TY - JOUR
T1 - A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis
AU - Bødker, Julie Støve
AU - Brøndum, Rasmus Froberg
AU - Schmitz, Alexander
AU - Schönherz, Anna Amanda
AU - Jespersen, Ditte Starberg
AU - Sønderkær, Mads
AU - Vesteghem, Charles
AU - Due, Hanne
AU - Nørgaard, Caroline Holm
AU - Perez-Andres, Martin
AU - Samur, Mehmet Kemal
AU - Davies, Faith
AU - Walker, Brian
AU - Pawlyn, Charlotte
AU - Kaiser, Martin
AU - Johnson, David
AU - Bertsch, Uta
AU - Broyl, Annemiek
AU - van Duin, Mark
AU - Shah, Rajen
AU - Johansen, Preben
AU - Nørgaard, Martin Agge
AU - Samworth, Richard J
AU - Sonneveld, Pieter
AU - Goldschmidt, Hartmut
AU - Morgan, Gareth J
AU - Orfao, Alberto
AU - Munshi, Nikhil
AU - Johnsen, Hans Erik
AU - El-Galaly, Tarec
AU - Dybkær, Karen
AU - Bøgsted, Martin
N1 - Erratum:
In the 25 September 2018 issue, an author’s name was misspelled in the byline on page 2400 and the deceased author statement under “Authorship” on page 2408. “Hans Erik Johnson” should read “Hans Erik Johnsen.” The error has been corrected in the published article.
DOI 10.1182/bloodadvances.2019032979
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - http://10.1182/bloodadvances.2019032979
U2 - 10.1182/bloodadvances.2018018564
DO - 10.1182/bloodadvances.2018018564
M3 - Journal article
C2 - 30254104
SN - 2473-9529
VL - 2
SP - 2400
EP - 2411
JO - Blood advances
JF - Blood advances
IS - 18
ER -