The evolving role of translocation t(11;14) in the biology, prognosis, and management of multiple myeloma

Abstract

Cytogenetic changes in multiple myeloma (MM) have emerged as one of the most important prognostic factors. Translocations of chromosomes 4 and 14 [t(4;14)], chromosomes 14 and 16 [t(14;16)] and deletion of chromosome 17p [del(17p)] have been incorporated in the Revised International Staging System as a measure of adverse disease biology. Ongoing research is unveiling a complex genomic landscape in MM, with new cytogenetic abnormalities important for prognosis identified and the significance of known cytogenetic changes revisited. In studies conducted before the novel agent era, t(11;14) was shown to carry standard risk for patients with MM. Findings from more recent retrospective reviews have shown that t(11;14) is associated with intermediate outcomes in patients treated with novel agents as compared with patients who have standard- or high-risk cytogenetic aberrations. MM cells with t(11;14) have a unique biology, with relatively higher expression of the antiapoptotic protein BCL2 and lower expression of MCL1, in contrast to MM cells without this translocation. Translocation t(11;14) has emerged as the first predictive marker in MM, indicating susceptibility to BCL2 inhibition. Future studies will be needed to explore if the combination of novel agents with BCL2 inhibitors can improve the prognosis of patients with t(11;14). In this article, current data on the evolving role of t(11;14) in the biology, prognosis, and treatment of MM are reviewed.

Introduction

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by clonal proliferation of plasma cells and secretion of a monoclonal protein. MM is the second most common hematologic malignancy, with approximately 30,000 new cases diagnosed yearly in the United States [1]. Substantial improvements have been made in the understanding of the disease biology and in diagnosis and prognostication of MM [[2], [3], [4]]. In particular, risk stratification with the revised International Staging System (R-ISS) including cytogenetic abnormalities has become a standard prognostic tool at diagnosis [5]. Despite this, risk-adaptive or targeted therapies have remained elusive.

At the same time, outcomes for patients with MM have improved vastly during the last decade because of the advent of novel agent therapies including proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) and, more recently, monoclonal antibodies (mAbs) [[6], [7], [8], [9], [10], [11], [12], [13], [14]]. Drugs targeting prosurvival proteins of the BCL2 family have shown significant promise in the treatment of hematologic malignancies [15,16]. Venetoclax has strong biologic rationale for its use to target MM with translocation of chromosomes 11 and 14 [t(11;14)], known to have higher dependence of antiapoptotic protein BCL2 [17,18]. Here, we review the evolving role of the prognostic significance of t(11;14) and its role in the biology of MM, with a particular focus on the BCL2 family and subsequent therapeutic implications.