• Document: Standardization of Minimal Residual Disease Testing in Multiple Myeloma
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OPINION Standardization of Minimal Residual Disease Testing in Multiple Myeloma Linda B. Baughn1 and Michael A. Linden2* Multiple myeloma (MM)3 is an incurable neo- approaches improve, the lower limit of detection plasm of the bone marrow characterized by a changes (2). clonal expansion of plasma cells with presence of a monoclonal spike (M-spike) in the serum and/or urine (1). However, there have been major im- FLOW CYTOMETRIC MRD TESTING provements in the way that MM is treated, pro- longing overall survival (OS). As OS increases, Multicolor flow cytometry has facilitated the rel- clinicians and researchers have been increasingly atively widespread adoption of flow cytometric investigating the utility of minimal residual disease MRD (FCMRD) testing. A recent survey estimates (MRD) testing by flow cytometry and molecular di- that there are more than 90 predominantly North agnostics. Simultaneously, clinical hematology and American laboratories that perform FCMRD (3). hematopathology teams are driving efforts to Most laboratories use similar markers to identify achieve standardization of these laboratory-devel- plasma cells, including CD45, CD38, and CD138 (4). oped tests (LDTs). These markers will identify plasma cells, but do not distinguish “normal” from “neoplastic” plasma cells (Fig. 1). Additional cell surface mark- MINIMAL RESIDUAL DISEASE ers include CD19, CD27, CD56, CD81, and CD117, which are differentially expressed among normal Historically, when a patient has a hematologic and neoplastic plasma cells (4). Cytoplasmic light malignancy such as MM, residual disease is de- chain restriction is helpful to confirm aberrant tected by morphologic examination of bone mar- immunophenotype and residual disease (4). Typ- row by light microscopy as well as serum/urine ical Boolean gating strategies to differentiate protein electrophoresis. However, as technology neoplastic from normal plasma cells are de- has improved, we are now able to detect very small picted in Fig. 1. populations of clonal cells that cannot be seen by There is no Food and Drug Administration– light microscopy—this is termed “MRD.” Some approved FCMRD test; therefore, they are all con- have suggested that the word “measurable” be sidered LDTs. However, the International Myeloma substituted for “minimal,” because as our analytical Working Group (IMWG) has encouraged researchers 1 Department of Laboratory Medicine and Pathology, Division of Laboratory Genetics and Genomics, Mayo Clinic, Rochester, MN; 2Department of Laboratory Medicine and Pathology, Division of Hematopathology, University of Minnesota, Minneapolis, MN. *Address correspondence to this author at: 420 Delaware St. SE, Minneapolis, MN 55455. Fax 612-626-6662; e-mail linde013@umn.edu. DOI: 10.1373/jalm.2016.020883 © 2017 American Association for Clinical Chemistry 3 Nonstandard abbreviations: MM, multiple myeloma; OS, overall survival; LDT, laboratory-developed test; MRD, minimal residual disease; FCMRD, flow cytometric minimal residual disease; IMWG, International Myeloma Working Group; ASO-qPCR, allele-specific oligonucleotide quan- titative PCR; NGS, next-generation sequencing; LOD, limit of detection; CAP, College of American Pathologists. .................................................................................................. 118 JALM | 118 –122 | 02:01 | July 2017 Standardization Myeloma MRD OPINION Fig. 1. Representative flow plots from validation of a standard sensitivity flow cytometry– based MRD assay. Row A represents a patient that has 0.8% clonal plasma cells. In the left column, plasma cells are first selected based on their bright expression CD38 and slightly dimmer CD45 expression. Plasma cells are then analyzed for CD19 and CD56 expression (middle column). The clonal/neoplastic plasm

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