High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

Abstract

Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta-analysis conducted across 3 data sets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of fluorescence in situ hybridization- and sequencing-based methods to identify TP53 deletions, estimate CCF, and establish that both CCF threshold of 0.55 and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis.

Graphical abstract

Figure 1.

Identification of 0.55 CCF threshold for del17p/TP53 deletion predictive of survival. Kaplan-Meier plot showing OS (A,C) and PFS (B,D) for patients from discovery cohort (A-B) and replication (RE) cohort (C-D) stratified by high or low CCF value. (E-F) Kaplan-Meier plots were generated for OS (A) and PFS (B) characteristics of patients in MGP del17p cohort stratified by 0.55 CCF value (hazard ratio [HR], 1.8; Cox P < .15 and HR, 1.5; Cox P < .15 for OS and PFS, respectively). Baseline OS and PFS data were not available for 1 patient in the CCF >0.55 group. (G) Meta-analysis shows replication of 55% CCF threshold to be an indicator of poor prognosis based on OS and PFS end points. Numbers on the right of each graph indicate HR and corresponding 95% confidence interval.

Figure 2.

Nonsynonymous mutations in TP53 are significantly enriched in population of patients with confirmed TP53 deletion. (A) Presence of TP53 mutations was examined in delTP53 patients from MGP data set (n = 108) stratified by CCF value >0.55 or <0.55. Kaplan-Meier plots were generated for OS (B) and PFS (C) for patients with TP53 mutation (mut) with CCF >0.55 (red line), patients with wild-type (wt) TP53 with CCF ≤0.55 (blue line), and patients with TP53wt with CCF >0.55 (green line). *One-sided Fisher’s exact test.