General MM

Patients with multiple myeloma with a high sub-clonal fraction of 17p deletion have poor prognosis

Alterations to the tumor protein 53 (TP53) gene, including deletions in chromosome 17p (del17p), have been associated with poor outcomes in patients with multiple myeloma (MM). However, the prognostic value of the del17p cancer clonal fraction (CCF) is unclear. In patients with newly diagnosed MM (NDMM), cytogenetic analysis by fluorescence in situ hybridization (FISH) is used for risk assessment.1 The threshold of del17p CCF that indicates a poor prognosis is not mutually agreed, and varies in different studies due to a lack of uniform analytical methods to reach an accepted conclusion. Defects in 17p can include deletions such as del17p, mutations, or both – also known as ‘double-hit’ (biallelic inactivation).2

In this study, a large cohort of patients with NDMM with varying levels of del17p was analysed by Anjan Thakurta, and colleagues. The study used interphase FISH analysis to determine a cytogenetic CCF threshold for poor prognosis that was recognized and replicable.3

Study Design
  • Bone marrow plasma cells were obtained from patients with NDMM at diagnosis
  • Cells were selected using CD138 and FISH analysis was conducted in samples with over 70% plasma cells using TP53 gene probes
  • Discovery dataset – Intergroupe Francophone du Myélome (IFM) (N = 605)
  • FISH replication dataset (N = 235)
  • Myeloma Genome Project (MGP) dataset (N = 1273) with different extents of del17p
    • Derived from; Myeloma XI trial, Dana-Farber Cancer Institute/IFM, The UAMS Myeloma Institute and the Multiple Myeloma Research Foundation (MMRF, IA1 – IA9)
Key Findings
  • Identification of CCF threshold using discovery dataset:
    • The optimal CCF range was 51–69% with two optimal cuts at 55% and 64%
    • A robust CCF threshold of 0.55 was selected and applied
    • Median progression free survival (PFS) (≤0.55 CCF vs >0.55 CCF): 23.9 vs 14.3 months
    • Median overall survival (OS) (≤0.55 CCF vs >0.55 CCF): 84.1 vs 36.1 months
  • Testing the robustness of 0.55 CCF threshold using FISH replication dataset:
    • Median PFS (≤0.55 CCF vs >0.55 CCF): 29 vs 17 months
    • Median OS (≤0.55 CCF vs >0.55 CCF): 54 vs 32 months
  • Confirmation of CCF threshold in genomic data set (MGP) demonstrated lower median PFS and OS in the >0.55 CCF group
  • Meta-analysis on all three cohorts showed an agreement in summary statistics
  • Impact of del17p and TP53 mutation on PFS and OS was analyzed using the MGP dataset:
    • Patients with TP53 mutation tend to cluster in the high CCF group
    • Patients with double-hit mutation had shorter PFS compared with patients with del17p only, regardless of CCF

In conclusion, this study demonstrated that a CCF threshold of >0.55 is robust and can identify patients with a poor prognosis (PFS and OS) as confirmed by meta-analysis across three datasets. In patients with double-hit mutation, prognosis is poor irrespective of CCF score. The study has also shown that FISH and sequencing-based methods are feasible to identify TP53 deletions and estimate CCF and the authors suggest this threshold is used for risk assessments in clinical trials and diagnostic testing of patients with NDMM.

References
  1. Kumar S. K. et al. Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017 Feb 01. DOI: 10.6004/jnccn.2017.0023
  2. Walker B. A. et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2018 Jul 02. DOI: 10.1038/s41375-018-0196-8
  3. Thakurta A. et al. High sub-clonal fraction of 17p deletion is associated with poor prognosis in Multiple Myeloma. Blood. 2019 Jan 28. DOI: 10.1182/blood-2018-10-880831
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