Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma.

Aline Rangel-Pozzo,Anu Tamm,Sherif Louis,Luiza Sisdelli,Mari Punab,Adebayo Olujohungbe,Sabine Mai,Sadhana Lal,Pille Tammur,Hans Knecht,Yasmin Asbaghi,Ludger Klewes,Pak Yu

doi:10.3390/cancers13081969

Abstract

Simple SummaryMultiple myeloma (MM) remains an incurable blood cancer. One of the current challenges in patient management is the risk assessment and subsequent treatment management for each patient with MM. Patients with an identical diagnosis may present very different disease courses and outcomes. This challenge of MM is a current focus of the scientific and medical communities. In our research, we have used an imaging approach to determine the risk of MM patients to progressive/aggressive disease. Using three-dimensional (3D) imaging of telomeres, the ends of chromosomes, we report that specific telomeric profiles are associated with aggressive disease.The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

Highlights

Multiple myeloma (MM) is a B-cell malignancy characterized by the extensive proliferation of malignant plasma cells (PCs) in the bone marrow (BM) and an abnormal increase in monoclonal immunoglobulins or M proteins [1]
To assess the potential of 3D telomere architecture as a reliable tool to differentiate MM from its precursor stages, we evaluated a total of 214 patients (54 monoclonal gammopathy of undetermined significance (MGUS), 24 smoldering multiple myeloma (SMM), and 136 MM)
We evaluated bone marrow samples from a cohort of 214 patients diagnosed with MGUS (54), SMM (24), and MM (136) having a clinical follow-up of at least 60 months

Summary

Introduction

Multiple myeloma (MM) is a B-cell malignancy characterized by the extensive proliferation of malignant plasma cells (PCs) in the bone marrow (BM) and an abnormal increase in monoclonal immunoglobulins or M proteins [1]. This aberrant plasma cell proliferation leads to lytic bone lesions, hypercalcemia, kidney failure, and severe anemia [1]. In SMM patients, the levels of M protein in the serum are higher than in MGUS (≥3 g/dL), with patients still showing no symptoms and no laboratory signs of end-organ damage, but the risk of progression to MM is approximately 10% per year in the first 5 years [4,5].

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