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Multiple myeloma gammopathies

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

Leukemia volume 33, pages 2022–2033 (2019)Cite this article

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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.

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Acknowledgements

We thank the staff and patients of Malignant Haematology & Stem Cell Transplantation, Alfred Hospital for the invaluable contribution towards sample collection.

Funding

Dr. Mithraprabhu was supported by a fellowship from the James and Elsie Borrowman Estate.

Author information

Authors and Affiliations

  1. Myeloma Research Group, Australian Centre for Blood Diseases, Alfred Hospital-Monash University, Melbourne, VIC, Australia

    Sridurga Mithraprabhu, Tiffany Khong, Anna Kalff, Krystal Bergin, Ioanna Savvidou, Malarmathy Ramachandran, Kawa Choi & Andrew Spencer

  2. Malignant Hematology and Stem Cell Transplantation, Alfred Hospital, Melbourne, VIC, Australia

    Sridurga Mithraprabhu, Tiffany Khong, Anna Kalff, Krystal Bergin, Jay Hocking, Ioanna Savvidou, Kathryn M. Bowen, Malarmathy Ramachandran, Kawa Choi & Andrew Spencer

  3. Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia

    Rachel Morley

  4. Haematology, Box Hill Hospital, Melbourne, VIC, Australia

    Jay Hocking

  5. Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia

    Boris Ka Leong Wong

  6. Epidemiology and Preventive Medicine, Alfred Health—Monash University, Clayton, VIC, Australia

    John Reynolds

  7. Department of Clinical Hematology, Monash University, Clayton, VIC, Australia

    Andrew Spencer

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Contributions

SM and AS had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SM and AS were involved in the study concept and design. SM, RM, TK, AK, KB, JH, IS, KB, MR, KW, BKLW, JR and AS contributed to acquisition, analysis and interpretation of data. SM, RM and AS drafted the manuscript. Critical revision of the manuscript was performed by all authors. Statistical analyses were performed by SM, RM and JR. Administrative, technical and/or material support were provided by TK, AK, KB, JH, IS, KB, MR, BKLW, KC and AS. The study was supervised by SM, TK, AK and AS.

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Correspondence to Andrew Spencer.

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Mithraprabhu, S., Morley, R., Khong, T. et al. Monitoring tumour burden and therapeutic response through analysis of circulating tumour DNA and extracellular RNA in multiple myeloma patients. Leukemia 33, 2022–2033 (2019). https://doi.org/10.1038/s41375-019-0469-x

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