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)

This study was undertaken to assess the significance of lung-resistance related protein (LRP) expression in plasma cells from untreated multiple myeloma (MM) patients and to determine whether LRP was associated with a poor response and survival in patients treated with different dose regimens of melphalan. Seventy untreated patients received conventional oral dose melphalan (0.25 mg/kg, day 1 to 4) combined with prednisone (MP) or intravenous intermediate-IDM; 70 mg/m2) or high- (140 mg/m2) dose Melphalan (HDM). LRP expression was assessed with immunocytochemistry using the LRP-56 monoclonal antibody. LRP expression was found in 47% of patients. In the MP treated patients, LRP expression was a significant prognostic factor regarding response induction (P < .05), event free survival (P < .003), and overall survival (P < .001). In the intensified dose melphalan treated patients LRP did not have a prognostic value. The response rates of LRP-positive patients to MP and IDM/HDM were 18% versus 81%, respectively (P < .0001). We conclude that LRP is frequently expressed in untreated MM patients and is an independent predictor for response and survival in patients treated with MP. Pretreatment assessment of LRP identifies a subpopulation of patients with a poor probability of response to conventional dose melphalan. Dose intensification of melphalan is likely to overcome LRP-mediated resistance.
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PMID:Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. 944 66

Here we review our recent experience addressing the issue of positive selection and transplantation of hematopoietic CD34+ cells to reduce neoplastic contamination in peripheral blood (PB) autografts from patients with multiple myeloma (MM). We evaluated PB samples from 30 pretreated MM patients following the administration of high dose cyclophosphamide (Cy; 7g/m2 or 4g/m2) and granulocyte-colony stimulating factor (G-CSF), for collection of circulating stem cells (PBSC) to support hematopoietic reconstitution following myeloablative radio-chemotherapy. Twenty six patients showed adequate mobilization of CD34+ progenitor cells and were submitted to PBSC collection. Circulating hematopoietic CD34+ cells were highly enriched by avidin-biotin immunoabsorption, cryopreserved, and used to reconstitute 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 increase compared to 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 of plasma cells and CD19+ B-lineage cells depletion as determined by immunofluorescence studies, although DNA analysis of CDR III region of IgH gene demonstrated the persistence of minimal residual disease (MRD) in 5 out 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 and 50 x 10(9) platelets/L of PB was 10, 11 and 12 days, respectively. When we analyzed the immunological reconstitution of this group of patients, we observed a rapid and full recovery of total lymphocyte and NK cell count, although the absolute CD4+ cell count was lower than pretreatment level. These results, as well as other clinically significant parameters, did not significantly differ from those of patients (=13) receiving unmanipulated PBSC following the same pretransplant conditioning regimen. The results of this trial demonstrate that 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 a normal hematopoiesis after a TBI-containing conditioning regimen. Based on this pilot trial, we have recently started a clinical study involving a double autotransplant, conditioned with melphalan (200 mg/m2) followed by melphalan (140 mg/m2) and busulphan (14 mg/kg), supported by the reinfusion of highly purified CD34+ cells.
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PMID:Selection and transplantation of autologous hematopoietic CD34+ cells for patients with multiple myeloma. 957 Jun 75

Between 1990 and 1997, 55 patients with high risk multiple myeloma underwent high-dose therapy with peripheral blood stem cell transplantation. Intensification consisted of high-dose L-PAM in 54 patients, and 15 patients underwent a second high-dose treatment. Thirty patients received total body irradiation. Twenty patients were more than 60 years old. Thirty-five patients were intensified during first response. The overall response rate was 78%. There were four toxic deaths. The median overall survivals after intensification and after first treatment of myeloma were greater than 48 months and 71 months, respectively. Conversely freedom from progression after intensification was short, with a median of 22 months. Freedom from progression was significantly shorter in patients older than 60 (12 months), and in patients who had received more than 75 mg/m2 of L-PAM before intensification (16 months). Although intensification is feasible in elderly patients the benefit appears to be reduced in this subgroup of patients. Prior therapy with high cumulative doses of L-PAM should be avoided in patients who will receive high-dose L-PAM for therapeutic intensification.
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PMID:Reduced progression-free survival in elderly patients receiving intensification with autologous peripheral blood stem cell reinfusion for multiple myeloma. 963 78

We investigated the feasibility of mobilizing peripheral blood stem cells (PBSC) with G-CSF alone in 24 patients with multiple myeloma. The median age was 53 years (range 33-62). All patients had stage II/III disease and responded to standard first-line (n = 6) or salvage chemotherapy (n = 18). The median number of previous chemotherapy cycles was 7 (4-18) and the median number of prior melphalan-cycles was 6 (0-14). Nine (35%) patients had experienced prior radiation therapy. The patients received either 10 microg/kg G-CSF (n = 18) or 24 microg/kg G-CSF (n = 7, including one patient with previous 10 microg/kg G-CSF stimulation) daily s.c. for 5 or more consecutive days until completion of harvesting, starting apheresis on the fifth day. G-CSF treatment was well tolerated, with only slight bone pain in half of the patients (51%). After a median of three (range 1-7) apheresis procedures, medians of 3.8 (0.3-17) x 10(6) CD34+ cells/kg, 8.5 (4.5-24) x 10(8) MNC/kg, 2.9 (0.6-39.4) x 10(4) CFU-GM/kg, and 5.6 (0.9-49) x 10(4) BFU-E/kg were harvested. Three patients (12%) with extensive melphalan pretreatment failed the target collection of at least 2.0 x 10(6) CD34+ cell/kg. Pretreatment with six or more cycles of melphalan yielded a smaller number of CD34+ cells than pretreatment with fewer than six cycles (2.5 vs 5.3 x 10(6)/kg; p = 0.001). Nineteen patients underwent high-dose chemotherapy consisting of either total marrow irradiation (9 Gy)/busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) (n = 10), or busulfan (14 mg/kg)/cyclophosphamide (120 mg/kg) (n = 5), or tandem melphalan (200 mg/m2). The median time for granulocyte (> 1.0/nl) and platelet (> 50/nl) recovery was 10 and 14 days (ranges 7-12 and 8-40), respectively. G-CSF alone is a safe, alternative approach to mobilizing sufficient PBSC in patients with multiple myeloma and allows an exact prediction of harvest time. G-CSF-mobilized PBSCs ensure rapid engraftment after myeloablative therapy. Melphalan treatment should be avoided in patients who are candidates for high-dose chemotherapy.
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PMID:Successful mobilization of peripheral blood stem cells in heavily pretreated myeloma patients with G-CSF alone. 969 13

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.
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PMID:Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study. 981 55

We describe a 68-year-old patient presenting with recurrent fever, who eventually turned out to suffer from multiple myeloma. He was treated with Vincristine, Doxorubicin and Dexamethasone combination chemotherapy and intermediate dose Melphalan (70 mg/m2), respectively. Apart from periods of fever due to sepsis following chemotherapy, the recurrent fever disappeared after response, but recurred synchronously with progression of the disease. Recurrent fever in this case should be considered as a symptom of active multiple myeloma. This form of presentation of multiple myeloma has been described in literature only a few times.
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PMID:Fever as presenting symptom of multiple myeloma. 988 3

Resistance of myeloma cells to melphalan (L-PAM) is a serious problem. To investigate mechanisms of drug resistance, we generated a monoclonal antibody, clone O3, to melphalan-resistant myeloma cells, KHM-11R. Western blot analysis showed that molecular weight of O3 antigen was approximately 90 kDa. Expression of O3 antigen was approximately two times higher in KHM-11R than in parental melphalan sensitive cell line, KHM-11. O3 was preferentially expressed in plasma cell, B-cell, and monocytic cell lines, but not in T-cell lines. Analysis of bone marrow samples from myeloma patients revealed that 13 of 23 samples expressed O3 antigen at various levels, and that O3 antigen expression in patients correlate with preceding chemotherapy, advanced clinical stage and extramedullar invasion of myeloma cells. Furthermore, patients expressing O3 antigen at the time of diagnosis tended to have poor prognosis. The investigation of O3 antigen in myeloma cells will be useful to reveal the pathophysiology of extramedullar invasion and the mechanism of cell killing by melphalan.
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PMID:Establishment of a monoclonal antibody to human myeloma cell: relation to chemotherapy and extramedullar infiltration. 995 88

In a prospective study, covering a 10-year period, 109 patients with multiple myeloma (56 men and 53 women of mean age of 62) were followed. The patients were grouped according to the staging system of Durie & Salmon. They were treated uniformally with monochemotherapy with Cyclophosphamid, Melphalan and Glicocorticosteroids. The median survival for the different clinical stages was: I--53 months, II--31 and III--24 months. Significant difference between stages II and III with 98 patients (89.9%), was not found. Authentically, patients in II A compared to II B clinical stage had higher median survival of 40 and 26 months, respectively. So was IIIA compared to IIIB--38 and 18 months. It was found that the prognosis for the life expectancy of the patients depended to a greater degree on the extent of the renal function impairment at the time of diagnosis of the process, e.g., on the A and B substage (serum creatinin level > 160 mmol/l) than on the size of the tumour mass, respectively the clinical stage according to Durie & Salmon system.
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PMID:Prognostic assessment of the Durie and Salmon staging system in patients with multiple myeloma. 1020 11

The patient registers of five prospective population based Nordic studies were reviewed for patients <60 yr. A total of 313 patients with symptomatic multiple myeloma were identified. Thirty-nine of them were judged retrospectively to have been ineligible for intensive chemotherapy regimens. The remaining 274 patients were considered appropriate as a historical control group for comparison with patients treated with high-dose chemotherapy and autologous stem cell support. Of these, 32 had been diagnosed during the period 1970-83, 101 during the period 1984-89 and 141 during the period 1990-92. The median age was 54 yr. Six percent were Durie/Salmon stage I, 38% stage II and 56% stage III. Melphalan-prednisone was used for initial therapy in 87%. Median survival for all patients with symptomatic myeloma was found to be 41 months, and for those selected for the control group 44 months, with no noted differences between the aforementioned diagnostic periods. We conclude that the expected median survival is 44 months for myeloma patients <60 yr who may be considered for high-dose therapy protocols. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high-dose chemotherapy with stem cell rescue, have not changed the overall prognosis in multiple myeloma.
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PMID:Survival in conventionally treated younger (<60 years) multiple myeloma patients: no improvement during two decades. Nordic Myeloma Study Group (NMSG). 1022 61

Although expression of CD95 (Fas/Apo-1) on myeloma cells has been reported, its significance is not clearly understood. We established a myeloma cell line, KHM-11ad (11ad), from a parental cell line, KHM-11, by collecting cells adhered to a plastic dish. KHM-11 cells have been reported to be positive for CD45 and CD95 (Fas/Apo1), and negative for a myelomonocytic antigen, CD13. Interestingly, CD95 was not detected in 11ad. Expression of CD45 was also significantly decreased in 11ad cells while expression of CD13 was detected in these cells. The growth rate of 11ad cells was 1.7 times lower than that of KHM-11 cells. Analysis of adhesion molecules showed that expression of VLA4 and CD44 was significantly suppressed in 11ad. The IC50 of melphalan (L-PAM) for 11ad cells was 50 times higher than that for KHM-11, indicating that 11ad is significantly refractory to L-PAM than KHM-11 cells. Induction of apoptosis by doxorubicin and cycloheximide was suppressed in 11ad cells compared with those in KHM-11 cells. Western blot analysis for Bcl-2 family of proteins showed that Bax was expressed at a 2.2 times lower level in 11ad cells than in KHM-11 cells while there was no difference in expression of Bcl-2, Bcl-Xs nor Bcl-XL. These results suggest that CD95-negative myeloma cells may have characteristics as follows: (1) slow proliferation; (2) low sensitivity to apoptosis; (3) low expression of VLA4, CD44 and Bax. Although these intraclonal variations were based on the findings of cell lines, these may reflect similar variations in vivo. The 11ad line may be a suitable model for analyzing intraclonal variation of myeloma cells.
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PMID:Establishment and characterization of a CD95 (Fas/Apo-1)-negative myeloma cell line. 1035 28


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