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

• Published in: Blood advances Vol. 2; no. 1; pp. 1 - 9
• Main Authors: Merz, Maximilian, Jauch, Anna, Hielscher, Thomas, Bochtler, Tilmann, Schönland, Stefan Olaf, Seckinger, Anja, Hose, Dirk, Bertsch, Uta, Neben, Kai, Raab, Marc Steffen, Hillengass, Jens, Salwender, Hans, Blau, Igor Wolfgang, Lindemann, Hans-Walter, Schmidt-Wolf, Ingo G.H., Scheid, Christof, Haenel, Mathias, Weisel, Katja C., Goldschmidt, Hartmut
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.01.2018; American Society of Hematology; Elsevier
• Subjects: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bortezomib - therapeutic use; Chromosome Aberrations; Humans; In Situ Hybridization, Fluorescence; Lymphoid Neoplasia; Middle Aged; Multiple Myeloma - diagnosis; Multiple Myeloma - genetics; Netherlands; Prognosis; Transplantation, Autologous; Young Adult; Netherlands
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2017013334

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. •Clonal heterogeneity detected by iFISH is common in newly diagnosed MM.•Treatment with bortezomib overcomes the negative impact of high-risk cytogenetic abnormalities if no further subclones are detected. [Display omitted]