ReviewThe evolving role of translocation t(11;14) in the biology, prognosis, and management of multiple myeloma
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.
Section snippets
The classification of cytogenetic aberrations in MM
MM is clinically and genetically a heterogeneous disease. Primary cytogenetic changes leading to oncogenesis in MM can be broadly divided into hyperdiploidy of odd numbered chromosomes and translocations involving chromosome 14. These genetic aberrations take place during B-lymphocyte differentiation in the germinal center during class switch recombination and less commonly in pro-B cells through Dh-Jh recombination activation gene-mediated mechanisms [19]. Translocation of chromosome 14 places
Role of the BCL2 family of proteins in MM
The discovery that increased expression of the oncogene BCL2 could prevent cell death and that it is an important factor in tumor survival subsequently led to the understanding of the importance of the BCL2 family of proteins in the regulation of apoptosis at the mitochondrial membrane [[49], [50], [51]]. Programmed cell death through the intrinsic apoptotic pathway is governed by a balance between antiapoptotic (BCL2, BCLXL, BCLW, and MCL1) and proapoptotic (BAX, BAK, BIM, and BAD) proteins [52
Predictive value of t(11:14) in MM
Human myeloma cell lines and primary myeloma cells demonstrate heterogeneity with respect to BCL2, BCLXL, or MCL dependence [18,66,74]. Identification of BCL2 dependence by BH3 profiling demonstrated in vitro sensitivity to BH3 mimetics [18,74], in particular to drugs like venetoclax (ABT-199)—an oral selective BCL2 inhibitor. In one study, sensitivity of venetoclax was restricted to human myeloma cell lines carrying CCND1 translocation, with increased sensitivity corresponding to higher BCL2
Conclusions and futures directions
MM is a heterogenous disease. Increased knowledge of the heterogeneity of the underlying genetic abnormalities, clinical presentation, and the response to treatment has resulted in a paradigm shift in the understanding of MM. Approximately 15% to 20% of MM patients harbor t(11;14), which is currently classified as a standard-risk abnormality; however, this classification has been challenged in the past few years because of emerging data showing inferior outcomes observed in these patients when
Practice points
- •
High-risk cytogenetic aberrations t(4;14), del(17p), and t(14;16) adversely impact prognosis of MM and are included in the Revised International Staging System
- •
t(11;14) was considered to confer standard risk in studies conducted prior to novel agent use
- •
In the era of novel agents, patients with t(11;14) have PFS and OS intermediate of patients with standard- and high-risk cytogenetics
- •
The BCL2 protein family plays a critical role in the apoptosis of clonal plasma cells
- •
MM cells harboring t(11;14)
Research agenda
1. Molecular mechanism of BCL-2 inhibition in MM and its impact on the clonal evolution.
2. Studies looking at the safety, efficacy, and optimal combinations of BCL-2 inhibitors in MM.
Author contributions
All authors contributed equally to the conception, design, and writing of the review article.
Disclosures
Agne Paner receives consulting fees and honoraria from Celgene, Takeda, Amgen, Janssen, AbbVie, Cellectar, and Oncopeptides.
Pritesh Patel receives consulting fees and honoraria from Celgene, Amgen, and Janssen.
Binod Dhakal receives honoraria from Celgene and serves on the advisory board of Takeda and Amgen.
Acknowledgments
The authors received editorial support from Swati Ghatpande, PhD and Mary Wiggin, BA of Bio Connections LLC, funded by AbbVie.
References (77)
How I treat myeloma with new agents
Blood.
(2017)- et al.
How I treat the young patient with multiple myeloma
Blood.
(2018) - et al.
Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial
Lancet.
(2017) - et al.
Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial
Lancet Oncol
(2017) - et al.
Targeting BCL-2-like proteins to kill cancer cells
Trends Cancer
(2016) - et al.
The rise of apoptosis: targeting apoptosis in hematologic malignancies
Blood.
(2018) - et al.
Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma
Blood.
(2017) - et al.
Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells
Blood.
(2013) - et al.
Outcomes of myeloma patients with deletion 1p receiving lenalidomide, bortezomib, and dexamethasone (RVD) therapy
Blood.
(2018) - et al.
Outcomes and clinical features of patients with 1q+ multiple myeloma treated with lenalidomide, bortezomib, and dexamethasone
Blood.
(2018)
Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients
Blood.
Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy
Blood.
Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy
Blood.
Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome
Blood.
Impact of t(11;14)(q13;q32) on the outcome of autologous hematopoietic cell transplantation in multiple myeloma
Biol Blood Marrow Transplant
Outcomes of myeloma patients with t(11;14) receiving lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy
Blood.
Differences in presentation and survival outcomes for African American patients with newly diagnosed multiple myeloma
Blood.
Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience
Blood.
Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics
Blood.
Characteristics of patients (pts) who relapse and die of multiple myeloma (MM) within one year post frontline autologous stem cell transplant (ASCT) in the novel agent era: an ultra-high risk population
Blood.
CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma
Blood.
bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation
Cell.
PUMA, a novel proapoptotic gene, is induced by p53
Mol Cell
bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death
Cell.
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics
Cancer Cell
Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells
Blood.
Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells
Blood.
Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1
Blood.
The multiple myeloma drug pipeline-2018: a review of small molecules and their therapeutic targets
Clin Lymphoma Myeloma Leuk
Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM
Blood.
Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma
Blood.
BH3 profiling--measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions
Cancer Lett
Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016
JAMA Oncol
New developments in diagnosis, prognosis, and assessment of response in multiple myeloma
Clin Cancer Res
Revised international staging system for multiple myeloma: a report from international myeloma working group
J Clin Oncol
Daratumumab, lenalidomide, and dexamethasone for multiple myeloma
N Engl J Med
Daratumumab, bortezomib, and dexamethasone for multiple myeloma
N Engl J Med
Elotuzumab therapy for relapsed or refractory multiple myeloma
N Engl J Med
Cited by (28)
Impact of Clonal Heterogeneity in Multiple Myeloma
2024, Hematology/Oncology Clinics of North AmericaCytogenetics in the management of multiple Myeloma: The guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH)
2023, Current Research in Translational Medicine
- 1
All authors contributed to the review article equally.