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Multiple myeloma is a disorder of B-lymphocytes characterized by infiltration of the bone marrow with a monoclonal population of atypical plasma cells. In most patients, an abnormal monoclonal protein can be detected in the serum and/or urine. Although this disorder involves a differentiated B-lymphocyte, there are data to suggest that the abnormality occurs early in the development of hematopoietic cells. The median survival is only three to four years with a five-year survival of 20-30%. Myeloma is believed to be incurable with standard chemotherapy and treatment with agents such as melphalan and prednisone has a response rate of 40-60% with less than 10% complete responses. Salvage regimens, such as vincristine, doxorubicin and dexamethasone (VAD) results in a higher response rate, however, long-term control of disease and survival remains poor.
Studies utilizing dose-intensity with high-dose chemotherapy with or without radiotherapy and autologous stem cell support have reported overall response rates of 50-100% with complete response rates of 15-50% which are superior to historical controls treated with standard chemotherapy. A prospective randomized trial from France was recently published that demonstrated improved survival in patients who received autologous transplants for newly diagnosed multiple myeloma1. In this study 200 patients with myeloma were randomized between standard chemotherapy (VMCP/BVAP) for 18 cycles versus four to six cycles of VMCP/BVAP followed by autologous bone marrow transplantation. The five-year probability of event-free survival was 10% in the standard therapy group and 28% in the transplantation group. Five-year overall survival estimates were also superior in the transplantation arm.
High-dose therapy with autologous peripheral blood progenitor cell rescue for multiple myeloma was initiated at Stanford University in 1990 and a total of 77 patients have been treated. In our current high-dose sequential regimen, patients are treated with four to six cycles of VAD and subsequently receive cyclophosphamide and G-CSF followed by peripheral blood progenitor cell collection. Patients then receive high-dose VP-16 and G-CSF, again followed by peripheral blood progenitor cell collection . The cyclophosphamide mobilized cells are stored as backup and the VP-16 mobilized cells are used for rescue following myeloablative therapy. When all patients who received autologous transplants at Stanford are analyzed, including a group of patients with resistant disease, the four year event-free survival is 26%, overall survival is 45% and the estimated relapse rate is 69%.
Relapse remains the major cause of treatment failure and although the results of high-dose therapy followed by autologous stem cell rescue appear to be superior to standard dose therapy there appears to be a continuous rate of relapse following these procedures. There is some suggestion that allogeneic transplantation may be curative for this disease due to a graft-versus-myeloma effect.
We recently began a trial in collaboration with Dr. Ronald Levy in the Division of Oncology and Dr. Edgar Engleman in the Department of Pathology in an attempt to decrease the relapse rate after transplantation using specific idiotype vaccines derived from the patient's monoclonal protein. In order to stimulate the immune system, dendritic cells, a potent antigen presenting cell which can be obtained from peripheral blood, are used to present the patient's specific myeloma protein and induce a cytotoxic immune response. We are able to prepare a vaccine from patients by isolating the myeloma protein from peripheral blood and we also clone the specific immunoglobulin gene rearrangement for molecular studies of the bone marrow after transplantation to follow disease activity, as well as to assess the development of an immune response. The patient receives standard cytoreductive chemotherapy with VAD administered by their primary hematologist/oncologist followed by the high-dose sequential therapy and transplantation. Three months following transplantation, the patient receives two monthly infusions of dendritic cells stimulated with the patient's specific immunoglobulin and subsequently five monthly vaccinations with the immunoglobulin protein alone. This study continues to accrue patients.
The randomized study from France confirms the role of autologous stem cell transplantation for multiple myeloma. We continue to perform standard autologous transplantation for patients with multiple myeloma and hope that the approach using dendritic cells as a form of immunotherapy after transplantation will allow us to improve the survival of patients with this disease.
Source: Dr. Keith S.
Phone: (408) 723-0822
FAX: (408) 725-8950
HEADLINE: Genzyme Transgenics' Cancer Vaccine Produces Immune Response in Multiple Myeloma Patients; Clinical Trial Will Be Accelerated Under New Agreement
Genzyme Transgenics Corp. (Nasdaq: GZTC) today announced that its idiotypic cancer vaccine produced a tumor-specific immune response in four of five multiple myeloma patients treated in a phase I clinical trial being conducted by researchers at the National Cancer Institute (NCI) and University of Arkansas for Medical Sciences (UAMS).
The tumor-specific response experienced by patients in the trial indicates the vaccine's potential ability to reduce or eliminate residual cancer in patients who have not responded to other therapies. Based on these preliminary results, the company will accelerate vaccine production and patient enrollment for an expanded phase I clinical trial under a new agreement with UAMS.
Idiotypic cancer vaccines contain proteins derived from a patient's own tumor. Results of the trial were recently presented at the Sixth International Workshop on Multiple Myeloma. FRAMINGHAM, Mass., July 31
"These results demonstrate that idiotypic vaccines can produce anti-tumor immunity in myeloma patients who have partially or completely responded to prior chemotherapy and transplantation," said Larry W. Kwak, M.D., Ph.D., principal investigator at the NCI, who vaccinates patients in the trial. "The new agreement between Genzyme Transgenics and UAMS allows us to vaccinate a greater number of myeloma patients and gives us the hope of improving and sustaining these immune responses."
The new agreement, which is an adjunct to the existing Cooperative Research and Development Agreement (CRADA) between Genzyme Transgenics and the NCI, will allow the company to manufacture myeloma vaccines for at least 30 patients this year. Genzyme Transgenics has produced 28 individual, patient- specific vaccines since 1994.
"These results give us further reason to believe that idiotypic vaccines may provide a uniquely effective approach to the treatment of myeloma and other incurable blood malignancies," said James A. Geraghty, Genzyme Transgenics' president and chief executive officer. "This agreement reflects Genzyme Transgenics' commitment to expand its production facilities and processes for cancer vaccines under the terms of our CRADA with the NCI."
Multiple myeloma is a type of cancer that is caused by an over- proliferation of plasma cells. This type of cancer often spreads to the bone marrow. Current treatment involves transplanting a patient's own blood stem cells into the blood stream, coupled with a high dose of chemotherapy. This therapy can induce an initial complete response in 40 to 50 percent of newly- diagnosed myeloma patients, but many patients experience disease relapse.
In addition to assessing safety, investigators in the phase I trial also hope to determine whether inoculating patients with idiotypic vaccines both before and after transplantation can induce sustained anti-tumor immunity that would eliminate any contaminating myeloma cells present in the transplant material or that remain in the patient. If the vaccines work, they could increase the chances for sustained complete response to the transplant.
"These findings are important because we can now combine autologous transplantation, which we know can induce remissions in some myeloma patients, with a therapy that may reduce or eliminate residual disease," said Bart Barlogie, M.D., Ph.D.,UAMS's chief of hematology and oncology.
Genzyme Transgenics chose UAMS as the trial site because researchers there transplant autologous stem cells into a substantial number of multiple myeloma patients each year.
Genzyme Transgenics is a biotechnology company focused on biopharmaceutical development through transgenic production of genetically engineered therapeutic products; specialized contract research services for pharmaceutical, biotechnology, medical device and other companies; and the production of cancer vaccines. Genzyme Corp. owns approximately 43 percent of the outstanding stock of Genzyme Transgenics and has allocated these shares to Genzyme General (Nasdaq: GENZ).
This press release contains forward-looking statements about the potential efficacy of idiotypic vaccines for the treatment of multiple myeloma. Actual results may differ materially from these projections, depending on the results of this and subsequent clinical trials.
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Source: Genzyme Transgenics
Contact: Patricia F. Dimond, Ph.D., 1 (508) 270-2374 , or Cheryl Greenhouse, 1 (617) 252-7785, both of Genzyme Transgenics