Plasma cell dyscrasias are a group of related disorders which include; Multiple Myeloma (multiple forms), Waldenström’s macroglobulinemia, Heavy and Light chain disease, and other Immunoglobulin secreting neoplasms. Generally, these all involve the expansion of a single clone of an Immunoglobulin secreting cell (end stage B cell to plasma cell). While this Webinar will focus primarily on important laboratory issues when developing clinical trials involving Multiple Myeloma, many of the issues to be discussed are also relevant to the other plasma cell dyscrasias. Multiple myeloma accounts for approximately 15% of all hematopoietic malignancies and has a bleak prognosis. To address this, there is considerable effort to develop new treatments for this not uncommon malignancy. Paramount to the correct assessment of the efficacy of these new treatment trials is accurate laboratory monitoring.
In Multiple Myeloma, it is the abnormal plasma cells, their products (immunogloublins; IgG, IgM, IgA, IgD, and IgE classes), and their effect on the body chemistries, which is the basis for laboratory diagnosis and monitoring of this disease. Specifically, quantitation of the monoclonal proteins secreted by the malignant plasma cells in the serum and urine are primary routine monitoring tools. In fact, the International Response Criteria (IRC) uses the quantification of the monoclonal proteins in the serum and urine using serum electrophoresis and Immunofixation testing to assess degrees of response to treatment in addition to a determination of the number of plasma cells found in the bone marrow. In addition, the monoclonal proteins are also often monitored by examining total immunoglobulin levels (usually only IgG, IgM, and IgA, as IgE and IgD myelomas are very rare). While these are very accurate when the tumor burden is high, they can become very inaccurate when the tumor burden is low. There are now new technologies available which can more accurately assess monoclonal antibodies via IgG, IgM, and IgA quantitation by further quantifying the immunoglobulins by their light chain as well (ex. IgG kappa and IgG lambda).
In assessing the involvement and response to treatment by serum electrophoresis and Immunofixation, variability in testing must be kept to a minimum. Both of these tests have degrees of subjectivity to the method which is highly dependent on the skills and experience of the technologists and the laboratory performing the test. In fact, a 2015 College of American Pathologists (CAP) proficiency survey demonstrated that between different manufacturers’ methods and across laboratories, a variation of 221% in the quantitation of the monoclonal protein in serum electrophoresis was found. When one compared different laboratories using the same method, this variation dropped, but still averaged 150%. In addition, the interpretation of serum electrophoresis and Immunofixation testing in Multiple Myeloma trials has been further complicated by many of the treatments themselves. In trials utilizing targeted therapeutic monoclonal antibodies, the drug itself has been reported to interfere with proper assessment of the patient. The ability to identify and recognize this is critical to proper interpretation and assessment of the therapeutic response, so that bone marrow evaluations can be performed at appropriate times to confirm the response. This underscores the importance of following myeloma patients in a laboratory with a dedicated group of myeloma experienced technologists. This is even more important in clinical trials as there are steps which a centralized myeloma experienced clinical trials laboratory can take to keep this variation to a minimum and insure accurate assessment of trial subjects.
Marc Golightly, PhD, SI (ASCP), Professor of Pathology, Stony Brook University, and Consultant, ICON Laboratory Services
Marc Golightly is a Professor of Pathology at Stony Brook University and is the director of the Medical Center’s Clinical Immunology Laboratory, Clinical Flow Cytometry Laboratory, and the University’s Research Flow Cytometry Core Facility. He graduated from UCLA with a Ph.D. in Microbiology and Immunology. Subsequently, he did a post doctorate at UCLA in Tumor Immunology, followed by a three year post doctorate/Fellowship in Clinical Immunology at Duke University. Since then, he rose through the ranks from assistant professor to full professor at Stony Brook University in New York and has been extensively involved with laboratory diagnosis of multiple myeloma for over 30 years. In addition, he has been a consultant at Icon Central Laboratories in Farmingdale, NY for Myeloma clinical trials and Flow cytometry since 2000. He has over 115 publications in peer reviewed journals and invited chapters in books and has been invited to speak at numerous national and international meetings.
Domenica Gandini, MD PhD, Medical Director, ICON Clinical Research
Dr. Domenica Gandini is a Medical Director, based in ICON’s Southampton, UK office. Domenica acquired her Medical degree from the University of Ferrara in Italy before gaining subsequent Completion of Specialization, Haematology credentials (Italian and GMC registry) and a Ph.D. in Experimental Haematology from the Universities of Modena and Ferrara. After her Clinical Training, Domenica worked as a Post-Doctoral fellow in Institutions both in Europe and US such as the Haematology Department of the University of Ferrara, the Haematology Department at the Royal Postgraduate Medical School in London, UK, the Human genetics Department at the Memorial Sloan Kettering Cancer Centre in New York, and the Haematology Department of the University College London, UK and attended the Lymphoma Clinic at Bart’s and the London Hospital, London. Domenica’ s research and interest mainly focused on Molecular mechanisms of both Myeloid and Lymphoid Haematological Malignancies.
Domenica joined ICON in 2008 and since then has been monitoring mainly clinical trials with Haematology/ Oncology Indications including, among others Multiple Myeloma, AML, Chronic Lymphocytic Leukaemia and Lymphomas.
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ICON plc is a global provider of drug development solutions and services to the Pharmaceutical, biotechnology and medical device industries. The company specialises in the strategic development, management and analysis of programs that support clinical development – from compound selection to Phase I-IV clinical studies. With headquarters in Dublin, Ireland, ICON currently, operates from 89 locations in 37 countries and has approximately 12,200 employees.
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