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Clinical Trial
. 2018 Dec 6;132(23):2465-2469.
doi: 10.1182/blood-2018-06-857250. Epub 2018 Oct 29.

Subclonal TP53 copy number is associated with prognosis in multiple myeloma

Vallari Shah  1 , David C Johnson  1 , Amy L Sherborne  1 , Sidra Ellis  1 , Frances M Aldridge  2 , Julie Howard-Reeves  2 , Farzana Begum  1 , Amy Price  1 , Jack Kendall  1 , Laura Chiecchio  3 , Suvi Savola  4 , Matthew W Jenner  5 , Mark T Drayson  6 , Roger G Owen  7 , Walter M Gregory  8 , Gareth J Morgan  9 , Faith E Davies  9 , Richard S Houlston  1 , Gordon Cook  10 , David A Cairns  8 , Graham Jackson  11 , Martin F Kaiser  1 ; National Cancer Research Institute Haematology Clinical Studies Group
Affiliations
Clinical Trial

Subclonal TP53 copy number is associated with prognosis in multiple myeloma

Vallari Shah et al. Blood. .

Abstract

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.

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Conflict of interest statement

Conflict-of-interest disclosure: V.S. received travel support from Sanofi and Janssen. S.S. is an employee of MRC-Holland. M.W.J. acted as a consultant for Janssen, Takeda, Amgen, Celgene Corporation, and Novartis; received travel support and honoraria from Janssen, Takeda, and Amgen; received honoraria from Celgene Corporation and Novartis; and received research funding from Janssen and Celgene Corporation. M.T.D. has equity ownership in and serves on the board of directors of Abingdon Health. R.G.O. received honoraria from Takeda and Celgene Corporation; received travel support from Takeda and Janssen; acted as a consultant for Janssen and Celgene Corporation; and received research funding from Celgene Corporation. G.J.M. received research funding from Janssen and Celgene Corporation and acted as a consultant for and received research funding from Bristol-Myers Squibb, Takeda, and Celgene Corporation. W.M.G. received research funding from Celgene Corporation, Amgen, Merck Sharp and Dohme; acted as a consultant for Celgene Corporation; received honoraria from Janssen and Abbvie. F.E.D. acted as a consultant for and received honoraria from Amgen, AbbVie, Takeda, Janssen, and Celgene Corporation. G.C. acted as a consultant for and received honoraria from Takeda, Glycomimetics, Sanofi, Celgene Corporation, Janssen, Bristol-Myers Squibb, and Amgen; received research funding from Takeda, Celgene Corporation, Janssen, and Amgen; and is a member of the speakers bureau for Sanofi, Celgene Corporation, Janssen, and Amgen. D.A.C. received research funding from Celgene Corporation, Amgen, and Merck Sharp and Dohme. G.J. acted as a consultant for and received honoraria from Roche, Amgen, Janssen, Merck Sharp and Dohme, Celgene Corporation, and Takeda; received travel support from Celgene Corporation and Takeda; received research funding from Takeda; and is a member of the speakers bureau for Roche, Amgen, Janssen, Merck Sharp and Dohme, Celgene Corporation, and Takeda. M.F.K. acted as a consultant for Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, and Celgene Corporation; received travel support from Bristol-Myers Squibb and Takeda; received honoraria from Janssen, Amgen, and Celgene Corporation; and received research funding from Celgene Corporation. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Association between subclonal and clonal TP53 deletion and survival in newly diagnosed myeloma. Kaplan-Meier survival curves showing progression-free survival (A) and OS (B) of 3 approximately equal-sized TP53-deleted clonal subgroups vs no TP53 deletion in 1777 patients in the Myeloma XI trial. OS evaluation of the above subgroups in landmarked analysis from the time of high-dose melphalan and autologous stem cell transplant (C) and from the time of maintenance randomization (D).
Figure 2.
Figure 2.
Relationship between subclonal and clonal TP53 deletion and clinical and genetic characteristics of myeloma. Percentage frequency of genetic changes (A) and clinical changes (B) associated with low, intermediate, and high deletion of TP53 clone. (C) MLPA values normalized for 13q probes in the same patients with low, intermediate, and high deletion of TP53 clone. (D) MLPA values across the subset of patients with del(TP53) and increasing size of del(13q) clone. Lower MLPA values represent increasing size of deleted clone.
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