Telomere Length is a prognostic indicator for MM

Multiple Myeloma (MM) is a highly heterogeneous disease, with huge variations in life expectancy and varying prognoses, that appear to depend on a huge number of variables such as patient age, general health and a range of biomarkers. Patients are now classified at diagnosis using the Revised International Staging System (RISS), a stratification tool that takes into account a number of prognostic factors, including the presence of chromosomal abnormalities known to dictate a poor prognosis, as well as serum biomarkers. However, whilst this classification appears to help identify groups of patients with a distinct outcome and stratify patients according to expected treatment responses, there is still a need for more robust prognostic indicators that are potentially independent of other factors.

A research group in Cardiff University School of Medicine, led by Duncan Baird, have been examining the prognostic capacity of high-resolution telomere analysis, combined with a functional definition of telomere length, in a range of cancers. In a study published in the British Journal of Haematology, Sam Hyatt and Rhiannon E. Jones applied this technology to MM, and found that short telomere length strongly correlated with shorter Overall Survival (OS).

Key Highlights:

• Patient (pt) samples were collected (between 1990 and 2005) at diagnosis, prior to treatment
• Single telomere length analysis (STELA) was performed to generate length profiles using DNA extracted from bone marrow (BM) biopsies
• Monoclonal gammopathy of undetermined significance (MGUS) = 61 pts and MM = 134 pts
• Telomeres from MGUS and MM BM samples were highly variable: Overall mean standard deviations (SD): MGUS = 2.23 kb and MM = 2.12 kb
• Cells from BM biopsies of five MM pts were sorted using CD138⁺ antibodies and telomere length distributions assessed: CD138⁺ = 2.40 kb and CD138^- = 5.26 kb (P = 0.008)
• Shorter telomere length in CD138⁺ cells related to the replicative history of MM cells; the short length observed in the unsorted samples therefore indicating the presence of MM cells
• Telomere length in MM pts was shorter compared to MGUS (P = 0.017)
• Age-related changes in telomere length were as predicted for changes in normal peripheral blood; no significant differences between sexes (P = 0.22)  
• Comparison of pts using International Staging System (ISS) indicated no significant differences in telomere length (P = 0.27), and thus independence of telomere length as a risk factor
• The effect of short telomeres was less pronounced in patients with high-risk ISS score (P = 0.05), although univariate analyses stratified by ISS score found that short telomeres were associated with significantly worse survival in high-risk ISS patients (P = 0.02), indicating some interaction between these predictors
• Prognostic resolution for median telomere length in MM pts: HR = 1.61 (95% CI, 1.04–2.53), P = 0.03
• Prognostic resolution for telomere dysfunction threshold: HR = 3.42 (95% CI, 3.67–15.81), P < 0.0001
• ISS as a prognostic indicator in MM cohort: HR = 3.56 (95% CI, 2.92–9.13) (P < 0.0001)
• Most important prognostic factors (as assessed using multivariate analysis of 113 MM samples) were ISS, followed by age and then telomere length <3.81 kb
• Telomere length <3.81 kb indicates significantly shorter survival: HR = 2.23 (95% CI, 1.26–3.96), P = 0.006

In conclusion, the prognostic power of a previously determined length threshold for telomere dysfunction gave a HR of 3.4, which is highly prognostic for OS in MM. This is a striking correlation given the use of unsorted cells, and therefore measurements in sorted cell samples could be even more striking. This technique could add further prognostic power to current risk assessments. Professor Duncan Baird who led the study said, “The next step is to assess telomere length in larger studies to establish how it can be integrated into existing assessments that predict patient outcome.” Patients with MM face a huge degree of uncertainty, but this finding is an exciting step forward. This relatively simple blood test could be developed for routine use in order to more accurately predict disease progression, and ultimately direct tailored treatment regimens.

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.