta2-microglobulin, CRP, paraprotein], and interleukin-6 (IL-6) in patients with MM in plateau phase under IFN-alpha maintenance. The above parameters were evaluated in 28 patients (13 M, 15 F, median age 70 years) during maintenance treatment, before the addition of pamidronate and after 1, 3, 6, 9, 12, and 14 months of the combined therapy. The addition of pamidronate to maintenance treatment resulted in a significant reduction of NTx, IL-6, beta2-microglobulin, CRP from the 3rd month and paraprotein from the 6th month of treatment, whereas BAP and OSC were significantly increased from the 6th month. These changes continued during the 14-month follow-up of the combined treatment. Multivariate analysis showed a significant negative correlation between changes of BAP and OSC and the patients' age. The greater increase of the bone formation markers was observed in younger patients. These results suggest that, in addition to the inhibition of osteoclastic activity, pamidronate in combination with IFN-alpha was shown to induce bone formation in patients with MM in the plateau phase.
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PMID:Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment. 1168 35

Treatment options for patients with myeloma who relapse after allogeneic stem cell transplantation are limited. Thalidomide, an antineoplastic agent, has been shown to be effective in multiple myeloma through proposed mechanisms that may include angiogenesis inhibition. Herein we report successful thalidomide treatment of four patients who relapsed following allogeneic transplantation, three of whom had predominantly extramedullary relapse. Thalidomide was well tolerated in all patients; in two patients interferon-alpha was subsequently added to thalidomide as maintenance therapy without worsening graft-versus-host disease. We suggest that extramedullary myeloma is particularly sensitive to thalidomide, speculating that growth biology may in part be dependent on angiogenesis.
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PMID:Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation. 1180 57

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal expansion of malignant plasma cells within the bone marrow. It accounts for 10% of all haematological malignant diseases and 1% of all malignancies. The median age of patients at the time of the diagnosis is 70 years. The characteristic clinical features of MM are bone marrow failure, susceptibility to infections, bone pain, pathological bone fractures, hypercalcaemia, and renal failure. Though MM is currently incurable, the important progress in chemotherapy has resulted in an improvement in survival from a median of 7 months in the 1950-ies to about 3 years today. Advances in the diagnosis and in supportive treatment of infections, hypercalcaemia, and renal failure also contributed to the prolongation of survival. For decades, the gold standard of treatment had been oral melphalan alone or in combination with prednisolone. Combination chemotherapy has not improved overall survival (OS), but these regimens have led to the prolongation of event-free survival (EFS) and also to a better quality of life. High-dose chemotherapy with haemopoietic stem cell rescue resulted in a great improvement in EFS as well as OS. For those very few who have an HLA-compatible donor and are under 55, allogeneic bone marrow transplantation offers the best hope of survival but comes at a greatly increased risk of toxicity. There are conflicting data in the literature concerning the role of interferon-alpha; it seems to be able to prolong the duration of the plateau phase. Current treatment is moving towards an approach using sequential therapy. This involves induction therapy proceeding to high-dose chemotherapy with some form of stem-cell rescue. Bisphosphonates reduce hypercalcaemia, bone pain and can inhibit bone destruction. They also possess a direct antitumor activity. The better understanding of the pathomechanism of the disease gives the opportunity of the application of new therapeutic modalities such as antagonising the effect of interleukin-6 (IL-6), or idiotypic vaccination.
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PMID:[Therapy of multiple myeloma] 1205 Jul 24

Multiple myeloma (MM) is an incurable plasma cell dyscrasia that remains fatal. Despite efforts over the past 3 to 4 decades, the median survival of patients with MM does not exceed 3 to 4 years. Although patients receiving combination chemotherapy have higher response rates compared with those receiving oral melphalan and prednisolone, they have no survival advantage. High-dose chemotherapy followed by autologous stem cell transplantation has documented benefit over conventional treatment and is currently the accepted mode of treatment for symptomatic MM. Allogeneic transplantation is associated with high complete remission rates, but at the cost of high therapy-related mortality. Maintenance treatment with interferon-alpha shows benefit, albeit in a small fraction of MM patients. The use of bisphosphonates in patients with MM has clearly demonstrated benefit and reduced morbidity associated with bone disease. All of these measures have improved remission rates and survival, but all patients with MM ultimately relapse and succumb to their disease. Novel therapeutic strategies are therefore required to improve outcome of MM patients. The responses noted to thalidomide in MM are encouraging. Immune-based strategies, including both adoptive immunotherapy and vaccinations, are currently being investigated in the preclinical and clinical setting, with the goal of enhancing autologous and allogeneic anti-MM immunity for therapeutic applications.
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PMID:Multiple myeloma. 1205 63

Bisphosphonates (BPs) are effective in the management of bone disease in patients with multiple myeloma. Recent reports have suggested that they may also have an antitumor activity. YM529 is a new synthetic BP with more than 1000 times the bone resorption inhibitory activity of pamidronate. To clarify the direct effects of YM529 on myeloma cells, the cell proliferation and cell cycle perturbation were analyzed using 12 myeloma cell lines established in our laboratory. The growth inhibition was dose dependent. The cells accumulated in [2n<<4n] of the cell cycle and subsequently formed an apoptotic sub-G1 fraction. Combined treatment with all-trans retinoic acid, thalidomide, or interferon-alpha enhanced the growth inhibitory effects of YM529 on these cells. However, there were no remarkable effects of YM529 on the messenger RNA expression for angiogenic factors, cell cycle regulators, or cytokines related to myeloma cells. These results indicate that YM529 is beneficial not only to bone lesions but also for its direct antitumor effects on myeloma cells.
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PMID:Synergistic growth inhibition of YM529 with biologic response modifiers (BRMs) in myeloma cells. 1209 56

Circulating monocytes from multiple myeloma patients enrolled in a clinical study of anti-idiotype vaccination were labelled with clinical-grade anti-CD14 microbeads and positively selected with the CliniMACS instrument. Cells were then grown, according to good manufacturing practice guidelines, in fetal-calf-serum-free medium in cell culture bags and differentiated to dendritic cells (DC) with granulocyte-macrophage colony stimulating factor plus interleukin 4 (IL-4), followed by either tumour necrosis factor-alpha (TNF-alpha) or a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. The CD14+ cell yield was increased from 17.6 +/- 6.5% to 93.8 +/- 6.3% (recovery 64.4 +/- 15.4%, viability > 97%). After cell culture, phenotypic analysis showed that 86.7 +/- 6.8% of the cells were DC: 2.27 +/- 0.9 x 108 DC/leukapheresis were obtained, which represented 20.7 +/- 4.6% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (28.6 +/- 3% of initial CD14+ cells) of DC than TNF-alpha alone, with secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic T cells and efficient presentation of tumour idiotype to autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of preloaded DC. The recovery of thawed, viable DC was 78 +/- 10%. Finally, interferon-alpha-2b was at least as efficient as IL-4 in inducing the differentiation of mature, functional DC from monocytes.
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PMID:Generation of dendritic cells from CD14+ monocytes positively selected by immunomagnetic adsorption for multiple myeloma patients enrolled in a clinical trial of anti-idiotype vaccination. 1269 45

We have previously demonstrated that the responsiveness of multiple myeloma (MM) cells to interferon-alpha (IFN-alpha) stimulation is variable, with an atypical growth response displayed by some cells. Here we report the ability of IFN-alpha to induce tyrosine phosphorylation of a 180 kDa band in the KAS-6/1 MM cell line, which is growth responsive to IFN-alpha. Further characterization demonstrated that this band corresponds to ErbB3. To our knowledge, this is the first report of ErbB3 expression in a cell type of the hematopoietic lineage. Although ErbB receptors have been shown to crosscommunicate with various other receptors, our results show for the first time that the IFN-alpha receptor can crosscommunicate with ErbB3. To address the significance of these observations, we transfected ErbB3-negative DP-6 MM cells with ErbB3 and used siRNA to silence ErbB3 in the KAS-6/1 cell line. Although IFN-alpha transactivated ErbB3 in the DP-6 transfectants, it did not confer growth responsiveness to IFN-alpha. Interestingly, silencing ErbB3 expression in the KAS-6/1 cells decreased the overall growth response to IFN-alpha and to interleukin-6. These results suggest that ErbB3 expression alone does not uniquely confer IFN-alpha growth responsiveness, but instead may amplify proliferation rates in MM cells that have acquired atypical expression of this receptor.
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PMID:Atypical expression of ErbB3 in myeloma cells: cross-talk between ErbB3 and the interferon-alpha signaling complex. 1278 68

Cyclophosphamide, interferon-alpha and betamethasone are all effective agents for the treatment of multiple myeloma (MM) with different mechanisms of action. The clinical effect of a combination of cyclophosphamide 725 mg/m(2) i.v. days 1 and 3, interferon-alpha 7 x 10(6) IE/m(2) s.c./day, days 1-4 and betamethasone 30 mg orally days 1-4 (CIB) was studied in patients aged 60-75 years with previously untreated MM stages II and III. Granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 microg/kg/day s.c. was administered to all patients from day 5 until the day the granulocyte count exceeded 1.0 x 10(9)/l. CIB was repeated every fourth week. Interferon-alpha 3 x 10(6) IE s.c. t.i.w. was given as maintenance therapy in responding patients.A total of 28 patients (median age: 67 years) entered the study. In all, 12 patients had stage II and 16 had stage III MM. A total of 22 patients (79%) showed an objective response, including five complete remissions (CR) and 17 partial remissions (PR). All seven patients with Bence-Jones MM responded (five CR and two PR). The median response duration time was 14 months (range 5-38+). CIB was relatively well tolerated although febrile neutropenia or septicaemia occurred in 5% of the cycles and a dose-reduction of cyclophosphamide due to grade IV neutropenia was performed in 11% of the patients.CIB seems to be an effective regimen for remission induction in MM patients aged up to 75 years as an alternative to VAD (vincristine, doxorubicin, dexamethasone) if a regimen with intensity higher than that of oral melphalan/prednisone is warranted.
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PMID:Phase II study of cyclophosphamide, interferon-alpha and betamethasone (CIB) as induction therapy for patients 60-75 years of age with multiple myeloma stages II and III. 1287 49

The development of various kinds of autoimmune disease as a result of interferon-alpha (IFN-alpha) therapy has been reported among chronic myeloproliferative disorders(CMPD) including chronic myeloid leukemia(CML). Therefore, we investigated the frequency of autoimmune disorders in 33 patients with hematopoietic diseases treated with IFN-alpha in our department. Thirty-three patients (12 females, 21 males) included cases of CML (n = 23), essential thrombocythemia (ET) (n = 1), multiple myeloma (n = 8), and hypereosinophilic syndrome (HES) (n = 1). Autoantibodies (ANA, dsDNA, and RAPA), thyroid grand functions, and coagulant functions were examined. Twenty-five out of 33 patients were treated with natural IFN-alpha, and 8 patients were treated with recombinant IFN-alpha 2b (rIFN alpha-2b). Three patients were treated with IFN and anticancer agents. Antinuclear antibodies were detected in 2 of 33 patients. RAPA and anti-thyroglobulin antibody became positive in 3 and 4 patients, respectively. Ten patients showed low serum levels of either free T3 and/or free T4. However, none of them showed any clinical symptoms for developing autoimmune diseases. In addition, circulating anticoagulant antibodies were detected in 3 of 23 patients with CML treated with rIFN alpha-2b, but in no cases treated with natural IFN-alpha. Although none of the patients developed autoimmune diseases, we concluded that patients receiving IFN therapy should be carefully monitored for clinical signs and symptoms of autoimmune disorders.
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PMID:[Autoimmune phenomena during interferon-alpha therapy for hematopoietic disorders]. 1465 Sep 58

We report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)-interferon-alpha 2b (IFN-alpha 2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN-alpha 2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P=0.81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.74-1.33, P=0.97] and overall survival (median: 34 months vs. 37 months; HR: 1.16, 95% CI: 0.85-1.59, P=0.35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2-4) was the predominant risk factor for poor survival followed by age >65 years, high beta2-microglobulin, and impaired renal function. There was more grades 3-4 dyspnoea and cardiac impairment and grades 1-2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP-IFN-alpha 2b did not improve outcome.
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PMID:Continuous prednisolone versus conventional prednisolone with VMCP-interferon-alpha2b as first-line chemotherapy in elderly patients with multiple myeloma. 1622 52


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