A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis.
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Date
2018-09-25Author
Bødker, JS
Brøndum, RF
Schmitz, A
Schönherz, AA
Jespersen, DS
Sønderkær, M
Vesteghem, C
Due, H
Nørgaard, CH
Perez-Andres, M
Samur, MK
Davies, F
Walker, B
Pawlyn, C
Kaiser, M
Johnson, D
Bertsch, U
Broyl, A
van Duin, M
Shah, R
Johansen, P
Nørgaard, MA
Samworth, RJ
Sonneveld, P
Goldschmidt, H
Morgan, GJ
Orfao, A
Munshi, N
Johnson, HE
El-Galaly, T
Dybkær, K
Bøgsted, M
Type
Journal Article
Metadata
Show full item recordAbstract
Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients' myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM.
Collections
Subject
B-Lymphocyte Subsets
Humans
Multiple Myeloma
Prognosis
Survival Analysis
Gene Expression Profiling
Immunophenotyping
Phenotype
Transcriptome
Biomarkers, Tumor
Research team
Myeloma Biology and Therapeutics
Myeloma Group
Language
eng
Date accepted
2018-07-17
License start date
2018-09
Citation
Blood advances, 2018, 2 (18), pp. 2400 - 2411
Publisher
ELSEVIER