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Clinical Trial
. 2017 Dec 27;2(1):1-9.
doi: 10.1182/bloodadvances.2017013334. eCollection 2018 Jan 9.

Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma

Maximilian Merz  1 , Anna Jauch  2 , Thomas Hielscher  3 , Tilmann Bochtler  1 , Stefan Olaf Schönland  1 , Anja Seckinger  1 , Dirk Hose  1 , Uta Bertsch  1   4 , Kai Neben  1 , Marc Steffen Raab  1   5 , Jens Hillengass  1 , Hans Salwender  6 , Igor Wolfgang Blau  7 , Hans-Walter Lindemann  8 , Ingo G H Schmidt-Wolf  9 , Christof Scheid  10 , Mathias Haenel  11 , Katja C Weisel  12 , Hartmut Goldschmidt  1   4
Affiliations
Clinical Trial

Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma

Maximilian Merz et al. Blood Adv. .

Abstract

We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial.

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Conflict of interest statement

Conflict-of-interest disclosure: M.M. received travel grants from Celgene, Abbvie, Amgen, and Janssen and acts on advisory boards for Amgen. D.H. received research funding from Sanofi and EngMab, as well as personal fees outside this work from Celgene. H.S. received speakers honoraria and travel grants from Celgene, Amgen, and Sanofi. I.G.H.S.-W. received research funding from Janssen and Novartis. C.S. received funding outside this work from Novartis, Celgene, and Janssen. K.C.W. received consultancy honoraria from Amgen, Takeda, and BMS, as well as honoraria from Novartis, research funding from Janssen and Celgene, and consultancy honoraria from Onyx. H.G. received consultancy honoraria and research funding from Janssen, Celgene, and Novartis, as well as consultancy honoraria from Onyx and Millenium and fees outside this work from BMS. J.H. received speakers honoraria from Celgene, acts on advisory boards for Janssen, BMS, and Amgen, and received consultancy honoraria from Janssen, Novartis, and Amgen as well as research funding from Sanofi. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Outcome of patients with or without high-risk aberrations. (A) +1q21: blue, no +1q21; red, subclone +1q21; green, main clone +1q21. (B) −17p: blue, no −17p; red, subclone −17p; green, main clone −17p. (C) ±MYC: blue, no ±MYC; red, subclone ± MYC; green, main clone ± MYC.
Figure 2.
Figure 2.
Outcome of patients with (red) or without (blue) subclones. (A) Entire cohort, (B) patients with standard-risk, and (C) high-risk main clone aberration.
Figure 3.
Figure 3.
Outcome of high-risk patients. (A) Standard- and (B) high-risk patients. Bortezomib arm: purple, no subclone; red, with subclone. Thalidomide arm: green, no subclone; blue, with subclone. Colored numbers below the plots represent uncensored patients at the respective time point.
Figure 4.
Figure 4.
Forest plots from univariate analysis. PFS (upper panel) and OS (lower panel) for the entire cohort and standard- and high-risk patients. Green, all patients; red, PAD arm; blue, VAD arm. CI, confidence interval; HR, hazard ratio; VAD, vincristine, Adriamycin, and dexamethasone.
See this image and copyright information in PMC

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