Is the risk of multiple myeloma increased in patients with silicone implants?
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Adult↗
Biomedical subjects
B Barlogie
Publications and source records attributed to B Barlogie.
Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma.
Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) have been reported after autologous transplantation (AT) for lymphoma. It is not clear whether myeloablative therapy used in conjunction with autologous transplantation contributes to the development of MDS/AML or whether the conventional chemotherapy preceding the transplant, and administered over a prolonged period, causes these secondary malignancies. To address this issue, we examined 188 patients with multiple myeloma (MM) who had received AT. 71 patients with no more than one cycle of standard chemotherapy were enrolled in our Total Therapy program, designed to avoid exposure to alkylating agents prior to peripheral blood stem cell mobilization (group 1). The median duration of pretransplant therapy in group 1 was 7.6 months and significantly shorter than the 24 months of 117 patients (group 2) with more prolonged conventional therapy (P = 0.0001). All seven patients developing MDS post-transplantation belonged to group 2 (P = 0.02); the median durations from initial therapy and first transplant were 66 months (range 38-86) and 24 months (range 9-39), respectively. Our findings provide evidence that prolonged standard-dose alkylating agent therapy prior to transplantation, rather than autotransplant-supported myeloablative treatment, is associated with development of MDS/AML. Stem cell damaging alkylator treatment should be avoided, not to compromise PBSC collection, but also to reduce the risk of treatment-related MDS/AML.
Aged↗
Autologous bone marrow and peripheral blood stem cell transplantation in multiple myeloma.
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Aged↗
Hematopoietic stem cell transplants for multiple myeloma.
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.
Adult↗
Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.
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.
Adult↗
Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities.
Chromosomal abnormalities have major biologic and prognostic implications in leukemias. Cytogenetic information in typically hypoproliferative multiple myeloma (MM) is limited because of difficulties in obtaining analyzable metaphases. In this study, karyotypes and other known prognostic factors were analyzed in 155 newly diagnosed MM patients, entered on an intensive treatment program with two autotransplants. Complete remission (CR), event-free (EFS) and overall survival (OS) were analyzed using standard statistical methods. Abnormal cytogenetics were found in 39% of patients and were associated with a significantly lower CR rate (27% v 48%; P = .008). EFS and OS were inferior in patients with either partial or complete deletion of chromosome 13 or 11q abnormalities ("unfavorable" karyotype) when compared with the remaining patients (P < .001) who, as a group, had a similar prognosis irrespective of cytogenetic findings, ie, inevaluable, normal, or abnormal but without an "unfavorable" karyotype. The patients with abnormalities of both chromosomes 11 and 13 had a dismal prognosis with median EFS and OS of only 11 and 12 months, respectively. Significant associations were noted between an "unfavorable" karyotype and IgA isotype, elevated levels of beta-2 microglobulin (B2M, > or = 3 mg/L) and age > 60 years. On multivariate regression analysis, the absence of an "unfavorable" karyotype was the most significant variable associated with prolonged EFS and OS (P = .0001 and .0002, respectively). Other independent favorable variables were age less than 60 years, C-reactive protein (CRP) < or = 0.4 mg/dL and bone marrow plasmacytosis < or = 50% before treatment. On a multivariate analysis without cytogenetics, these same three standard parameters were identified as the only favorable variables. Patients not having all three standard favorable variables had a significantly lower CR rate (P = .03), EFS (P = .0001), and OS (P = .002) if an unfavorable karyotype was detected. We conclude that, in this program of uniformly treated MM patients, a poor prognosis was associated predominantly with abnormalities of chromosomes 11 and 13.
Chromosome Aberrations↗
Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma.
In patients with advanced multiple myeloma (MM) there is an excess of production of interleukin-6 (IL-6) in vivo, and elevated serum levels are associated with plasmablastic proliferative activity and short survival. These data prompted us to perform a clinical trial with a murine anti-IL-6 monoclonal antibody (MoAb) to neutralize the excess of this putatively deleterious factor in these patients. Ten MM patients with extramedullary involvement frequently were treated with anti-IL-6 MoAb. The MoAb was administered intravenously to 9 patients; 1 patient with malignant pleural effusion received intrapleural therapy. Of the 3 patients who succumbed to progressive MM after less than 1 week of treatment (including the only 1 treated locally), 2 with evaluable data exhibited marked inhibition of plasmablastic proliferation. Among the 7 patients remaining more homogeneous receiving the anti-IL-6 MoAb for more than 1 week, 3 had objective antiproliferative effect marked by a significant reduction of the myeloma cell labelling index within the bone marrow. One of these 3 patients achieved a 30% regression of tumor mass. However, none of the patients studied achieved remission or improved outcome as judged by standard clinical criteria. Of major interest, objective antiproliferative effects were associated with complete inhibition of C-reactive protein (CRP) synthesis and low daily IL-6 production in vivo. On the other hand, the lack of effect in 4 patients was associated with a higher IL-6 production and inability of the MoAb to neutralize it. Anti-IL-6 was also associated with resolution of low-grade fever in all the patients and with worsening thrombocytopenia and mild neutropenia. The generation of human antibodies to Fc fragment of the murine anti-IL-6 MoAb observed in 1 patient was associated with dramatic progression. These data show that anti-IL-6 MoAb can suppress the proliferation of myeloma cells and underscore the biologic role of IL-6 for myeloma growth in vivo. Furthermore, suppression of CRP and worsening of neutropenia/thrombocytopenia both indicate that IL-6 is critically involved in acute-phase responses and granulopoiesis/thrombopoiesis.
Acute-Phase Reaction↗
Cytogenetic findings in 200 patients with multiple myeloma.
Cytogenetic studies were performed in 200 consecutive patients with multiple myeloma and related disorders. Structurally or numerically abnormal clones were found in 63 patients (32%), including 8 of 45 untreated patients (18%), and 55 of 155 treated patients (35%). The abnormal karyotypes generally showed numerous numerical and structural aberrations and in some patients multiple abnormal clones. The most striking feature of patients with hyperdiploid karyotypes was the finding of consistent recurring trisomies for chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, cosegregating together in many cases. Monosomy for chromosome 13 was the most common chromosome loss, occurring in 18 abnormal patients (29%), while interstitial deletions involving band 13q14 occurred in an additional 9 patients, indicating a loss of all or part of chromosome 13 in a high percentage of patients with abnormal karyotypes (43%). Structural aberrations of chromosome 1 were most frequent, occurring in 30 of 63 patients (48%), and involved almost equally the short and long arms. The single most frequent chromosome breakpoint involved band 14q32 and was found in 21 patients (33%), including 11 patients with a 14q+ chromosome, 8 with t(11;14)(q13;q32), and 2 with t(8;14)(q24;132).
Adult↗
Purified CD34+ Lin- Thy+ stem cells do not contain clonal myeloma cells.
High-dose therapy with autologous marrow or peripheral blood stem cell (PBSC) rescue has been extensively applied in the treatment of multiple myeloma (MM) patients during the past 10 years resulting in improved event-free and overall survival when compared with standard chemotherapy. However, relapses are common and cure is unlikely in the majority of patients. Because both bone marrow and PBSCs are contaminated with myeloma cells it is conceivable that relapse after autotransplantation originates at least in part from autografted tumor cells. In this study, mobilized PBSCs were examined for the presence of myeloma cells based on immunophenotyping and sensitive polymerase chain reaction (PCR)-based techniques. In addition, CD34+ Lin- Thy+ stem cells were purified from mobilized PBSC harvests of 10 MM patients by sequentially using counterflow elutriation centrifugation, treatment with phenylalanine methylester, and flow sorting, using 5-parameter gating (propidium iodide, forward scatter, side scatter, CD34+ v Lin- and CD34+ v Thy+). Virtually all mobilized unsorted PBSC preparations contained myeloma cells in sufficient quantities (range, < 0.01 to > 10%) potentially causing a disease relapse. Stem cell purification led to an overall enrichment by about 50-fold in all 10 patients; approximately 90% of the final cell population expressed CD34+ Lin- Thy+ with no evidence of myeloma cell contamination based on flow cytometric analysis of CD38bright cells (< 0.1%). Quantitative PCR amplification of patient-specific complementarity determining region III (CDRIII) DNA sequences showed depletion of clonal B cells by 2.7 to 7.3 logs, with the highest log reduction noted in the samples initially containing the most tumor cells. Our results show that purification of CD34+ Lin- Thy+ cells depletes myeloma cells to undetectable levels from up to 10% present in unsorted PBSCs, thus offering a tool to investigate whether MM relapse after autotransplantation can be reduced markedly.
ADP-ribosyl Cyclase↗
Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients.
Transfusion of autologous peripheral blood stem cells (PBSCs) of good quality ensures fast hematopoietic engraftment after myeloablative therapy with a decrease in procedure-related morbidity and mortality. We have analyzed variables influencing the kinetics of engraftment, and therefore reflecting the quality of PBSC collections, in 225 patients with newly diagnosed or refractory multiple myeloma (MM) who received an autotransplant in support of high dose melphalan (200 mg/m2); 132 of these patients also completed a second transplant. All PBSCs were collected before the first transplant after high-dose cyclophosphamide (6 g/m2) and hematopoietic growth factors, mainly granulocyte-macrophage colony-stimulating factor. PBSCs were administered either alone (91 patients) or with bone marrow (134 patients). A highly significant correlation was observed between the number of CD34+ cells per kilogram infused and prompt recovery of both granulocytes (P = .0001) and platelets (P = .0001). After correction for the proportion of patients with > or = 2 x 10(6)/kg CD34 PBSCs infused and with < or = 12 months of prior therapy, no difference in engraftment kinetics was seen between patients receiving PBSCs only and those also receiving bone marrow. Exposure to chemotherapy, even to < or = 6 months of alkylating agents, significantly delayed hematopoietic recovery posttransplantation. The threshold dose of CD34 cells necessary for prompt engraftment was > or = 2.0 x 10(6)/kg for patients with < or = 24 months of chemotherapy before the first transplant, whereas greater than 5 x 10(6)/kg CD34 cells were required to assure rapid recovery also in those with longer exposure. Such quantities, easily collected in the large majority of patients with shorter exposure (91%), were obtained in only 28% of patients with more than 24 months of prior chemotherapy. Rapid platelet recovery within a narrow range of time (before day 14) was almost invariably seen (94%) when greater than 5 x 10(6)/kg CD34 cells were infused, irrespective of the duration of prior therapy, whereas the range widened progressively when less CD34 cells were infused. In the absence of CD34 measurements, fast recovery of platelets to greater than 50 x 10(9)/L within 14 days after high-dose cyclophosphamide and < or = 12 months of prior chemotherapy were the best predictors of early engraftment. Prudent use of stem cell-damaging agents, such as melphalan and nitrosoureas, is recommended in MM patients who might be candidates for autotransplantation. Alternatively, PBSCs should be collected early after diagnosis.
Adult↗
Multiple myeloma--recent developments in molecular and cellular biology.
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Aneuploidy↗
Biological aspects of multiple myeloma.
Although considerable progress has been made towards understanding many aspects of myeloma, the myeloma stem cell and the factors that drive the disease remain elusive. Recent developments in the molecular analysis of clonality have helped to confirm the presence of pre-switch B cells that are of the same clone as the myeloma plasma cells. The role of these cells in myelomagenesis has not been demonstrated, and the isotypic heterogeneity of the clonally-relevant cells suggests that the pre-switch B cells are pre-malignant progenitors of the tumour cells. Thus, the circulating clonal B cells appear to be the earliest progenitors of the mature, monoclonal plasma cells. IL-6, and possibly other cytokines, are involved in driving this process. The role of IL-6 in myeloma is complex and more involved than its proposed growth factor function. In the absence of IL-6, dependent cells become apoptotic. Increased IL-6 signalling also leads to apoptosis of myeloma cells, possibly as a result of terminal differentiation. In the presence of exogenous IL-6, the IL-6 receptor appears to be the rate-limiting factor in the pathway's activity. IL-6 may regulate the survival of myeloma cells by stimulating c-myc transcription, possibly from the P0 promoter. The high levels of c-myc transcripts and protein could regulate myeloma cell proliferation and apoptotic death by controlling p53 expression and, through it, the expression of the Rb and BAX genes. Proliferative signalling in myeloma cells is likely to be intrinsic, within the tumour cell compartment. Molecules such as CD28 and B7, both expressed by less mature myeloma cells, could represent one such self-self stimulatory mechanism, with IL-6, possibly through stimulation of c-myc expression, providing the signals for survival and differentiation.
B7-1 Antigen↗
Autoregulatory circuits in myeloma. Tumor cell cytotoxicity mediated by soluble CD16.
BACKGROUND: Multiple myeloma remains an incurable malignancy due to marked resistance of the tumor to standard doses of chemotherapy. Treatment approaches, using chemotherapeutic dose escalation and hematopoietic stem cell support have resulted in significant augmentation of tumor mass reduction such that complete remissions are effected in approximately 50% of patients. These remissions are however, often not durable. In the setting of minimal residual disease, therefore, adjunctive immunotherapy may be useful. METHODS: Peripheral blood mononuclear cells were studied from 28 untreated patients with multiple myeloma (MM). Mononuclear cell CD16 (FcR gamma III) expression was determined by flow cytometry. The effect of lymphocyte-derived soluble CD16, isolated by affinity chromatography, on MM cell growth and differentiation was assessed. MM cell proliferation, viability, immunoglobulin production and gene expression was studied. RESULTS: Data are presented indicating that cells expressing CD16 are increased in untreated patients with IgG-secreting myeloma. The predominant phenotype of these cells is CD8+ or CD56+. These CD16+ cells can produce a soluble form of the Fc receptor (sFcR, sCD16) that can bind to surface Ig on cultured human IgG-secreting myeloma cells and effect suppression of tumor cell growth and Ig secretion. This effector function is accompanied by concomitant suppression of c-myc as well as IgH and IgL gene transcription. Finally, prolonged exposure to sCD16 causes myeloma tumor cell cytolysis. CONCLUSIONS: sCD16 and possibly other soluble FcR are candidate molecules for adjunctive immunotherapy of myeloma, once complete responses have been effected by intensive cytotoxic therapy, now possible in up to 50% of newly diagnosed patients.
Adult↗
Cytokine-mobilized peripheral blood CD34+Thy-1+Lin- human hematopoietic stem cells as target cells for transplantation-based gene therapy.
Gene-therapy of blood-borne disorders may be best achieved using hematopoietic stem cells (HSC) which have extensive self renewal potential as well as multilineage repopulating potential as a cellular target. The human HSC, which is CD34+Thy-1+Lin- has been isolated from fetal, adult bone marrow and cytokine-mobilized peripheral blood (MPB) (1-3). Results presented in this study show that the degree of mobilization of HSC into peripheral blood of cancer patients is highly variable and that the combined use of high dose chemotherapy and GM-CSF as a mobilization strategy is superior to the use of G-CSF with regard to the mobilization of true HSC. A multistep cell isolation procedure has been developed which utilizes high speed flow-cytometric cell sorting and allows the isolation of sufficient numbers of HSC from MPB to permit their use as an hematopoietic graft for clinical transplantation. Hematopoietic stem cells isolated from MPB are capable of self-renewal and differentiation into multiple hematopoietic lineages as shown by their behavior in both in vitro and in vivo assays. Mobilized PB mononuclear cells isolated from cancer patients are frequently contaminated with tumor cells. Using this cell isolation procedure, HSC preparations from patients with multiple myeloma have been created with greatly reduced tumor cell burdens. These CD34+Thy-1+Lin- cells are capable of being stably transduced at high efficiency (32-75%) by co-culture on a cell line producing recombinant retroviruses containing the neomycin-resistant gene. These HSC cell populations are likely ideal targets for hematopoietic cell-based gene therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Relapse of multiple myeloma after autologous transplantation: survival after salvage therapy.
Owing to lack of progress with standard chemotherapy and the presence of a dose response effect for alkylating agents, autotransplantation is performed with increasing frequency for multiple myeloma (MM). However, sustained relapse-free survival is still infrequent. We studied 94 patients who had relapsed following autotransplantation, in order to evaluate the efficacy of further therapy. Post-transplant salvage treatment consisted of either standard dose therapy (53) or transplantation with an intensive preparative regimen (with autograft support in 31 and allogeneic transplantation in 10). Complete remission (CR) rate, event-free and overall survival were assessed and prognostic variables identified in a multivariate regression analysis. With a median follow-up of 11 months, the projected overall survival at 18 months for all patients is 59%. A multivariate analysis identified pre-salvage beta-2-microglobulin (B2M) < or = 2.5 mg/l (P = 0.0002) and late relapse after the preceding transplant ( > 12 months; (P = 0.02) as independent significant favorable variables for overall survival. By combining pre-salvage B2M and the time to relapse, 2 risk groups of patients could be identified with significantly different overall survival: those with at least one favorable variable had a projected survival at 18 months of 79%, compared to 38% for patients with no favorable variable. Transplantation performed as primary salvage therapy was associated with a significantly prolonged survival (P = 0.009), although this may be more a reflection of the way salvage therapy was selected.
Follow-Up Studies↗
Autologous and allogeneic transplants for multiple myeloma.
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Bone Marrow Transplantation↗
Interleukin-6 prevents dexamethasone-induced myeloma cell death.
The effects of dexamethasone on the growth of four human multiple myeloma cell lines were studied. In addition, the effects on the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes were investigated by the use of reverse-transcriptase polymerase chain reaction. Dexamethasone (Dex) concentrations of 10(-7) to 10(-6) mol/L inhibited IL-6 gene expression in three of four cell lines studied, whereas the higher concentration of the hormone inhibited also IL-6R gene expression. Dex effects were modulated through the glucocorticoid receptor (GR). Dex treatment resulted in killing of sensitive cells associated with DNA fragmentation, which could be reversed by concomitant treatment with IL-6. The reversal of Dex-mediated effects by IL-6 did not result from an inhibition of GR function as measured by receptor nuclear translocation or Dex-regulated reporter gene function. These results indicate that blockage of the IL-6 signaling pathway is essential for effective myeloma cell kill by Dex.
Base Sequence↗
High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants.
One hundred and thirty-five patients with advanced and refractory myeloma received one of three high-dose therapy regimens: melphalan at doses of 90 to 100 mg/m2 (MEL 100; 47 patients) without autotransplant; total body irradiation (TBI; 850 cGy) with either melphalan 140 mg/m2 or thiotepa 750 mg/m2 and autologous bone marrow transplant (ABMT) (< or = 30% plasma cells; 21 patients); melphalan 200 mg/m2 (MEL 200) supported by both peripheral blood stem cells (PBSC) and ABMT plus GM-CSF intended as a double-transplant program (67 patients; 42 have completed and 3 are still awaiting a second autotransplant; 5 additional patients received an allograft for their second transplant). Mortality within 2 months of therapy was 20% to 25% with MEL 100 and TBI regimens, but less than 1% with MEL 200, mainly because severe neutropenia (< 500/microL) was shortened to less than 1 week due to infusion of PBSC and use of growth factor therapy. Low beta 2-microglobulin (beta 2M) levels < or = 2.5 mg/L and MEL 200 therapy were identified as the two most important independent favorable variables associated with prolonged event-free survival (EFS) and overall survival (OS). On the basis of these two parameters, three risk groups were defined: 29 good-risk patients with low beta 2M receiving MEL 200 had the best outcome, with median durations of EFS of 37 months and projected OS of > or = 43 months; 54 intermediate-risk patients displaying one of the two favorable parameters had EFS and OS durations of 16 and 36 months, respectively; and 52 poor-risk patients with high beta 2M not receiving MEL 200 had a dismal prognosis, with EFS of 3 months and OS of 5 months (all P < .0001). Further analysis that excluded treatment as a variable identified high beta 2M and resistant relapse as the two major adverse prognostic factors, one of which was present in 80% of the 135 patients. Among these 108 high-risk patients, prognosis was improved markedly with MEL 200 because of both better supportive care (PBSC and hematopoietic growth factors) and more intensive therapy using the double-transplant approach. This study supports the concept that safer and potentially more-effective therapies can be developed in the setting of advanced and resistant disease.
Age Factors↗