Abstract
8520 Background: Total Therapy 3 (TT3) incorporated bortezomib (BOR) to co-target ME that plays an important role in MM progression and drug resistance. Consenting patients received a BOR test dose of 1mg/m2 to determine whether ME alterations induced 48hr post-BOR could clarify the drug's in-vivo mechanism of action in the context of achieving MM control. Methods: Bone marrow biopsies were obtained at baseline (BL) prior to and 48hr after BOR (PB) in 70 of 303 patients receiving TT3a (training set) and in 45 of 177 patients enrolled in TT3b (test set). Among 608 ME genes distinguishing BL and PB training samples, 58 were identified as being significantly linked to short event-free survival (EFS). A summary score was computed based on the percent change of these 58 genes (PB-ME-S). Additionally, 20 ME genes were selected whose BL expression predicted OS, arriving at a BL score (BL-ME-S). Results: Applying the PB-ME-S score, 3-yr OS and EFS estimates were 96% and 96% among the 49 patients with low PB-ME-S and 50% and 38% in the 21 with high PB-ME-S (both p<0.0001). Follow-up is too short to validate the PB-ME-S model in the test set of 45 patients in TT3b. The BL-ME-S distinguished OS and EFS in the training set of 70 patients, with 3-yr OS and EFS estimates of 92% and 91% among the 50 patients with low and 54% and 45% in the 20 patients with high BL-ME-S (both P<0.0001). These data were validated in 113 patients with only BL-ME data: 3-yr OS and EFS were 90% and 85% among the 89 patients with low as opposed to 70% and 55% among the 14 patients with high BL-ME-S (p=0.001, p=0.002). TT3 survival was independently significantly affected by PB-ME-S (OS: HR=12.74, p=0.002; EFS: HR=14.32, p<0.001) and BL-ME-S (EFS: HR=3.10, p=0.045), whereas the univariately significant role of BL-PC-S for both endpoints could not be confirmed on multivariate analysis. Conclusions: To our knowledge, this is the first report documenting a validated prognostic role of ME for cancer survival. Key genes shared by both PB-ME-S and BL-ME-S models are involved in endothelial and mesenchymal stem-cell signaling, the details of which will be reported at the meeting. [Table: see text]
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