Hans Erik Johnsen, Aalborg University Hospital, Denmark.
by Maria Dalby: The gene expression profiles of myeloma plasma cells in the normal bone marrow can be used for defining B-cell subset-associated gene signatures (BAGS) that can predict survival outcomes in MM patients.
A group of researchers in Denmark, Germany, the Netherlands, the UK, USA and Spain have proposed a new classification system for MM based on BAGS subtyping based on a cell of origin (COO) approach. The results of a proof-of-concept study were presented by Professor Hans Erik Johnsen from Aalborg University Hospital in Denmark.
The methodology used was analogous to that used for generating the BAGS classifiers in diffuse large B-cell lymphoma in a recently published study.1 Fluorescence-activated cell sorting (FACS) and gene expression profiling (GEP) data sets were combined for cells in the normal B-cell hierarchy in the bone marrow: PreB-I, PreB-II, immature, naive, memory, and plasma cells. Regularised multinomial regression generated six discrete classifiers representing one BAGS per subset, from a total of 55 genes ranging from 15-24 genes per subtype. BAGS assignment was validated in a prognostic meta-analysis comprising 926 patients who had received melphalan as first-line therapy in three clinical trials including the HOVON65/GMMG-HD4 and MRC Myeloma IX trials.2-5Five BAGS subtypes were identified in the meta-analysis cohort: PreB-II, immature, naive, memory, and plasma cells. A highly significant correlation was found between BAGS subtype and overall survival (p=5.2·10-8) and progression-free survival (p=1.5·10-6). The PreB-II and memory subtypes were associated with worse survival and a greater likelihood of ISS stage III disease compared with the immature, naive, and plasma cell subtypes. Cox proportional hazard meta-analysis showed that the five BAGS subtypes added significant and independent prognostic information to that provided by the translocation and cyclin D (TC) classification system and plasma beta-2 microglobulin levels. Significant correlation was also found between the PreB-II subtype and proliferation index, risk profiling (p<0.0001) and beta-2 microglobulin levels (p<0.001). Based on the observations in the proof-of-concept study in MM the investigators concluded that the prognostic impact of the BAGS subtypes supports reversible phenotypic plasticity in MM and provides a model for further investigation of clonal plasticity associated with oncogenesis and dedifferentiation
- Dybkaer K, Bogsted M, Falgreen S, et al. Diffuse large B-cell lymphoma classification system that associates normal B-cell subset phenotypes with prognosis. J Clin Oncol 2015;33:1379-88.
- Zhan F, Huang Y, Colla S, et al. The molecular classification of multiple myeloma. Blood 2006;108:2020-8.
- Barlogie B, Mitchell A, van Rhee F, et al. Curing myeloma at last: defining criteria and providing the evidence. Blood 2014;124:3043-51.
- Broyl A, Hose D, Lokhorst H, et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood 2010;116:2543-53.
- Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica 2012;97:442-50.