A bendamustine resistance gene signature in diffuse large B-cell lymphoma and multiple myeloma

Aim: Bendamustine is primarily used for treatment of indolent lymphomas but has shown efficacy in some patients with diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Molecular-based patient stratification for identification of resistant patients, who will benefit from alternative treatments, is important. The aim of this study was to develop a resistance gene signature (REGS) from bendamustine dose-response assays in cultures of DLBCL and MM cell lines, enabling prediction of bendamustine response in DLBCL and MM patients. Methods: Bendamustine response was determined in 14 DLBCL and 11 MM cell lines. Using baseline gene expression profiles and degree of growth inhibition after bendamustine exposure, a bendamustine REGS was developed and examined for the risk stratification potential in DLBCL (n = 971) and MM (n = 1,126) patients divided into prognostic subtypes. Results: Bendamustine resistance significantly correlated with resistance to cyclophosphamide in DLBCL and melphalan in MM cell lines. The bendamustine REGS showed significantly lower bendamustine resistance probabilities in DLBCL patients with GCB subtype tumors and in tumors of the differentiation dependent centrocyte and plasmablast subtypes. In MM patients, pre-BII classified tumors displayed high bendamustine resistance probabilities and the plasma cell subtype had lower bendamustine resistance probability than memory cells. Furthermore, tumors belonging to the 4p14, MAF, and D2 TC subclasses consistently displayed high bendamustine resistance probabilities. Conclusion: Significant differences in predicted response to bendamustine were found in molecular subtypes of DLBCL and MM, encouraging validation in prospective bendamustine-treated cohorts with available gene expression profiles and follow-up data.