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)

Standard chemotherapy with melphalan-prednisone or a combination of alkylating agents has not extended the overall survival of patients with multiple myeloma during the last 30 years and strictly defined complete remissions (CR) are exceedingly rare. The early mortality with conventional therapy varies between 2 and 10 percent. A substantial increase in the dose of melphalan (100-140 mg/m2) has resulted in a 30-45% CR rate in newly diagnosed patients and an overall survival advantage of approximately 1 year. However, treatment related morbidity and mortality, due to prolonged cytopenia was unacceptably high. Based on these findings the dose intensity was further increased by either escalating melphalan to 200 mg/m2 or by adding total body irradiation, while at the same time providing stem cell support to shorten the duration of cytopenia. Autologous transplants, especially with peripheral blood stem cells and hematopoietic growth factors, can now be performed safely up to the age of 70 with a low transplant-related mortality (2-10%). A CR is attained in approximately 50% of previously untreated patients and 10-20% of refractory cases. Overall survival of newly diagnosed and refractory patients treated with autotransplants appears superior to that of patients receiving conventional chemotherapy. Therefore, autotransplantation should be considered as a treatment option in all patients with multiple myeloma at least up to the age of 65. Despite these encouraging findings, most myeloma patients ultimately relapse and the survival curves do not suggest that autotransplantation as currently performed is a curative approach in a substantial proportion of patients. Further improvement with autotransplants should be achieved by providing tumor-free grafts and by introducing post-transplantation manipulations, aimed at eradicating minimal residual disease.
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PMID:Hematopoietic stem cell transplants for multiple myeloma. 872 25

It was the aim of this study to examine the prognostic value of the detection of minimal residual disease (MRD), with the help of the polymerase chain reaction (PCR), in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) who underwent sequential high-dose therapy with peripheral blood progenitor cell (PBPC) support, and in patients with acute myeloid leukemia (AML) of the subclass M4Eo who underwent high-dose consolidation therapy. Basis for the application of a PCR assay in these disease entities are the following specific gene rearrangements: the t(14;18) translocation in a high percentage of NHL, the clonal rearrangement of the Ig heavy chain locus resulting in a unique complementary determining region 3 (CDR3) for MM region and the inversion 16 characteristic for the M4Eo subclass of AML. Before the G-CSF-supported cytotoxic chemotherapy was given, 65% of the 52 patients with low- and intermediate-grade NHL enrolled into the study had PCR+ bone marrow (BM) and/or peripheral blood (PB) samples. The majority of patients (29 of 52) were autografted with a PCR+ transplant. The proportion of harvests containing t(14;18)+ cells was two-fold less in patients mobilized in first remission than in those with a history of previous treatment failure. This was also reflected when examining the B cell contents of the harvests measured as CD19+ cells with a 3.3-fold smaller proportion of CD19+ cells in leukapheresis (LP) products of patients mobilized in first remission. Patients who received a PCR- transplant are in remission and remained PCR- in BM and PB samples post-transplantation. Conversion to PCR-negativity in BM and PB samples post-transplantation was observed in 11 of 19 patients who were also in remission. In contrast, 6 of 29 patients who were autografted with PCR+ products relapsed, while 4 of them presented with PCR- samples on several occasions post-transplantation. In patients with MM, the assessment of MRD in PBPC harvests was based on the CDR3 regions of the Ig heavy chain locus as a marker for clonality. The great majority of LP products (17 out of 19) contained tumor cells. To prove positive enrichment procedures for the elimination of tumor cells, CD34+ and CD19+ cell fractions obtained from LP samples in an experimental setting via preparative flow cytometry were analyzed for MRD resulting in PCR-negativity for all CD34+ fractions. The results of the four patients with AML M4Eo and inversion 16 are preliminary, with a tendency of persistence of PCR-positivity after finishing the high-dose consolidation therapy. In one case, recurrence of disease was accompanied by an increase of the signal strength in the PCR assay. Longer follow-up periods are necessary to determine the prognostic value of these PCR findings in the different disease entities.
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PMID:Detection of minimal residual disease by polymerase chain reaction in B cell malignancies. 874 88

A new era of multiple myeloma management includes new approaches such as genetic marking and gene therapy, immunotherapy, stimulation of graft versus myeloma effect, etc. Intensive clinical research is also focused on the detection of minimal residual disease and bone marrow purging. Clinical trials have begun and the first results are promising, though preliminary. The combinations of new types of therapeutical approaches with the most efficient regimens used until now could form a new type of MM management strategy that better involves minimal residual disease.
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PMID:[Treatment of multiple myeloma]. 876 95

A new era of multiple myeloma (MM) management includes new approaches such as genetic marking and gene therapy, immunotherapy, stimulation of graft versus myeloma effect, etc. Intensive clinical research is also focused on the detection of minimal residual disease and bone marrow purging. Autoregulatory loop of myeloma cells and detection of genes responsible for pathological transformation of B-line cells is of great research interest. Clinical trials have begun and the first results are promising, though preliminary. The safety of the patients and the public must be major concern of all investigators. The combinations of new types of therapeutical approaches with the most efficient regimens used until now could form a new type of MM management strategy that better involves minimal residual disease.
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PMID:New approaches to management of multiple myeloma. 879 82

During the last decade, the availability of large numbers of cytokines and growth factors has greatly favoured the use of biotherapies in several haematological disease. For MM, the majority of clinical studies have dealt with the use of IFN-alpha. From these studies it appears that IFN-alpha has a definite role in the treatment of MM especially in the setting of minimal residual disease, as maintenance therapy after response to conventional therapies or HDC followed by BMT procedures or PBSCI. Data on the use of EPO have consistently demonstrated the role of this growth factor in ameliorating the grade of anaemia as well as the quality of life of those MM patients whose disease is complicated by the presence of a severe or moderate anemia. Despite the large amount of experimental data indicating a role for IL-2 and IL-6 in controlling tumour growth, there are only a few clinical studies dealing with their use in MM. From these, it appears that IL-2 and anti-IL-6 antibodies should be further investigated as therapeutic tools useful in maintaining responses, because results show that they arrest tumour progression rather than aid, tumour regression. Finally, in the next years, there will be a wider diffusion of biotherapies in MM that should take into account the roles that IL-1 beta and TNF alpha play in myeloma cell proliferation and bone destruction and the finding that retinoic acid is capable of inhibiting the growth of human myeloma cells in vitro through modulation of IL-6 and its receptor.
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PMID:The role of biotherapies (interleukins, interferons and erythropoietin) in multiple myeloma. 884 74

High-dose chemo-radiotherapy with autologous stem cell transplantation (ASCT) has introduced the concept of complete remission for multiple myeloma, and can improve survival and life quality for selected groups of myeloma patients. A number of prognostic factors have been identified, where ASCT in early disease, i.e. as part of front-line treatment, seems to be of particular importance for a favourable outcome. Even so, most myeloma patients will not be cured by high-dose therapy, but new strategies such as repeated autografting and post-graft alpha-interferon maintenance treatment seem to add additional advantages with respect to survival and freedom of disease progression. The technical development has enabled efficient in vitro myeloma cell depletion of the autograft as well as highly sensitive detection of minimal residual disease after treatment, but the clinical significance of these issues remains to be determined, and this question is addressed in ongoing gene marking studies. The application of novel therapeutic principles, e.g. gene therapy and immunotherapy, might further ameliorate the outcome for patients with multiple myeloma.
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PMID:Multiple myeloma, high-dose treatment and autologous stem cell transplantation--current status. 886 36

In this article, we review neoplastic contamination in the peripheral blood (PB) of patients with multiple myeloma (MM) upon stem cell mobilization. We first evaluated PB samples from pretreated MM patients following administration of high-dose cyclophosphamide (Cy, 7 g/m2 or 4 g/m2) and granulocyte colony-stimulating factor (G-CSF) for the presence of myeloma cells as well as hematopoietic progenitors. Plasma cells containing intracytoplasmic immunoglobulin (cIg) were counted by immunofluorescence microscopy after incubation with appropriate antisera against light and heavy chain Ig. Flow cytometry studies were performed to determine the presence of malignant B lineage elements, using monoclonal antibodies against the CD19 antigen and the monotypic light chain. Prior to PBSC mobilization, circulating plasma cells were detected in all MM patients at 0.1%-1.8% of the mononuclear cell (MNC) fraction (mean value 0.7 +/- 0.4% SD). In these patients, a higher absolute number of PB neoplastic cells was detected after administration of chemotherapy and G-CSF. Kinetic analysis showed a pattern of tumor cell mobilization similar to that of normal hematopoietic progenitors, with the peak coinciding with the optimal period for the collection of PBSC. The absolute number of plasma cells showed a 10-50-fold increase over the baseline value. Apheresis products contained 0.7 +/- 0.2% SD myeloma cells (range 0.2%-2.7%), which demonstrated the capacity of plasma cells to proliferate, differentiate, and mature in response to c-kit ligand (SCF), IL-3, IL-6, and a combination of IL-3 and IL-6. Subsequently, in an attempt to reduce tumor cell contamination prior to autologous transplantation, circulating hematopoietic CD34+ cells were highly enriched by avidin-biotin immunoabsorption, cryopreserved, and used to reconstitute bone marrow (BM) function after myeloablative therapy in 13 patients. The median purity of the enriched CD34+ cell population was 89.5% (range 51%-94%), with a 75-fold enrichment compared with the pretreatment samples. The median overall recovery of CD34+ cells and CFU-GM was 58% (range 33%-95%) and 45% (range 7%-100%), respectively. Positive selection of CD34+ cells resulted in 2.5-3 log depletion of plasma cells and CD 19+ B lineage cells as determined by immunofluorescence studies, although DNA analysis of the CDR III region of the IgH gene demonstrated the persistence of minimal residual disease (MRD) in 5 of 6 patient samples studied. Myeloma patients were reinfused with enriched CD34+ cells after myeloablative therapy consisting of total body irradiation (TBI, 1000 cGy) and high-dose melphalan (140 mg/m2) or melphalan (200 mg/m2) alone. They received a median of 5 x 10(6) CD34+ cells/kg and showed a rapid reconstitution of hematopoiesis. The median time to 0.5 x 10(9) neutrophils, 20 x 10(9) and 50 x 10(9) platelets/L of PB was 10, 11, and 12 days, respectively. These results, as well as other clinically significant parameters, did not significantly differ from those of patients (n = 13) receiving unmanipulated PBSC following the same pretransplant conditioning regimen. Our data demonstrate the concomitant mobilization of tumor cells and hematopoietic progenitors in the PB of MM patients. Positive selection of CD34+ cells reduces the contamination of myeloma cells from the apheresis products up to 3 log and provides a cell suspension capable of restoring normal hematopoiesis following a TBI-containing conditioning regimen.
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PMID:Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of patients with multiple myeloma. 887 9

The surface expression of CD117 on plasma cells (PCs) from normal individuals and patients with multiple myeloma (MM) has been analysed using triple-stained cells for flow cytometry. In addition, the clinical significance of CD117 expression in MM patients and its possible value for the evaluation of minimal residual disease was explored. A total of 11 healthy volunteers and 56 untreated MM patients were included in the study. The expression of CD117 was analysed by flow cytometry, using simultaneous staining with the MAbs BB4, CD117 and CD38. Cell acquisition was performed in two consecutive steps using a live gate drawn on SSC/CD38 cells and a total of 300,000 events were acquired. For data analysis, the Paint-a-Gate Plus software (Becton Dickinson) was used. PCs were identified according to their strong reactivity for CD38 and their positivity for BB4, as well as by their light scatter distribution. Dilution experiments of CD117+ myelomatous PCs with normal bone marrow (BM) cells were performed in order to assess the sensitivity level of the technique for detection of CD117+ residual PCs. None of the PCs from normal BM samples showed reactivity for the CD117 antigen. In contrast, CD117 antigen was present in 18/56 MM patients (32%), the proportion of positive cells in these cases being as high as 92.1 +/- 9%. Therefore, within PC lineage the c-Kit antigen would be restricted to the myelomatous population and thus could be considered as a 'tumour-associated marker' for monitoring minimal residual disease in about one third of MM patients. Dilution experiments indicate that the detection limit with this marker would be 10(-4) (one myelomatous PC/10(4) normal BM cells). Upon comparing the clinical and haematological disease characteristics of CD117-positive and CD117-negative cases, no significant differences were found.
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PMID:Expression of the CD117 antigen (c-Kit) on normal and myelomatous plasma cells. 894 89

The importance of minimal residual disease detection has increased due to the advanced therapeutic protocols available for multiple myeloma and acute leukaemia. High-dose chemotherapy, followed by stem cell transplantation is often used in patients with multiple myeloma. But despite a longer disease-free period and overall survival, all patients relapse. In the treatment of acute leukaemia, there are similar problems. The present strategy is to give continuous chemotherapy to eradicate minimal residual disease. In this review, we consider the methods used to detect and quantify minimal residual disease. At present, the most effective seem to be those based on the use of polymerase chain reactions to detect the malignant cells.
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PMID:Detection of minimal residual disease in multiple myeloma and acute leukaemia. 901 76

The success of autologous stem cell transplantation (ASCT) for hematologic malignancy is limited largely by a high relapse rate. It is postulated that IL-2 administered after ASCT may eliminate minimal residual disease and thereby reduce relapses. A phase I/II study was performed to identify a regimen of IL-2 (Chiron) that could be given early after ASCT in phase III trials. In the phase I study, beginning a median of 46 days after ASCT for hematologic malignancy, cohorts of three to four patients received escalating doses of 'induction' IL-2 of 9, 10, or 12 x 10(6) IU/m2/day for 4 or 5 days by continuous i.v. infusion (CIV), followed by a 4-day rest period, and then 1.6 x 10(6) IU/m2/day of maintenance IL-2 by CIV for 10 days. The maximum tolerated dose (MTD) of induction IL-2 was 9 x 10(6) IU/m2/day x 4. In the phase II study, 52 patients received the MTD. Eighty percent of patients completed induction IL-2. Most patients exhibited some degree of capillary leak. One patient died of CMV pneumonia and one died of ARDS. Maintenance IL-2 was well tolerated. In the phase I/II study, 16 of 31 patients with non-Hodgkin lymphoma (NHL), 3/8 with Hodgkin disease (HD), 4/17 with AML, and 4/5 with ALL remain in CR. Two of six multiple myeloma (MM) patients remain in PR. Although the regimen of IL-2 identified had significant side-effects in some patients, it was well tolerated in the majority of patients. Phase III prospectively randomized clinical trials are in progress to determine if this IL-2 regimen will decrease the relapse rate after ASCT for AML and NHL.
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PMID:Interleukin-2 after autologous stem cell transplantation for hematologic malignancy: a phase I/II study. 905 8


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