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Genomic classification and individualized prognosis in multiple myeloma

Purpose - Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. - Methods - To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available...

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Main Authors: Maura, Francesco (Author) , Rajanna, Arjun Raj (Author) , Ziccheddu, Bachisio (Author) , Poos, Alexandra (Author) , Derkach, Andriy (Author) , Maclachlan, Kylee (Author) , Durante, Michael (Author) , Diamond, Benjamin (Author) , Papadimitriou, Marios (Author) , Davies, Faith (Author) , Boyle, Eileen M. (Author) , Walker, Brian (Author) , Hultcrantz, Malin (Author) , Silva, Ariosto (Author) , Hampton, Oliver (Author) , Teer, Jamie K. (Author) , Siegel, Erin M. (Author) , Bolli, Niccolò (Author) , Jackson, Graham H. (Author) , Kaiser, Martin (Author) , Pawlyn, Charlotte (Author) , Cook, Gordon (Author) , Kazandjian, Dickran (Author) , Stein, Caleb (Author) , Chesi, Marta (Author) , Bergsagel, Leif (Author) , Mai, Elias K. (Author) , Goldschmidt, Hartmut (Author) , Weisel, Katja C. (Author) , Fenk, Roland (Author) , Raab, Marc-Steffen (Author) , Van Rhee, Fritz (Author) , Usmani, Saad (Author) , Shain, Kenneth H. (Author) , Weinhold, Niels (Author) , Morgan, Gareth (Author) , Landgren, Ola (Author)
Format: Article (Journal)
Language:English
Published: January 9, 2024
In: Journal of clinical oncology
Year: 2024, Volume: 42, Issue: 11, Pages: 1229-1240
ISSN:1527-7755
DOI:10.1200/JCO.23.01277
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1200/JCO.23.01277
Verlag, kostenfrei, Volltext: https://ascopubs.org/doi/10.1200/JCO.23.01277
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Author Notes:Francesco Maura, Arjun Raj Rajanna, Bachisio Ziccheddu, Alexandra M. Poos, Andriy Derkach, Kylee Maclachlan, Michael Durante, Benjamin Diamond, Marios Papadimitriou, Faith Davies, Eileen M. Boyle, Brian Walker, Malin Hultcrantz, Ariosto Silva, Oliver Hampton, Jamie K. Teer, Erin M. Siegel, Niccolò Bolli, Graham H. Jackson, Martin Kaiser, Charlotte Pawlyn, Gordon Cook, Dickran Kazandjian, Caleb Stein, Marta Chesi, Leif Bergsagel, Elias K. Mai, Hartmut Goldschmidt, Katja C. Weisel, Roland Fenk, Marc S. Raab, Fritz Van Rhee, Saad Usmani, Kenneth H. Shain, Niels Weinhold, Gareth Morgan, and Ola Landgren
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Summary:Purpose - Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. - Methods - To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. - Results - Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. - Conclusion - Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.
Item Description:Gesehen am 09.12.2024
Physical Description:Online Resource
ISSN:1527-7755
DOI:10.1200/JCO.23.01277

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