The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the Myeloma XI trial

Abstract

Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches.

Fig. 1

Kaplan–Meier survival curves by age group. a Progression free survival b Overall survival

Fig. 2

Baseline patient characteristics and laboratory parameters by age group. a Distribution of WHO performance status by age group. b Median eGFR by MDRD values indicative of renal impairment by age group. c Median values of B₂M and albumin by age group. d Distribution of ISS by age group. In all graphs p values indicate an assessment of difference between the age groups (Fisher’s Exact test for categorical variables and the Wilcoxon–Mann–Whitney test for continuous variables). NS = not significant. n/a = not available. WHO PS = World Health Organization Performance Status. eGFR (MDRD) = estimated glomerular filtration rate by Modification of Diet in Renal Disease Study equation. ISS = International Staging Score

Fig. 3

Molecular risk parameters at baseline by age group. a Adverse translocations and adverse copy number abnormalities. b Distribution of molecular risk group by age group. SR = standard risk, HiR = high risk, UHiR = Ultra-high risk. High-risk molecular abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), and del(17p). Ultra-high risk was defined as the presence of more than one high-risk lesion

Fig. 4

Kaplan–Meier survival curves by molecular risk group within each age group. a Progression free survival b Overall survival. SR = standard risk (red), HiR = high risk (blue), UHiR = Ultra-high risk (green). High-risk molecular abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), and del(17p). Ultra-high risk was defined as the presence of more than one high-risk lesion

Fig. 5

The percentage of variance explained by molecular risk, ISS, and WHO PS. a Progression free survival b Overall survival. The effect of age (PFS: P < 0.0001; OS: P < 0.0001), performance status (PFS: P = 0.0001; OS: P < 0.0001), ISS (PFS: P < 0.0001; OS: P < 0.0001) and molecular risk (PFS: P < 0.0001; OS: P < 0.0001) on clinical outcomes is statistically significant. SR = standard risk, HiR = high risk, UHiR = Ultra-high risk. High-risk moelcular abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), and del(17p). Ultra-high risk was defined as the presence of more than one high-risk lesion. ISS = International Staging Score. WHO PS = World Health Organization Performance Status