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)

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor-risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4-21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.
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PMID:Timed sequential chemotherapy of cytoxan-refractory multiple myeloma with cytoxan and adriamycin based on induced tumor proliferation. 700 9

The current status of treatment for multiple myeloma was reviewed. Recently, the response rate and survival for patients with multiple myeloma have improved with an introduction of combination chemotherapy. The addition of prednisolone to the regimen including alkylating agents clearly improved a response rate by 20% and extended survival by approximately 5 months. More recently, the use of multiple-drug combinations, such as VMCP and VMCBP schedules, seems to yield the best response rate. However, current improvements in survival of myeloma patients cannot be attributed fully to improved chemotherapy on the basis of the findings that the annual incidence and the number of patients with low tumor burden increase progressively, and the patients in the early stage of the disease have a high value for the incidence of long survival. Furthermore, earlier diagnosis, a low frequency of severe renal failure, and superior control of infections may likely influence the duration of survival. In order to cure the malignant tumor disease, it is necessary to eradicate every viable tumor cell in the host. Unfortunately, the most recently utilized combination chemotherapy has shown little evidence of permanent cure of multiple myeloma, even in patients with low tumor burden, i.e., effective treatment with currently available agents causes only an initial 1-2 log fall in the total body myeloma cell mass and an additional treatment does not reduce the residual tumor cell mass. Therefore, further studies of new drugs with major activity against plasma cell myeloma are expected.
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PMID:[Current status of treatment for multiple myeloma]. 718 81

A major potential problem of autologous transplantation in the treatment of advanced malignancy is the infusion of tumor cells. A multi-institutional study of purified CD34-selected peripheral blood progenitor cell (PBPC) transplantation was conducted in 37 patients with advanced multiple myeloma receiving myeloablative chemotherapy. Fourteen days after intermediate-dose cyclophosphamide, prednisone, and granulocyte colony-stimulating factor (G-CSF), a median of 3 (range, 2 to 5) 10-L leukaphereses yielded 9.8 x 10(8)/kg (range, 3.7 to 28.3) mononuclear cells. The adsorbed (column-bound) fraction contained 5.9 x 10(6) cells/kg (range, 1.6 to 25.5) with 4.65 x 10(6) CD34 cells/kg (range, 1.2 to 23.3). Using Poisson distribution analysis of positive polymerase chain reactions with patient-specific complementarity-determining region 1 (CDR1) and CDR3 Ig-gene primers, tumor was detected in leukapheresis products from 8 to 14 unselected patients and ranged from 1.13 x 10(4) to 2.14 x 10(6) malignant cells/kg. After CD34 selection, residual tumor was detected in only three patients' products. Overall, a greater than 2.7- to 4.5-log reduction in contaminating multiple myeloma cells was achieved. CD34 PBPCs were infused 1 day after busulfan (14 mg/kg) and cyclophosphamide (120 mg/kg), and granulocyte-macrophage colony-stimulating factor was used until hematologic recovery. The median time to both neutrophil and platelet recovery was 12 days (range, 11 to 16 days and 9 to 52 days, respectively). The median number of erythrocyte and platelet transfusions was 7 (range, 2 to 37) and 3 (range, 0 to 85), respectively. Patients receiving fewer than 2 x 10(6) CD34 cells/kg had significantly prolonged neutropenia, thrombocytopenia, and an increased red blood cell and platelet transfusion requirement. Thus, CD34 selection of PBPCs markedly reduces tumor contamination in multiple myeloma and provides effective hematopoietic support for patients receiving myeloablative therapy.
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PMID:Transplantation of CD34+ peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma. 754 Aug 88

We report the complications and outcome of high-dose melphalan and TBI combined with ABMT used in the treatment of multiple myeloma at a single centre. Twenty-three patients, aged 65 years or less, who underwent the procedure are reviewed. All had chemosensitive disease. Response to ABMT assessed at 3 months showed 75% of evaluable patients to have further tumour cytoreduction of at least 50%, with 24% of patients who entered ABMT with residual disease eventually achieving CR. There was one toxic death. The overall survival is 60% and the progression-free survival is 49.8% at a median follow-up time of 17 months. Relapse or disease progression has occurred in 27% of patients, of whom half have died. No significant prognostic factors affecting survival were found although those patients with IgG myeloma had a better outcome. Patients transplanted in first plateau appeared to do significantly better if they had been resistant to their first-line chemotherapy but had then responded to further conventional chemotherapy (p = 0.029).
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PMID:Autologous bone marrow transplantation in multiple myeloma: a single centre experience of 23 patients. 786 75

Mafosfamide (ASTA-Z) is a chemotherapeutic agent currently in use for in vitro purging of tumor-bearing human BM cells prior to autologous bone marrow transplantation (ABMT). We tested the efficacy of ASTA-Z against mouse plasmacytoma cells MOPC-315 (MOPC), a model of human multiple myeloma. BALB/c mice were injected intraperitoneally with different doses of MOPC preincubated with ASTA-Z. All control mice receiving > or = 10(4) MOPC intraperitoneally (ip) died within 23 days. All recipients of ASTA-Z pretreated MOPC remained healthy for > 180 days. To simulate the clinical situation, BALB/c mice received lethal doses of 10(3) MOPC ip prior to ABMT. Subsequently, mice were treated with cyclophosphamide 200 mg/kg one day prior to syngeneic BMT with 10(7) BMC containing 10(6) MOPC; 90% of the mice receiving unpurged syngeneic BMC died within 45 days whereas all mice transplanted with ASTA-Z-treated BMC/MOPC mixtures remained disease-free for > 100 days. Our results suggest that a similar approach may be successful in patients with multiple myeloma and residual disease prior to cryopreservation of their BM for ABMT. Bone marrow purging with ASTA-Z is effective and under certain conditions could be critical for prevention of relapse following ABMT, provided that effective elimination of residual disease in the host can be achieved by the conditioning regimen prior to ABMT.
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PMID:Successful purging of murine plasmacytoma by mafosfamide (ASTA-Z). 801 50

Allogeneic bone marrow transplantation remains the only therapeutic approach with documented curative potential for patients with multiple myeloma. A survey of recently published trials reveals a 40% long-term survival rate with no evidence of residual disease in a majority of patients. While morbidity and mortality from myelosuppression and graft-versus-host disease are relatively high, allogeneic bone marrow transplantation should be considered early in the course of treatment for patients with high-risk myeloma.
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PMID:Allogeneic bone marrow transplantation for multiple myeloma. 821 Dec 18

lt could be speculated for patients with myeloma and other lymphoproliferative disorders that peripheral blood stem cells may be preferable to bone marrow for autologous transplantation because they may be less contaminated by neoplastic cells. To test this possibility, the immunoglobulin heavy chain gene rearrangement and limiting dilution polymerase chain reaction were used to sensitively quantify myeloma cells in bone marrow and peripheral blood stem cell collections, taken at a similar time, from eight patients with multiple myeloma. Levels of residual disease in the peripheral blood stem cell harvests were variable and did not reflect the tumour burden in the marrow. Peripheral blood stem cells contained 1.7 to 23700-fold fewer myeloma cells compared with the bone marrow and would have resulted in reinfusion of 0.08 to 59480-fold fewer myeloma cells based on total reinfused CFU-GM and 0.24 to 24700-fold fewer myeloma cells based on total reinfused nucleated cells. Assuming that the proportion of clonogenic myeloma cells is equivalent, peripheral blood stem cells may be better than bone marrow as a source of haemopoietic stem cells for transplantation in multiple myeloma. The clinical followup suggested that patients transplanted with peripheral blood stem cells containing a low number of myeloma cells had better disease control than those transplanted with peripheral blood stem cells containing a high number.
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PMID:Comparison of myeloma cell contamination of bone marrow and peripheral blood stem cell harvests. 861 25

Malignant cells in haemopoietic autografts can contribute to post-transplant relapse. Engraftment of myeloma patients with CD34+ peripheral blood progenitors selected from total autografts reduces the number of tumour cells infused by 2.7-4.5 logs. Residual tumour cells detected in CD34+ selected cells may be due to selection impurity or the existence of malignant CD34+ progenitors. In three patients we evaluated the CD34 purity and tumour load of total autografts, CD34+ progenitors selected with immunomagnetic beads and highly purified CD34+ progenitors obtained in two rounds of selection (combining magnetic with flow cytometry activated cell sorting) to determine the cause of residual tumour cells in CD34 selections. Using allele-specific oligonucleotides (ASO) complementary to the unique Ig heavy chain sequence (CDRIII region) of the malignant clone, semi-quantitative ASO-PCR was capable of detecting one malignant cell in 10(4)-10(5) normal white blood cells. Selection of CD34+ cells from bone marrow (BM) with approximately 20% malignant plasma cells resulted in a 1.4 log reduction of tumour burden. Using two-colour flow-cytometry we observed CD34-, BB4+ malignant plasma cells contaminating this CD34 selection. Prior to sorting, peripheral blood cell autografts (PBCA) contained approximately 0.1% malignant cells. Selection of > 99% pure CD34+ cells using immunomagnetic beads (Dynal) resulted in an approximate 2 log reduction of malignant cells, but residual tumour cells were still detectable. ASO-PCR detected no malignant cells in > 99.9% pure CD34+ peripheral blood progenitors obtained with two rounds of selection (combining magnetic with flow cytometry activated cell sorting). We conclude that CD34+ malignant cells are not detectable in myeloma PBCA and that residual tumour cells in CD34 selections are due to contaminating CD34-negative cells.
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PMID:CD34 selections from myeloma peripheral blood cell autografts contain residual tumour cells due to impurity, not to CD34+ myeloma cells. 865 82

The presence of complex karotypes with frequent numerical and structural abnormalities has been reported in 20 to 50% of multiple myeloma (MM) patients. This variability is mainly due to the difficulty of conventional cytogenetics to obtain tumor metaphases representative of all possible neoplastic clones in MM. To gain insight into the real incidence of numerical chromosome changes in MM we have studied by fluorescence in situ hybridization technique 15 different human chromosomes, 1, 3, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, X, and Y, in a series of 52 MM patients. In all cases, the DNA index assessed by a propidium iodide/CD38 double-staining technique with flow cytometry was simultaneously investigated for correlation, with fluorescence in situ hybridization results. Additional aims of this study were 1) to analyze whether the abnormalities detected were common to all plasma cells or were present in only a subpopulation of tumor cells, 2) to explore changes caused by disease progression, and 3) to establish possible associations among the altered chromosomes. Although the overall incidence of numerical abnormalities was 67%, this frequency increased to 80% in the 41 cases in which 7 or more chromosomes were analyzed. Trisomies were significantly more common than monosomies (84% versus 16%). Chromosomes 9 and 15 were the most frequently altered (52% and 48% of cases, respectively), with all of their abnormalities corresponding to trisomies. The most frequent losses involved chromosomes 13 (26%) and X in females (32%). Other common numerical changes corresponded to chromosomes 1 (39%), 11 (37%), 6 (32%), 3 (31%), 18 (29%), 7 (28%), and 17 (22%). By contrast, chromosomes 8(13%), 10(8%), and 12(3%) were rarely altered. DNA aneuploidy by flow cytometry was detected in 67% of patients, and a high degree of correlation was observed between the DNA index obtained by flow cytometry and the chromosome index derived from fluorescence in situ hybridization studies, calculated according to two mathematical formulas (coefficient of correlation of 0.82 and 0.91 when at least 7 or 12 chromosomes were considered, respectively). The frequency of numeric chromosome aberrations was higher in those patients with progressive disease and, interestingly, trisomy of chromosome 8 was exclusively detected in this latter group of patients. Our study shows that, with the exception of chromosome 8, a possible marker of clonal evolution, the numeric chromosome changes are present in nearly all malignant plasma cells (r > 0.84). Finally, frequent associations between chromosomal aberrations were observed (ie, chromosomes 6, 7, 9, and 17; 7 and 15; and 11 and 17). By excluding them, it was found that two triple combinations of chromosome-specific probes, chromosomes 1 and 9 together with either chromosome 13 or 15, could be a useful marker for detection of residual disease, as it permits the identification of most MM patients displaying numerical changes.
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PMID:Incidence of chromosome numerical changes in multiple myeloma: fluorescence in situ hybridization analysis using 15 chromosome-specific probes. 868 39

Serial peripheral blood specimen from eight adult patients after sex-mismatched bone marrow transplantation (BMT) for Chronic Myeloid Leukemia (CML) (N = 3). Ewing sarcoma (N = 1), Acute Myeloid Leukemia (AML) in second remission (N = 1), Acute Lymphoid Leukemia (ALL) (N = 1), of multiple myeloma (N = 2) were analyzed by the simultaneous immunophenotypic (moAbs/ APAAP-staining) and genotypic analysis (for X and Y chromosomes) of interphase cells to characterize mixed chimerism, residual host cells, and leukemic relapse. Although a stable donor chimerism for T cells, myelomonocytic cells, and granulocytes was developed in seven of the eight patients at Days +21 to +28 post BMT, 0.5 to 1% host cells of different lineages remained continuously in five of the eight patients post BMT (> day 100). In two patients, one with common ALL and the other with multiple myeloma and long-term stable mixed chimerism, a tumor cell relapse was detected first in a sample at Day +176 and confirmed at Day +294. These malignant cells were genotypically of host origin and presented phenotypes identical to those at diagnosis. In the three patients with CML, residual host cells were identified as CD13 (Patient 3) of CD13/CD34 (Patient 4) positive and in one case as CD4/CD8 positive (Patient 7). Since no exclusive antigenic marker is available for this discrimination in these CML patients, normal host hematopoiesis can interfere with the identification of residual disease. Therefore, the identification of the bcr-abl transcripts by a two-step reverse transcriptase-polymerase chain reaction (RT-PCR) was included in this analysis. Patient 3 was bcr-abl positive at [Days +21, +28, +35, and +311, but negative at Days +121 and +400; Patient 4 was bcr-abl positive at only Day +166 post BMT. These results are interpreted as signaling a continuing risk of relapse. In Patient 7, the bcr-abl RT-PCR was negative at Days +142, +166, and +237. Thus, the combination of the simultaneous immunophenotypic and genotypic analysis and the bcr-abl detection by RT-PCR clearly improves the discrimination between malignant cells and normal residual host cells.
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PMID:Qualitative assessment of mixed chimerism after allogeneic bone marrow transplantation with regard to leukemic relapse. 893 46


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