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Leukemia. 2019 Apr 16. doi: 10.1038/s41375-019-0469-x. [Epub ahead of print]

Monitoring tumour burden and therapeutic response through analysis of circulating tumour DNA and extracellular RNA in multiple myeloma patients.

Author information

1
Myeloma Research Group, Australian Centre for Blood Diseases, Alfred Hospital-Monash University, Melbourne, VIC, Australia.
2
Malignant Hematology and Stem Cell Transplantation, Alfred Hospital, Melbourne, VIC, Australia.
3
Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
4
Haematology, Box Hill Hospital, Melbourne, VIC, Australia.
5
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.
6
Epidemiology and Preventive Medicine, Alfred Health-Monash University, Clayton, VIC, Australia.
7
Myeloma Research Group, Australian Centre for Blood Diseases, Alfred Hospital-Monash University, Melbourne, VIC, Australia. aspencer@netspace.net.au.
8
Malignant Hematology and Stem Cell Transplantation, Alfred Hospital, Melbourne, VIC, Australia. aspencer@netspace.net.au.
9
Department of Clinical Hematology, Monash University, Clayton, VIC, Australia. aspencer@netspace.net.au.

Abstract

Monitoring tumour burden and therapeutic response through analyses of circulating cell-free tumour DNA (ctDNA) and extracellular RNA (exRNA) in multiple myeloma (MM) patients were performed in a Phase Ib trial of 24 relapsed/refractory patients receiving oral azacitidine in combination with lenalidomide and dexamethasone. Mutational characterisation of paired BM and PL samples at study entry identified that patients with a higher number of mutations or a higher mutational fractional abundance in PL had significantly shorter overall survival (OS) (p = 0.005 and p = 0.018, respectively). A decrease in ctDNA levels at day 5 of cycle 1 of treatment (C1D5) correlated with superior progression-free survival (PFS) (p = 0.017). Evaluation of exRNA transcripts of candidate biomarkers indicated that high CRBN levels coupled with low levels of SPARC at baseline were associated with shorter OS (p = 0.000003). IKZF1 fold-change <0.05 at C1D5 was associated with shorter PFS (p = 0.0051) and OS (p = 0.0001). Furthermore, patients with high baseline CRBN coupled with low fold-change at C1D5 were at the highest risk of progression (p = 0.0001). In conclusion, this exploratory analysis has provided the first demonstration in MM of ctDNA for predicting disease outcome and of the utility of exRNA as a biomarker of therapeutic response.

PMID:
30992504
DOI:
10.1038/s41375-019-0469-x

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