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)

Multifocal extramedullary plasmacytomas (EMP) are an uncommon manifestation of plasma cell malignancies. We report two patients with multiple EMP who developed rapidly progressive and ultimately fatal disease shortly after undergoing nonmyeloablative, matched-related donor allogeneic peripheral blood stem cell transplantation (PBSCT). We have not observed a similar course in patients transplanted for multiple myeloma without extramedullary manifestations and hypothesize that the intense immunosuppression associated with the fludarabine, busulfan and anti-thymocyte globulin conditioning regimen may have contributed to rapid disease progression in the two EMP patients. Our observations support the assertion that extramedullary disease is a marker for an aggressive, refractory plasma cell malignancy and suggest that patients should be treated intensively from the time of diagnosis. The utility of a graft-versus-tumor effect and the role of nonmyeloablative allogeneic PBSCT is yet to be defined in patients with extramedullary plasma cell malignancies, but it is logical to consider using it at the time of minimal residual disease rather than at disease relapse or progression. Nevertheless, we recommend circumspection in the administration of highly immunosuppressive conditioning regimens to patients with refractory EMP and encourage further clinical research in this area.
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PMID:Nonmyeloablative allogeneic peripheral blood stem cell transplantation for multifocal extramedullary plasmacytomas progressing after autologous transplantation. 1184 Jan 48

We recently described a two-step negative selection procedure whereby peripheral blood stem cells (PBSCs) were efficiently purged of contaminating neoplastic cells by a combination of monoclonal antibodies. Here, we report 60 newly diagnosed multiple myeloma (MM) patients treated with a double transplant programme and randomized to receive either unmanipulated or in vitro purged PBSCs. We demonstrated that this technique is feasible and safe without significant loss of either CD34+ or CD3+ cells. Haematological engraftment and immunological reconstitution were rapid without treatment-related mortality. Using polymerase chain reaction (PCR), we compared the level of minimal residual disease (MRD) in PBSC before and after in vitro purging and in vivo after transplant. A median of one tumour cell per 10(2) normal cells (range 10(1)-10(5)) was seen in the unmanipulated aphereses with a 3-4 log reduction after manipulation in vitro. However, despite this tumour debulking, all patients remained PCR positive in vivo. At 3 years, the estimated event-free survival was 40% in the control arm and 72% in the experimental arm (P = 0.05), whereas the estimated overall survival was 83% in both arms. This suggests that autologous transplantation using efficiently purged PBSCs can be performed safely, but confirms the need for innovative protocols for MRD eradication in vivo.
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PMID:Negative selection of peripheral blood stem cells to support a tandem autologous transplantation programme in multiple myeloma. 1184 18

Multiple myeloma (MM) responds to, but is not cured by, chemotherapy and may therefore be amenable to tumor-specific immunization in the setting of minimal residual disease. The idiotype of the monoclonal immunoglobulin expressed by the tumor provides a clear tumor-specific antigen. Patients with follicular lymphoma have unequivocally established that idiotypic vaccination, administered when patients have minimal residual disease, has an antitumor effect and potential to improve the clinical outcome. This result and preclinical studies demonstrating that MM cells display idiotypic peptides on their surface in a form suitable for recognition and killing by host T cells, foster the application of idiotypic vaccination in MM. The current vaccine production involves idiotype protein purification for each patient followed by conjugation to exogenous, immunogenic carriers in order to break immunological tolerance. Furthermore, recent advances in molecular cloning and development of novel antigen delivery systems are making it possible to streamline the production of equally or more effective idiotypic vaccines. Particularly, DNA vaccines utilising genetic carriers to target idiotype on dendritic cells in vivo have proven successful in preclinical models. Additional candidate T cell antigens, such as MUC1, the cancer-testis antigens, and telomerase have been identified as potential targets for immunization. The possibility of using whole myeloma cells as a source of tumor antigens for immunotherapy is also being actively explored. Finally, clinical studies have begun in which dendritic cells are generated ex vivo, loaded with tumor antigen(s), and reinfused to immunize patients.
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PMID:Recent advances in multiple myeloma immunotherapy. 1204 83

Myeloma cells secrete monoclonal immunoglobulin (Ig), called myeloma protein. The variable (V) regions of myeloma proteins are unique to each plasma cell tumor, and therefore contain highly tumor-specific antigenic determinants called idiotopes (Id). In ongoing clinical trials, myeloma patients are vaccinated against the Id of their own myeloma protein. T cells with specificity for Id are thought to be of importance in eradication of multiple myeloma. We have developed a mouse model to study the molecular and cellular mechanisms for how Id-specific T cell protect against myeloma. A T cell receptor (TCR) transgenic mouse model has been established. CD4+ T cells in these mice recognize a particular Id-peptide presented on a MHC class II molecule. The Id-peptide represents an 11-mere of the variable region L chain of a particular mouse myeloma, MOPC315. TCR-transgenic mice are protected against a challenge with MOPC315 cells. Id-specific CD4+ cells protect in the absence of anti-Id antibodies. Dendritic cells in s.c. tumors take up myeloma protein and present Id-peptide on class II molecules to CD4+ cells which become activated and then kill bystander myeloma cells by an unknown mechanism. When TCR-transgenic mice are injected with large amounts of MOPC315 myeloma cells, resistance is overcome and some 30% of mice develop tumors. In these mice, Id-specific T cells become deleted as the myeloma protein serum concentration exceeds 50 microg/ml. In conclusion, in an experimental model, Id-specific CD4+ T cells protect against myeloma. However, once a tumor is established, Id-specific T cells become incapacitated. Based on these results, it is suggested that Id-vaccination in humans should be reserved for eradication of minimal residual disease, eg after high dose chemotherapy and stem cell transplantation.
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PMID:A mouse model for immunotherapy of myeloma. 1239 39

The concept of utilizing enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells from related and unrelated donors with lower early transplant-related mortality (TRM) and morbidity. This approach shifts tumor eradication to the graft-vs-host immune response directed against minor histocompatibility antigens expressed on tumor cells. This is not without risk, as the long-term effects of graft-versus-host disease (GVHD), it's treatment, or resulting complications and immunodeficiency may be life threatening. However, this approach does allow the application of a potentially curative procedure to elderly or medically infirm patients who would not tolerate high-dose conditioning regimens. Section I, by Dr. Sandmaier, describes the current use of nonmyeloablative regimens and matched related or unrelated donors for the treatment of patients with CLL, CML, acute leukemia, MDS, lymphoma, and myeloma. In Section II, Dr. Maloney discusses the use of cytoreductive autologous followed by planned non-myeloablative allografts as treatment for patients with myeloma or NHL. This tandem transplant approach has a lower TRM than conventional high dose allografting. The nonmyeloablative allograft may allow the graft-versus-tumor (GVT) immune response to eradicate the minimal residual disease that causes nearly all patients with low-grade NHL or myeloma to relapse following autologous transplantation. In Section III, Dr. Mackinnon discusses the risks and benefits of T cell depletion strategies to prevent acute GVHD, while retaining GVT activity by planned donor lymphocyte infusions. Finally, in Section IV, Dr. Shizuru discusses the relationship between GVHD and GVT activity. Future studies, employing a greater understanding of these issues and the separation of GVHD from GVT activity by immunization or T cell cloning, may allow nonmyeloablative allogeneic transplantation to be safer and more effective.
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PMID:Non-myeloablative transplantation. 1244 34

Bone marrow angiogenesis has been reported to increase in several hematologic malignant diseases, including multiple myeloma. Because high-dose chemotherapy combined with autologous stem cell transplantation (SCT) improves the response rate, event-free survival, and overall survival in patients with multiple myeloma (MM), we studied the changes in bone marrow microvessel density (MVD) in 21 patients who underwent high-dose chemotherapy combined with autologous SCT to determine whether there was persistently increased angiogenesis at the time of response. Bone marrow biopsy specimens were obtained before and after SCT for each patient and immunostained with anti-CD34 antibodies for the identification of microvascular endothelial cells. The mean value of MVD in 21 MM patients at initial diagnosis was 46.0 +/- 24.0 and in healthy controls was 26.8 +/- 8.54 (P = .046). The mean MVD at initial diagnosis was 46.0 +/- 24.0 compared with 29.0 +/- 12.5 after achievement of response with SCT, and there was a statistically significant difference (P = .004). Sixteen of 21 patients (76.2%) had decreased MVD after SCT, and 5 patients were found to have a greater than 50% decrease in MVD after SCT. However, there was no difference in overall survival between the patient group with decreased MVD after SCT and that without decreased MVD (P = .9370). These results suggest that angiogenesis plays an important role in MM. In addition, the persistence of MVD at the time of response indicates continuous stimulus of microvessels by minimal residual disease even after SCT.
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PMID:Comparison of microvessel density before and after peripheral blood stem cell transplantation in multiple myeloma patients and its clinical implications: multicenter trial. 1251 42

To evaluate the clinical impact of minimal residual disease in multiple myeloma, apheretic products from 51 autotransplanted patients were tested by fluorescent (GeneScan) polymerase chain reaction (PCR). Sixty-nine per cent of harvests were contaminated when evaluated for IgH rearrangement. Forty-six patients responded to transplant, with 52.9% achieving complete response (CR). The clinical response of patients was significantly influenced by the number of re-infused CD34+ cells. Positive PCR results of re-infused harvests were not significantly related to patient outcome. Median overall survival (OS) was 33 months, and a significant advantage for patients transplanted by 12 months from diagnosis was observed. Moreover, OS was longer for patients receiving PCR-negative stem cells, with 72% of patients surviving to 70 months in the group receiving PCR-negative harvests vs 48% in the group transplanted with contaminated precursors (not statistically significant). Ex vivo purging caused a reduction of contamination of up to 3 logs; nevertheless, 80% of purged harvests remained PCR-positive and the purging procedure did not alter response or survival rates. Thus, the failure of a predictive role for this highly sensitive molecular method could be explained by the assumption that in vivo persisting malignant cells are the true source of relapse in MM.
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PMID:Peripheral blood stem cell contamination evaluated by a highly sensitive molecular method fails to predict outcome of autotransplanted multiple myeloma patients. 1258 Sep 54

The use of high-dose chemotherapy and autologous stem cell support in the past decade has changed the outlook for patients with multiple myeloma. In newly diagnosed patients, complete remission rates of 25% to 50% can be achieved, with median disease-free and overall survivals exceeding 3 and 5 years, respectively. Despite these results, autologous transplantation has not changed the ultimately fatal outcome of the disease, as there is no substantial evidence of "cure" in most published studies. An additional high-dose chemotherapy course (with tandem transplants) appears to improve progression-free survival, although the effect is not discernible until 3 to 5 years posttransplant. The recent reports of tandem autologous transplant for maximum cytoreduction followed by nonmyeloablative allogeneic transplant for eradication of minimal residual disease appears promising and deserve further investigation. A central issue of tandem transplants, whether they involve autologous or allogeneic transplants, revolves around defining the subsets of patients who will benefit from the procedure. Good-risk patients (defined by normal cytogenetics and low beta-2-microglobulin levels), especially those who achieve a complete or near-complete response after the first transplant, appear to benefit the most from a second cycle. High-risk patients (defined by chromosomal abnormalities usually involving chromosomes 11 and 13 and high beta-2--microglobulin levels) whose median survival after tandem transplant is less than 2 years should be offered novel therapeutic interventions such as tandem "auto/allo" transplants. Until the efficacy and safety of this procedure is fully established, it should be limited to high-risk patients.
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PMID:Tandem transplantation in multiple myeloma. 1266 Dec 71

PRAME (Preferentially expressed antigen of melanoma), highly expressed in various solid tumor cells and normal testis, was first isolated as a human melanoma antigen recognized by cytotoxic T cells (CTL). This gene was also expressed in some of the hematological malignancies, including acute myelogenous leukemia (AML) and multiple myeloma. We and others have extensively evaluated the PRAME expression in various hematological malignancies and demonstrated high expression of the PRAME gene in subsets of AML, chronic myelogenous leukemia, acute lymphocytic leukemia, lymphoma and multiple myeloma. In addition, we have demonstrated that PRAME was a useful marker for detection of minimal residual disease (MRD) in patients with leukemia, particularly those leukemias in which tumor specific markers are currently unavailable. Since PRAME was first identified as a tumor antigen recognized by T cells, the possibility that PRAME is a leukemia antigen recognized by T cells was evaluated, and it was found that PRAME-positive leukemia cell lines and fresh leukemia cells were susceptible to lysis by the PRAME-specific CTL. Five CTL epitopes associated with either HLA-A*0201 or HLA-A*2402 have recently been identified. It is, therefore, an attractive strategy to apply PRAME specific immunotherapy on patients with PRAME positive leukemia in MRD condition.
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PMID:Preferentially expressed antigen of melanoma (PRAME) in the development of diagnostic and therapeutic methods for hematological malignancies. 1268 12

Since cancer is the result of genetic mutations, it should be well suited for correction through gene therapy. Hematological malignancies in which human gene transfer has been performed are leukemias, lymphomas, graft-versus host disease after allogeneic bone marrow transplantation in leukemia, and multiple myeloma. Gene therapy may be used to induce or enhance an antitumor immunological reaction, to correct a genetic defect in the tumor cells, to render the malignant disease more susceptible to conventional therapies, to make the normal host cells more resistant to conventional therapies, or to track cells used for therapy. Gene therapy will probably be most valuable for the eradication of minimal residual disease after the use of conventional therapies.
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PMID:Gene therapy for hematological malignancies. 1274 73


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