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High sub-clonal fraction of 17p deletion is associated with poor prognosis in Multiple Myeloma

Anjan Thakurta, Maria Ortiz, Pedro Blecua, Fadi Towfic, Jill Corre, Natalya V. Serbina, Erin Flynt, Zhinuan Yu, Zhihong Yang, Antonio Palumbo, Meletios A. Dimopoulos, Norma Guttierez, Hartmut Goldschmidt, Pieter Sonneveld and Herve Avet-Loiseau

Key points

  • Robust del17p cancer clonal fraction threshold associated with poor prognosis in NDMM is established through FISH and sequencing methods.

  • TP53 mutations are enriched in a high-risk patient segment characterized by high del17p CCF.

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 to 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 0.55 CCF threshold was established in the discovery and replication datasets. Following stratification on the 0.55 CCF threshold, high-risk patients had statistically significant poorer outcomes compared to low-risk patients (median PFS and OS of 14 and 32 months compared to 23.1 and 76.2 months, respectively). Analyses of a third data set comprised of whole exome sequencing data from NDMM patients identified the presence of TP53 deletions/mutations as a necessary requirement for high risk stratification in addition to exceeding del17p CCF threshold. Meta-analysis conducted across three datasets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of FISH and sequencing-based methods to 1) identify TP53 deletions, 2) estimate CCF and 3) establish that both 0.55 CCF threshold and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis.

  • Submitted October 17, 2018.
  • Accepted January 2, 2019.