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PubMed2003

Genetically targeted radiotherapy for multiple myeloma.

Multiple myeloma is a disseminated neoplasm of terminally differentiated plasma cells that is incurable with currently available therapies. Although the disease is radiosensitive, external beam radiation leads to significant toxicity due to sensitive end-organ damage. Thus, genetic approaches for therapy are required. We hypothesized that the incorporation of immunoglobulin promoter and enhancer elements in a self-inactivating (SIN) lentiviral vector should lead to specific and high-level transgene expression in myeloma cells. A SIN lentivector with enhanced green fluorescent protein (EGFP) expression under the control of a minimal immunoglobulin promoter as well as the Kappa light chain intronic and 3' enhancers transduced myeloma cell lines with high efficiency (30%-90%). EGFP was expressed at a high level in myeloma cells but silent in all nonmyeloma cell lines tested compared with the cytomegalovirus (CMV) promoter/enhancer. Transduction of myeloma cells with the targeted vector coding for the human sodiumiodide symporter (hNIS) led to hNIS expression by these cells allowing them to concentrate radioiodine up to 18-fold compared with controls. Tumor xenografts in severe combined immunodeficiency mice expressing hNIS could be imaged using iodine-123 (123I) and shown to retain iodide for up to 48 hours. These tumor xenografts were completely eradicated by a single dose of the therapeutic isotope iodine-131 (131I) without evidence of recurrence up to 5 months after therapy. We conclude that lentivectors can be transcriptionally targeted for myeloma cells and the use of hNIS as a therapeutic gene for myeloma in combination with 131I needs further exploration.

Animals↗
PubMed1998

Homing behaviour of the malignant cell clone in multiple myeloma.

Multiple myeloma (MM) represents a B cell malignancy characterised by the presence of a monoclonal population of end-stage B cells in the bone marrow. Although fully matured bone marrow plasma cells are the predominant cell type in MM, there is much evidence that also more immature B cells are included in the malignant cell clone which are considered to be the myeloma precursor cells. The fact that these cells are detectable in the blood circulation and that their number increases with disease progression, makes it very likely that they represent the component of the tumour clone that mediates disease dissemination. This implies that these cells must have the potential to extravasate and home to the bone marrow environment. Like the migration mechanisms used by normal leukocytes and/or metastatic tumour cells of non-haematopoietic origin, it can be assumed that this bone marrow homing process is mediated by adhesive interactions and chemotactic signals provided by the microenvironment of the tumour. Once in the bone marrow compartment, myeloma cells will receive the appropriate signals to grow and survive. This aspect of tumour-homing is found to be the result of a functional interplay between the myeloma cells and the surrounding microenvironment, involving the action of several cytokines and adhesion molecules. In the end phase of the disease, myeloma cells can lose their stroma-dependency resulting in extramedullary tumour growth. We review normal B cell homing and discuss molecular mechanisms that determine the homing behaviour of the malignant cell clone in MM.

Animals↗
PubMed1992

SDZ PSC-833--a novel potent in vitro chemosensitizer in multiple myeloma.

Multiple myeloma cell lines and patient tumor samples with and without the expression of the classical multidrug resistance (MDR) phenotype were investigated in vitro for drug induced cytotoxicity and modulation of drug resistance. Overall there was a good correlation in the cell lines between MDR expression, as measured by immunocytochemistry with monoclonal antibodies against P-glycoprotein 170 (Pgp), and in vitro resistance to doxorubicin (dox) and vincristin (vcr). Drug resistance in the cell line RPMI 8226 dox 40, expressing a high level of Pgp, was almost completely reversed by the novel non-immunosuppressive cyclosporin A (CsA) analog SDZ PSC-833 (PSC), while the chemosensitizers verapamil, CsA and quinine, in clinically achievable concentrations, were much less effective. In cell lines with low Pgp expression, PSC and the other chemosensitizers seem equally effective. The patient tumor samples were selected to represent different combinations of Pgp expression, drug resistance and effects of chemosensitizers. PSC and CsA appeared equally potent and resistance modulation was detected not only in Pgp positive, but also in Pgp negative tumor samples. Furthermore, in one case of a Pgp expression myeloma, chemosensitizers were without effect. These findings indicate the need to incorporate in vitro chemosensitivity assays with Pgp determination when the effects of MDR modulating chemosensitizers are to be studied in the clinic.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Thymoglobulin targets multiple plasma cell antigens and has in vitro and in vivo activity in multiple myeloma.

Multiple myeloma is characterized by the proliferation of clonal plasma cells that have a heterogeneous expression of various cell surface markers, precluding successful use of monoclonal antibodies for therapeutic targeting of the tumor cell. Thymoglobulin (rabbit-derived polyclonal anti-thymocyte globulin), by virtue of its method of preparation, contains antibodies against several B-cell and plasma cell antigens and offers an attractive option for immunotherapy of myeloma. Here, we demonstrate potent anti-myeloma activity of the rabbit anti-thymocyte globulin preparation Thymoglobulin in vitro and in vivo in an animal model of myeloma. Thymoglobulin was able to induce dose- and time-dependent apoptosis of several myeloma cell lines, including those resistant to conventional anti-myeloma agents. Importantly, the anti-myeloma activity was preserved even when myeloma cells were grown with different cytokines demonstrating the ability to overcome microenvironment-mediated resistance. Thymoglobulin induced apoptosis of freshly isolated primary myeloma cells from patients. Using a competitive flow cytometric analysis, we were able to identify the potential antigen targets for Thymoglobulin preparation. Finally, in a plasmacytoma mouse model of myeloma, Thymoglobulin delayed the tumor growth in a dose-dependent manner providing convincing evidence for continued evaluation of this agent in the clinic in patients with myeloma, either alone or in combination with other agents.

Animals↗
PubMed2005

Drug insight: thalidomide as a treatment for multiple myeloma.

Multiple myeloma (MM)--a malignancy of the bone marrow--remains incurable by current therapies, and there is an urgent need for new drugs based on a better understanding of the underlying disease biology. MM is characterized by monoclonal plasma cells that accumulate in the bone marrow, which provides a microenvironment that promotes tumor cell growth and survival and protection against various therapeutic agents. The MM cell interacts with bone marrow stromal cells and endothelial cells, as well as osteoblasts and osteoclasts. Our understanding of the tumor microenvironment has already prompted the development of new agents that are aimed at disrupting the multiple facets of these interactions. It has also enabled the development of a comprehensive and rational approach to preclinical evaluation of new agents, facilitating the translation of in vitro studies to in vivo tumor models and, subsequently, to clinical trials. In this review, we describe the preclinical studies that led to the development of clinical trials of thalidomide and its immunomodulatory derivatives as therapeutic agents for MM. These drugs, alone or in combination, have shown impressive activity at all stages of the disease, and these demonstrations of clinical benefit have in turn validated our model systems for drug discovery in MM. Integration of data from clinical trials and laboratory studies will allow the design of future clinical trials that combine thalidomide and its derivatives with other drugs, ultimately leading to more effective therapies and better outcomes in patients with MM.

Animals↗
PubMed2005

The relationship between proliferation and apoptosis in patients with monoclonal gammopathy of undetermined significance or multiple myeloma.

Multiple myeloma (MM) is a clonal neoplastic lymphoproliferative disease affecting terminally differentiated B cells i.e. plasma cells characterized by slow proliferation activity and different resistance to apoptosis with latent accumulation of myeloma cells in the bone marrow. This process is induced by failure of normal tissue homeostatic mechanisms. We compared plasma cell proliferation and apoptic indices in various phases of MM and in monoclonal gammophaty of untetermined significance.

Adult↗
PubMed2005

Early genetic events provide the basis for a clinical classification of multiple myeloma.

Multiple myeloma is a tumor of somatically mutated, isotype-switched plasma cells that accumulate in the bone marrow leading to bone destruction and bone marrow failure. The germinal center processes of somatic hypermutation and switch recombination are implicated in the development of recurrent immunoglobulin gene translocations in 40% of patients. These affect five loci: 11q13, 6p21, 4p16, 16q23 and 20q11, leading to dysregulation of CCND1, CCND2, FGFR3/MMSET, c-MAF and MAFB respectively. The remaining 60% of patients can be divided into four groups based on their expression of CCND1 and CCND2. The largest group (40%) ectopically express CCND1 bi-allelically and have hyperdiploidy with multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. The translocation and cyclin D (TC) groups identify patients with different genetics, biology, clinical features, prognosis and response to therapy.

B-Lymphocytes↗
PubMed2002

Altered mRNA expression of Pax5 and Blimp-1 in B cells in multiple myeloma.

Multiple myeloma (MM) is a plasma cell disorder that potentially initiates during an early stage of B-cell development. We encountered an unidentified isoform of B cell-specific activator protein (BSAP, or Pax5) in MM cells while performing differential analyses to compare mRNA expression in malignant and normal plasma cells. Pax5 is a transcription factor that plays a central role throughout B-cell development until the point of terminal differentiation. Our finding of this unique isoform prompted us to investigate Pax5 isoform usage in plasma cells and B-cell populations in other MM and healthy subjects. In contrast to normal Pax5 expression, we observed multiple isoforms of Pax5 in conjunction with low levels of expression of the full-length Pax5 in B cells from MM patients. The expressed isoforms in MM varied considerably from patient to patient, with no clear pattern. We also performed semiquantitative analyses of the mRNA expression levels of B lymphocyte-induced maturation protein (Blimp-1), because expression levels of Pax5 and Blimp-1 have been shown to be inversely correlated. We observed the expression of Blimp-1 in the B-cell populations in all 11 MM patients but in none of 11 healthy subjects. We hypothesize that premature Blimp-1 expression coupled to altered and deficient Pax5 expression causes some proliferating B cells to prematurely differentiate to plasma cells in MM.

Amino Acid Sequence↗
PubMed2002

Negative regulation of erythroblast maturation by Fas-L(+)/TRAIL(+) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma.

Multiple myeloma (MM) is associated with severe normochromic/normocytic anemia. This study demonstrates that the abnormal up-regulation of apoptogenic receptors, including both Fas ligand (L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), by highly malignant myeloma cells is involved in the pathogenesis of the ineffective erythropoiesis and chronic exhaustion of the erythroid matrix. By measuring Fas-L and TRAIL in plasma cells and the content of glycophorin A (GpA) in erythroblasts from a cohort of 28 untreated, newly diagnosed patients with MM and 7 with monoclonal gammopathy of undetermined significance (MGUS), selected in relation to their peripheral hemoglobin values, results showed that both receptors occurred at high levels in 15 severely anemic MM patients. Their marrow erythropoietic component was low and included predominantly immature GpA(+dim) erythroblasts, in contrast with the higher relative numbers of mature GpA(+bright) erythroid cells observed in the nonanemic patients and those with MGUS. In cocultures with autologous Fas-L(+)/TRAIL(+) myeloma cells, the expanded GpA(+dim) erythroid population underwent prompt apoptosis after direct exposure to malignant plasma cells, whereas erythroblasts from nonanemic patients were scarcely affected. The evidence that Fas-L(+)/TRAIL(+) malignant plasma cells prime erythroblast apoptosis by direct cytotoxicity was also supported by the increase of FLICE in fresh immature GpA(+dim) erythroid cells, whereas ICE and caspase-10 increased in subsequent maturative forms. In addition, GATA-1, a survival factor for erythroid precursors, was remarkably down-regulated in fresh erythroblasts from the severely anemic patients. These results indicate that progressive destruction of the erythroid matrix in aggressive MM is due to cytotoxic mechanisms based on the up-regulation in myeloma cells of Fas-L, TRAIL, or both. It is conceivable that the altered regulation of these receptors defines a peculiar cytotoxic phenotype that drives the progression of aggressive MM.

Anemia↗
PubMed1998

Role of hepatocyte growth factor and its receptor c-met in multiple myeloma.

Multiple myeloma is characterised by the clonal expansion of malignant plasma cells. Recently, we reported that a new cytokine, hepatocyte growth factor (HGF), and its receptor c-met are related to this disease. Here we review the observations that associate HGF with myeloma. Malignant plasma cells produce HGF and express the receptor c-met. Many patients have elevated HGF levels, which is unfavourable both in terms of survival and response to treatment. Possible biological roles of HGF in this disease are discussed, with special focus on bone homeostasis and its binding to heparan sulphate proteoglycans.

Bone Diseases↗
PubMed2000

Role of INTERLEUKIN-6 in the pathogenesis of multiple myeloma.

Multiple myeloma (MM) is a currently incurable disease caused by the proliferation of malignant plasma cells. Although the pathogenesis of the disease still remains unclear, recent research in the biology of MM has produced new insights into the factors that control the growth and survival of myeloma cells. Among the growth factors, interleukin-6 (IL-6) has an essential role. Evidence suggests that IL-6 is not only a growth factor, but also a survival factor in MM, inhibiting apoptosis in myeloma cells. IL-6 interacts with several factors which are involved in the pathogenesis of MM, such as adhesion molecules, tumour suppressor genes and oncogenes. Considering the essential role of IL-6, it could serve as a target for new therapeutic interventions. Neutralizing the effect of IL-6 may result in a regression of tumour progression.

Cell Adhesion Molecules↗
PubMed2004

Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma.

Multiple myeloma (MM) is a neoplastic proliferation of plasma cells and remains an incurable disease because of the development of drug resistance. Histone deacytylase (HDAC) inhibitors are a new class of chemotherapeutic reagents that cause growth arrest and apoptosis of neoplastic cells. Depsipeptide, a new member of the HDAC inhibitors, was found to be safe in humans and has been shown to induce apoptosis in various cancers. In order to evaluate the effects of depsipeptide, a MM cell line, U266 [interleukin (IL)-6 dependent], was analysed for viability and apoptosis. The combined effect of depsipeptide with melphalan and changes in BCL-2 family proteins (BCL-2, BCL-XL, BAX and MCL-1) were also investigated. In addition, the RPMI 8226 cell line (IL-6 independent), and primary patient myeloma cells were also analysed for apoptosis after depsipeptide treatment. Depsipeptide induced apoptosis in both U266 and RPMI 8226 cell lines in a time- and dose-dependent fashion, and in primary patient myeloma cells. We also demonstrated that depsipeptide had an additive effect with melphalan (10 micromol/l). BCL-2, BCL-XL and MCL-1 showed decreased expression in depsipeptide-treated samples. Based on recent clinical trials demonstrating minimal clinical toxicity, our study supports the future clinical utilization of depsipeptide in the management of MM.

Antibiotics, Antineoplastic↗
PubMed1986

[Treatment of multiple myeloma].

Multiple myeloma comprises widely varying clinical varieties of a more or less evolutive character. Establishment of an effective therapeutic plan requires inter alia an analytical study of tumor mass (stages) and cytokinetics. Thus, "indolent", "slow" or "aggressive" myelomas have been reported. 19 consecutive symptomatic patients (12 with stage II, 6 with stage III) have been treated, with overall 5-year survival of 42%. In the light of these observations and the recent literature it appears essential to adopt a flexible therapeutic approach which allows a rapid switch from simple chemotherapy to heavy polychemotherapy when necessary, or postponement of treatment or halting of chemotherapy under selected conditions.

Drug Therapy, Combination↗
PubMed1984

[Studies on the mechanism of defective natural killer cytotoxicity in patients with multiple myeloma].

Multiple myeloma patients in the advanced or remission stage exhibit significantly lower natural killer (NK) activity than normal subjects. Single-cell assay showed that the number of active NK cells was the same for all patients. The maximum killing potential (Vmax) in advanced patients was lower than in normal subjects. These results suggest that defective NK activity in advanced patients is due to a reduced recycling capacity.

Adult↗
PubMed2002

Novel therapies for multiple myeloma.

Multiple myeloma (MM) continues to evade cure by conventional therapies, increasing the urgency for new, biologically based treatments. Reviewed in this discussion are novel chemotherapies under clinical trial that capitalize upon greater comprehension of tumor pathophysiology. In targeting tumor biology, these therapies serve as a model of treatment with great potential for improving outcomes in patients with MM.

2-Methoxyestradiol↗
PubMed2001

Infections in multiple myeloma.

Multiple myeloma is a relatively rare but severe hematologic malignancy. Marked depression in production of normal immunoglobulins, mild neutropenia, and alkylant/steroid therapy or BMT/SCT all produce major suppression of the immune system in the totality of patients. Recurrent bacterial, fungal, and viral infections are an important cause of morbidity and the most common cause of death in these subjects. Prompt diagnosis and appropriate anti-infective chemotherapy are essential in order to reduce the risk of mortality.

Bacterial Infections↗
PubMed2003

Vascular endothelial growth factor and its receptors in multiple myeloma.

Multiple myeloma (MM) progresses from an avascular to a vascular phase (active MM) accompanied by a significant increase in microvessel density in the bone marrow. This article summarizes the literature concerning the specific role played by vascular endothelial growth factor (VEGF) in this process. Recent applications of antiangiogenic agents that interfere with VEGF signaling and block MM progression are also described.

Angiogenesis Inhibitors↗