Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allogeneic hematopoietic stem cell transplantation with an human leukocyte antigen-matched related or unrelated donor has been the curative treatment of choice for young patients with chronic phase chronic myelogenous leukemia. The introduction of imatinib, a selective inhibitor of the Bcr-Abl protein kinase, as well as a new generation of other tyrosine kinase inhibitors that are effective in obtaining major and complete cytogenetic responses with minimal toxicity, has resulted in significant changes in the standard approach for newly diagnosed patients. In this article, we will address the role of allogeneic transplantation in the context of imatinib and other tyrosine kinase inhibitors.
Clin Lymphoma Myeloma 2007 Mar
PMID:Allogeneic hematopoietic progenitor cell transplantation for the treatment of chronic myelogenous leukemia in the era of tyrosine kinase inhibitors: lessons learned to date. 1738 18

The identification of novel tumor-associated antigens, especially those shared among patients, is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we examined whether Dickkopf-1 (DKK1), a protein that is not expressed in most normal tissues but is expressed by tumor cells from almost all patients with myeloma, could be a good candidate. We identified and synthesized DKK1 peptides for human leukocyte antigen (HLA)-A*0201 and confirmed their immunogenicity by in vivo immunization in HLA-A*0201 transgenic mice. We detected, using peptidetetramers, low frequencies of DKK1 peptide-specific CD8-positive (CD8(+)) T cells in patients with myeloma and generated peptide-specific T-cell lines and clones from HLA-A*0201-positive (HLA-A*0201(+)) blood donors and patients with myeloma. These T cells efficiently lysed peptide-pulsed but not unpulsed T2 or autologous dendritic cells, DKK1-positive (DKK1(+))/HLA-A*0201(+) myeloma cell lines U266 and IM-9, and, more importantly, HLA-A*0201(+) primary myeloma cells from patients. No killing was observed on DKK1(+)/HLA-A*0201-negative (HLA-A*0201(-)) myeloma cell lines and primary myeloma cells or HLA-A*0201(+) normal lymphocytes, including B cells. These results indicate that these T cells were potent cytotoxic T cells and recognized DKK1 peptides naturally presented by myeloma cells in the context of HLA-A*0201 molecules. Hence, our study identifies DKK1 as a potentially important antigen for immunotherapy in MM.
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PMID:Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma. 1751 99

The human leukocyte antigen (HLA) system could play an essential role in multiple myeloma (MM) disease control. This report describes the results comparing HLA-DRB1 phenotypic frequencies in 181 MM patients (53 smoldering/indolent MM and 128 symptomatic MM patients) and healthy individuals. Higher DRB1*01 phenotypic frequencies were found in the smoldering patients compared with symptomatic MM patients (38% vs 14%, P = 0.001) and with the healthy individuals (38% vs 22%, P = 0.01). Additionally, higher DRB1*07 phenotypic frequencies were found in symptomatic MM compared with control population (38% vs 28%, P = 0.01). The present data suggest that HLA-DRB1*01 individuals may have a better ability to efficiently present myeloma-related antigens to immunocompetent cells, which could favor a better immune response against the tumor. This would translate into a more appropriate disease control associated with more indolent disease and prolonged survival.
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PMID:The presence of DRB1*01 allele in multiple myeloma patients is associated with an indolent disease. 1839 87

One hundred ten patients with multiple myeloma (MM) failing to achieve at least near-complete remission (nCR) after a first autologous stem cell transplantation (ASCT) were scheduled to receive a second ASCT (85 patients) or a reduced-intensity-conditioning allograft (allo-RIC; 25 patients), depending on the human leukocyte antigen (HLA)-identical sibling donor availability. There was a higher increase in complete remission (CR) rate (40% vs 11%, P = .001) and a trend toward a longer progression-free survival (PFS; median, 31 months vs not reached, P = .08) in favor of allo-RIC. In contrast, it was associated with a trend toward a higher transplantation-related mortality (16% vs 5%, P = .07), a 66% chance of chronic graft-versus-host disease and no statistical difference in event-free survival and overall survival. Although the PFS plateau observed with allo-RIC is very encouraging, this procedure is associated with high morbidity and mortality, and therefore it should still be considered investigational and restricted to well-designed prospective clinical trials. This trial is registered at ClinicalTrials.gov ID number NCT00560053.
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PMID:A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. 1894 79

Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cytoreduction and graft-versus-myeloma effects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft followed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT from human leukocyte antigen-identical siblings. Postgrafting immunosuppressive agent was cyclosporine or tacrolimus and mycophenolate mofetil. Forty-two percent of patients developed grade 2 to 4 acute graft-versus-host disease (GVHD) and 74% extensive chronic GVHD. Five-year nonrelapse mortality after allografting was 18%, 95% related to GVHD or infections. Among 95 patients with detectable disease, 59 achieved complete remissions. Median time to progression was 5 years. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 3 years. Five-year OS and PFS were 64% and 36%, respectively. Seventy-three patients receiving autoHCT within 10 months from treatment initiation had 5-year OS of 69% and PFS of 37%. In multivariate analysis, beta-2-microglobulin of more than 3.5 microg/mL at diagnosis and auto/alloHCT more than 10 months after treatment initiation correlated with shorter OS (P = .03 and P = .02) and PFS (P = .04 and P = .03), whereas Karnofsky scores less than 90% at allotransplantation correlated with shorter PFS only (P = .005). Long-term disease control and GVHD remain key issues.
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PMID:Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. 1934 98

Monosodium urate (MSU) crystals have been reported to evoke specific cell immunity and to work as an adjuvant in a mouse model. The crystals also have another unique characteristic to bind with positively charged proteins, which could help to deliver some antigens into human dendritic cells (DC). We focused on the application of MSU crystals as not only an adjuvant but also as a carrier of positively charged antigenic protein to induce human cytotoxic T cells (CTL) efficiently in vitro. We selected human leukocyte antigen (HLA)-A2 expressing the multiple myeloma IM-9 cell line and its product idiotype (Id) protein as one of the best pairs of target cells and positively charged tumor-specific antigen, respectively. Following the sensitization of DC derived from HLA-A2-positive volunteers pulsed with tumor-specific monoclonal immunoglobulin G-Fab fragments (IM-9 Fab) attached to MSU crystals, the DC-stimulated CD8(+) T cells killed significantly more target cells (40.1 +/- 1.7%) than those stimulated by DC pulsed with MSU crystals alone (6.2 +/- 8.6%, P < 0.01) or IM-9 Fab alone (4.7 +/- 8.1%, P < 0.01). These cytotoxic effects of the DC-stimulated CD8(+) cells were reduced when MSU crystals were precoated with fetal bovine serum. In addition, we confirmed that MSU crystals facilitated human DC to express the maturation marker, CD83 and deliver (Fab')(2), attaching to the crystals by flow cytometer analysis. MSU crystals have distinct advantages of a protein carrier binding with positively charged proteins and delivering antigenic protein into DC, as well as an adjuvant promoting DC maturation and inducing CTL.
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PMID:Binding of monosodium urate crystals with idiotype protein efficiently promote dendritic cells to induce cytotoxic T cells. 1903 77

Down-regulation of conventional human leukocyte antigen (HLA) class I and II molecules from the surface of tumor cells is an important mechanism for tumor immune evasion, survival, and progression. Whether CD1d, a nonconventional, glycolipid-presenting HLA class I-like molecule instructing the function of the immunoregulatory invariant NKT cells can affect tumor cell survival is not known. Here we show that CD1d is highly expressed in premalignant and early myeloma, but with disease progression its expression is reduced and eventually in advanced stages and myeloma cell lines is lost altogether, suggesting that CD1d impacts negatively on myeloma cell survival. Consistent with this, engagement of CD1d by anti-CD1d monoclonal antibodies (mAbs) induces cell death of myeloma cell lines with restored CD1d expression and primary myeloma cells. Cell death induced by monoclonal antibody engagement of CD1d is associated with overexpression of proapoptotic Bax and mitochondrial membrane potential loss but it is caspase-activation independent; in addition, it requires the cytoplasmic tail but not the Tyr residue critical for lysosomal sorting of CD1d. Finally, anti-CD1d cooperates with antimyeloma agents in the killing of myeloma cells. Thus, this work provides evidence linking a novel function of CD1d in the regulation of cell death with tumor survival and progression in humans.
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PMID:Regulation of multiple myeloma survival and progression by CD1d. 1905 91

Despite recent advances, allografting remains the only potential cure for myeloma. From July 1999 to June 2005, 100 newly diagnosed patients younger than 65 years were enrolled in a prospective multicenter study. First-line treatment included vincristin, adriamycin, and dexamethasone (VAD)-based induction chemotherapy, a cytoreductive autograft (melphalan 200 mg/m(2)) followed by a single dose of nonmyeloablative total body irradiation and allografting from an human leukocyte antigen (HLA)-identical sibling. Primary end points were the overall survival (OS) and event-free survival (EFS) from diagnosis. After a median follow-up of 5 years, OS was not reached, and EFS was 37 months. Incidences of acute and chronic graft-versus-host disease (GVHD) were 38% and 50%, respectively. Complete remission (CR) was achieved in 53% of patients. Profound cytoreduction (CR or very good partial remission) before allografting was associated with achievement of posttransplantation CR (hazard ratio [HR] 2.20, P = .03) and longer EFS (HR 0.33, P < .01). Conversely, development of chronic GVHD was not correlated with CR or response duration. This tandem transplantation approach allows prolonged survival and long-term disease control in patients with reduced tumor burden at the time of allografting. We are currently investigating the role of "new drugs" in intensifying pretransplantation cytoreduction and posttransplantation graft-versus-myeloma effects to further improve clinical outcomes. (http://ClinicalTrials.gov; NCT-00702247.).
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PMID:Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. 1934 98

The Melan-A(aa26-35) (EAAGIGILTV) peptide is a human leukocyte antigen (HLA)-A2-restricted T-cell epitope within the Melan-A/MART-1 tumor antigen expressed on malignant melanoma cells. Melan-A and Melan-A analog (ELAGIGILTV, Melan-A(aa26-35*A27L)) specific T-cells can be expanded reliably for immunotherapeutic approaches in vitro. We studied the ability of Melan-A analog (ELAGIGILTV, Melan-A(aa26-35*A27L)) specific T-cells to recognize the HM1.24(aa22-30) (LLLGIGILV) peptide within the HM1.24 antigen presented by normal and malignant plasma cells. Peripheral blood mononuclear cells from HLA-A2+ healthy donors and HLA-A2+ multiple myeloma (MM) patients were stimulated with Melan-A analog peptide-loaded autologous dendritic cells, and expanded in vitro. T-cell activation was assessed by interferon-gamma specific enzyme-linked immunosorbent spot and cytotoxicity by (51)Chromium-release-assays. The frequency of Melan-A analog specific CD8+ T-cells was detected by using tetramers. Melan-A analog specific T-cells from HLA-A2+ healthy donors and HLA-A2+ MM patients showed a interferon-gamma secretion mediated by HM1.24(aa22-30) peptide-pulsed T2 cells and lysed the HLA-A2+ HM1.24+ U266 and XG-1 human myeloma derived cell-lines as well as the B-lymphoblastoid cell-line IM-9. Melan-A analog specific T-cells from MM patients specifically lysed autologous MM cells. The current data demonstrate that Melan-A analog specific T-cells crossreact with HM1.24(aa22-30). They might be a tool for the future use in immunotherapy against MM.
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PMID:Melan-A/MART1 analog peptide triggers anti-myeloma T-cells through crossreactivity with HM1.24. 1948 48

The molecular basis of monoclonal gammopathy of undetermined significance (MGUS) progression to a malignant monoclonal gammopathy remains poorly understood. It was recently suggested that this process involves the suppression of innate and adaptive immunity. In this study, we examined immunogenic differences in bone marrow plasma cells among individuals without gammopathy (controls) and patients with MGUS, multiple myeloma (MM), and plasma cell leukemia. We detected differences in major histocompatibility complex (MHC) class I expression, MHC class I chain-related molecule A, and CD95 that were more evident between MGUS and MM samples; there appeared to be a critical imbalance between natural killer (NK)-cell activating and inhibitory signals during the transition from MGUS to MM. Our results indicate that the human leukocyte antigen (HLA) class I(bright), MICA(dim/-), and CD95(dim/-) immunophenotype reported in myeloma cells may result from an extensive interaction of malignant cells with cytotoxic T and NK cells and appears to be immunoedited for the evasion of immunosurveillance.
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PMID:Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma: implications for tumor evasion of T and NK cells. 1958 Aug 33


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