Complete Response to First-Line Bortezomib-Thalidomide-Dexamethasone Therapy in Multiple Myeloma Patients with t(4;14): Analysis of Gene Expression Profile.

The recurrent translocation t(4;14)(p16;q32) occurs in less than 20% of patients with newly diagnosed Multiple Myeloma (MM) and is associated with a poor clinical outcome following either conventional or high-dose chemotherapy. Recently, it has been reported that patients carrying t(4;14) are prognostically heterogeneous and that the novel agents bortezomib and lenalidomide may overcome the poor prognosis related to this cytogenetic abnormality. In the present study, we analyzed the gene expression profile of patients who carried or not t(4;14) and were primarily treated with a bortezomib-based regimen.

Two hundred thirty six patients with MM who received a combination of bortezomib-thalidomide-dexamethasone (VTD) as first-line therapy were evaluated for the presence at diagnosis of t(4;14). Of these, 41 patients (17.3%) were t(4;14) positive. On an intention-to-treat basis, the rate of CR and near CR (nCR) to VTD induction therapy among patients carrying t(4;14) was 41%, a value higher than the 29% observed among t(4;14) negative patients. In 218 patients for whom data on t(4;14), del(13q) and del(17p) were available, the differential gene expression of CD138+ enriched plasma cells was evaluated by means of expression microarray using the Affymetrix platform. The analysis was performed in t(4;14) negative patients and patients carrying t(4;14), either alone or combined with other abnormalities; t(4;14) negative patients included those with del(13q) alone and with any of these abnormalities.

In 27 patients, t(4;14) was associated with either del(13q) (24 patients) or del(17p) (3 patients); the remaining 14 patients carried t(4;14) alone. The expression profiles of patients carrying either t(4;14) alone or t(4;14) combined with del(13q) significantly clustered apart when compared with those of cytogenetic negative patients. Similarly, the expression profiles of patients with del(13) alone clustered with those of cytogenetic negative patients. De-regulated expression of similar molecular pathways was demonstrated in patients carrying t(4;14) alone or combined with del(13q). Thus, the analysis of gene expression profiles according to response or no response to VTD was performed in two subgroups of patients, including those carrying t(4;14) alone or combined with del(13q) and those carrying either del(13q) alone or without cytogenetic abnormalities. By comparing the lists of genes differentially expressed (P '0.05) in patients who responded (e.g. those who achieved CR+nCR) and failed to respond (NR) to VTD according to the presence or absence of t(4;14), we found that the differential expression of 3719 genes characterized CR+nCR vs NR patients in the t(4;14) positive subgroup. At the opposite, the differential expression of 3182 genes characterized CR+nCR vs NR patients in the t(4;14) negative subgroup. 271 genes which were common to the two groups of genes were excluded from the list of genes found to be differentially expressed in t(4;14) positive patients who responded to VTD. Among these patients, we observed the de-regulated expression of genes involved in cell cycle progression (e.g. MDM2, CDK6 and SMAD2), Wnt signalling pathway (e.g. FZD7, WNT10A, MMP7,WNT2B, WNT6, WNT9A and DAAM2), and Hedgehog signalling pathway (GAS1, STK36 and GLI1). Overall, genes involved in cell cycle progression resulted over-expressed, thus suggesting a more aggressive phenotype of t(4;14) positive plasma cells of responder patients; nevertheless, the overall down-regulation of genes involved in Wnt and Hedgehog signalling pathways (known to be involved in the maintenance of a putative tumoral stem cell compartment) might mitigate this phenotype and predispose t(4;14) positive plasma cells to more favourably respond to VTD induction therapy. Supported by: BolognAIL, Fondazione Carisbo, Progetto di Ricerca Finalizzata (M.C).

No relevant conflicts of interest to declare.