Abstract 2207: A 41-gene signature predicts complete response (CR) to Bortezomib-Thalidomide-Dexamethasone (VTD) as induction therapy prior to autologous stem-cell transplantation (ASCT) in multiple myeloma (MM).
Authors: Terragna Carolina , Remondini Daniel , Martello Marina , Pezzi Annalisa , Patriarca Francesca , Levi Anna , Pantani Lucia , Donnarumma Daniela , Montanaro Lorenzo , Crippa Claudia , Bringhen Sarah , Rambaldi Alessandro , Offidani Massimo , Corradini Paolo , Narni Franco , Fioritoni Giuseppe , Zaccaria Alfonso , Baldini Luca , Caravita Tommaso , La Nasa Giorgio , Cortellazzo Sergio , Martinelli Giovanni , Cavo Michele 
Published: August 2014

Background. Achievement of CR is generally associated with improved clinical outcomes for patients (pts) with MM and represents a primary endpoint of current clinical trials. The GIMEMA Italian Myeloma Network phase 3 study demonstrated that VTD regimen was superior over thalidomide-dexamethasone (TD) as induction therapy prior to and as consolidation therapy after the double ASCT for newly diagnosed MM (rate of &gt;nCR: 31% vs 11% (p&lt;0.0001) for the 236 pts on VTD and the 238 pts on TD, respectively). Since enhanced rates of &gt;nCR affected by VTD resulted in extended progression-free survival (PFS), prediction of CR by pharmacogenomic tools is likely to be an important goal to prospectively select those pts who are more likely to benefit from a given therapy.

Methods. We assessed the ability of GEP to predict attainment of CR in 122 pts enrolled in the VTD arm of the study. CD138+ plasma cells were obtained at diagnosis from each pts and were profiled for their gene expression (Affymetrix U133 Plus2.0 platform).

Results. 34/122 pts (28%) who were included in the present analysis achieved a ≥nCR after VTD induction therapy and were characterized by the differential expression of 2157 probesets (p≤0.01). According to the unsupervised hierarchical clustering, the population of 122 profilated pts resulted stratified into 2 subgroups, the first one including 79% and the second one 21% of ≥nCR pts.

To obtain a classifier for response to VTD induction therapy, the differentially expressed genes was analyzed to identify a small group of predictor genes. The best predictive capability was obtained with a 41-gene classifier that provided 88% sensitivity, 97% specificity, 91% PPV and 95% NPV. A GeneGo® network analysis showed that the most relevant network nodes included tumour suppressor genes, genes involved in inflammatory response and genes involved in B cell development.

To asses the relevance to know since diagnosis the sensitivity for a particular therapy, we evaluated the prognostic impact of the response prediction in our clinical context. Pts predicted to be responder to VTD induction therapy according to the 41-gene classifier were more likely to attain a ≥nCR after the consolidation therapy. The 3 years estimate of PFS of pts ≥nCR after the consolidation therapy was significantly higher as compared to pts who failed this objective (p=0.03).

Conclusions. GEP analysis of a subgroup of pts who received VTD induction therapy provided a 41-gene classifier that was able to predict attainment of &gt;nCR and, conversely, failure to achieve at least nCR in 91% and 95% of cases, respectively. These favorable results might represent a first step towards the possible application of a tailored therapy based on the single patient's genetic background.

Supported by: Fondazione Del Monte di Bologna e Ravenna, Ateneo RFO grants (M.C.) BolognAIL.

Citation Format: Carolina Terragna, Daniel Remondini, Marina Martello, Annalisa Pezzi, Francesca Patriarca, Anna Levi, Lucia Pantani, Daniela Donnarumma, Lorenzo Montanaro, Claudia Crippa, Sarah Bringhen, Alessandro Rambaldi, Massimo Offidani, Paolo Corradini, Franco Narni, Giuseppe Fioritoni, Alfonso Zaccaria, Luca Baldini, Tommaso Caravita, Giorgio La Nasa, Sergio Cortellazzo, Giovanni Martinelli, Michele Cavo. A 41-gene signature predicts complete response (CR) to Bortezomib-Thalidomide-Dexamethasone (VTD) as induction therapy prior to autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2207. doi:10.1158/1538-7445.AM2013-2207