Telomere length is a critical determinant for survival in multiple myeloma

Hyatt, Sam, Jones, Rhiannon E, Heppel, Nicole H, Grimstead, Julia W, Fegan, Chris, Jackson, Graham H, Hills, Robert, Allan, James M, Pratt, Guy, Pepper, Christopher and Baird, Duncan M (2017) Telomere length is a critical determinant for survival in multiple myeloma. British Journal of Haematology, 178 (1). pp. 94-98. ISSN 00071048

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Abstract

The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high‐resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0·0001; HR = 3·4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk‐stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS.

Despite the introduction of novel therapeutic modalities, patients with multiple myeloma (MM) display a heterogeneous clinical course, with survival ranging from a few months to over 10 years. Therefore, there is a requirement for reliable prognostic and predictive markers in this disease to allow for risk stratification and rational clinical decision‐making. The most commonly used prognostic system in MM is the International Staging System (ISS) that is based on serum levels of both β2‐micoglobulin and albumin (Greipp et al, 2005). Recently the ISS has been improved upon by the inclusion of cytogenetic information to take into account the level of lactate dehydrogenase and the considerable genetic heterogeneity known to occur in this disease (Palumbo et al, 2015). Hyperdiploidy and the loss of whole chromosome arms is frequently detected in MM, which includes, amongst others, gains of 1q in 30% of cases and the loss of 17p in 7% of cases (Walker et al, 2010).

Short dysfunctional telomeres are susceptible to DNA repair activities that can result in chromosomal fusion and the initiation of cycles of anaphase‐bridging, breakage and fusion that can drive genomic instability and clonal evolution (Artandi et al, 2000; Roger et al, 2013; Jones et al, 2014). Telomere dysfunction has been documented in numerous haematological malignancies (Jones et al, 2012), and is one putative mechanism that may lead to the genetic and clinical heterogeneity observed in MM (Wu et al, 2003) and may relate to changes in the 3D telomeric architecture that have been documented in MM cells (Klewes et al, 2013). Recently, we have shown that high‐resolution telomere analysis, combined with a functional definition of telomere length, can provide powerful prognostic information in several tumour types, including chronic lymphocytic leukaemia (CLL)(Lin et al, 2014), myelodysplasia (unpublished observations) and breast cancer (Simpson et al, 2015). Here we sought to apply these technologies to examine the prognostic utility of telomere length in MM.

Item Type: Article
Keywords: multiple myeloma, prognosis, telomere, genome instability.
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: R Medicine
Depositing User: Gemma Hamilton
Date Deposited: 28 Mar 2018 16:18
Last Modified: 02 May 2018 15:37
URI: http://sro.sussex.ac.uk/id/eprint/74713

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