Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma

Abstract

BackgroundProliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds. Design and MethodsWe assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores. ResultsIn the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progressionassociated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P<0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β2-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores. ConclusionsProliferation assessed by gene expression profiling, being independent of serum-β2-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for riskadapted anti-proliferative treatment on the background of conventional and gene expressionbased risk factors.

A gene expression signature for high-risk multiple myeloma

“…To this end, the following signatures were evaluated: UAMS-70, UAMS-17, UAMS-80, IFM-15, gene proliferation index (GPI-50), MRC-IX-6 and MILLENNIUM-100. [9][10][11][12][13][14] These signatures were evaluated as continuous variables as well as using the cut-off values as published (Figures 2a-e, Supplemental Figure S2 and Supplemental Documents A and B). Overall, the performance of the EMC-92 signature is robust, consistent and compares favorably with previously published signatures.…”

Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy

“…The prognostic impact of this gene correlates well with the known poor prognosis of MM with high proliferation. 38 Previous studies confirm the presence call of CTAG2 and MAGEA6 to be of prognostic importance in terms of event free survival alongside the presence call of MAGEA3, MAGEA1, MAGEA2 and CTAG1B. 16 Others have demonstrated prognostic impact of MAGEC1, SSX2 and CT45.…”

Kruppel-like factor 4 blocks tumor cell proliferation and promotes drug resistance in multiple myeloma

“…First, in 50 previously untreated patients with t(4;14)(p16.3;q32), there was a significant (P<0.05) inverse correlation between KLF4 expression in MMC and a gene expression-based proliferation index, 32 suggesting that the in vitro observation of a KLF4…”