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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


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


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

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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).

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