Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul 12;10(7):1674.
doi: 10.3390/biomedicines10071674.

Tracking Clonal Evolution of Multiple Myeloma Using Targeted Next-Generation DNA Sequencing

Aleksander Salomon-Perzyński  1 , Joanna Barankiewicz  1 , Marcin Machnicki  2 , Irena Misiewicz-Krzemińska  3 , Michał Pawlak  3 , Sylwia Radomska  4 , Agnieszka Krzywdzińska  5 , Aleksandra Bluszcz  6 , Piotr Stawiński  7 , Małgorzata Rydzanicz  7 , Natalia Jakacka  1 , Iwona Solarska  4 , Katarzyna Borg  6 , Zofia Spyra-Górny  8 , Tomasz Szpila  1 , Bartosz Puła  1 , Sebastian Grosicki  8 , Tomasz Stokłosa  2 , Rafał Płoski  7 , Ewa Lech-Marańda  1 , Jana Jakubikova  9 , Krzysztof Jamroziak  10
Affiliations

Tracking Clonal Evolution of Multiple Myeloma Using Targeted Next-Generation DNA Sequencing

Aleksander Salomon-Perzyński et al. Biomedicines. .

Abstract

Clonal evolution drives treatment failure in multiple myeloma (MM). Here, we used a custom 372-gene panel to track genetic changes occurring during MM progression at different stages of the disease. A tumor-only targeted next-generation DNA sequencing was performed on 69 samples sequentially collected from 30 MM patients. The MAPK/ERK pathway was mostly affected with KRAS mutated in 47% of patients. Acquisition and loss of mutations were observed in 63% and 37% of patients, respectively. Four different patterns of mutation evolution were found: branching-, mutation acquisition-, mutation loss- and a stable mutational pathway. Better response to anti-myeloma therapy was more frequently observed in patients who followed the mutation loss-compared to the mutation acquisition pathway. More than two-thirds of patients had druggable genes mutated (including cases of heavily pre-treated disease). Only 7% of patients had a stable copy number variants profile. Consequently, a redistribution in stages according to R-ISS between the first and paired samples (R-ISS″) was seen. The higher the R-ISS″, the higher the risk of MM progression and death. We provided new insights into the genetics of MM evolution, especially in heavily pre-treated patients. Additionally, we confirmed that redefining R-ISS at MM relapse is of high clinical value.

Keywords: clonal evolution; multiple myeloma; next-generation sequencing.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The functional categorization of all mutant genes.
Figure 2
Figure 2
The proportions of multiple myeloma patients bearing mutations in genes involved in a particular cellular process.
Figure 3
Figure 3
Evolution of single-nucleotide variants during multiple myeloma progression based on the next-generation sequencing data from the first and paired samples. Description: A—patients who presented a branching evolution with mutations lost and gained during multiple myeloma progression; B—patients who only acquired new mutations during multiple myeloma progression; C—patients who only lost mutations during multiple myeloma progression; D—patients with stable mutations during multiple myeloma progression.
Figure 4
Figure 4
Evolution of copy number variants during multiple myeloma progression based on the next-generation sequencing data from the first and paired samples. Description: A—patients who presented a branching evolution of single-nucleotide variants with mutations lost and gained during multiple myeloma progression; B—patients who only acquired new single-nucleotide variants during multiple myeloma progression; C—patients who only lost single-nucleotide variants during multiple myeloma progression; D—patients with a stable profile of single-nucleotide variants during multiple myeloma progression.
Figure 5
Figure 5
Kaplan–Meier survival curves for (a) PFS, (b) OS after the paired sample collection (OS″) and (c) OS after the first sample collection (OS′) according to the R-ISS″ (assessed at the time of the paired sample collection). The comparison of survival groups was assessed by log rank test (p values).
Figure 5
Figure 5
Kaplan–Meier survival curves for (a) PFS, (b) OS after the paired sample collection (OS″) and (c) OS after the first sample collection (OS′) according to the R-ISS″ (assessed at the time of the paired sample collection). The comparison of survival groups was assessed by log rank test (p values).
See this image and copyright information in PMC

References

    1. Rajkumar S.V. Multiple Myeloma: 2020 Update on Diagnosis, Risk-Stratification and Management. Am. J. Hematol. 2020;95:548–567. doi: 10.1002/ajh.25791. - DOI - PubMed
    1. Rasche L., Chavan S.S., Stephens O.W., Patel P.H., Tytarenko R., Ashby C., Bauer M., Stein C., Deshpande S., Wardell C., et al. Spatial Genomic Heterogeneity in Multiple Myeloma Revealed by Multi-Region Sequencing. Nat. Commun. 2017;8:268. doi: 10.1038/s41467-017-00296-y. - DOI - PMC - PubMed
    1. Melchor L., Brioli A., Wardell C.P., Murison A., Potter N.E., Kaiser M.F., Fryer R.A., Johnson D.C., Begum D.B., Wilson S.H., et al. Single-Cell Genetic Analysis Reveals the Composition of Initiating Clones and Phylogenetic Patterns of Branching and Parallel Evolution in Myeloma. Leukemia. 2014;28:1705–1715. doi: 10.1038/leu.2014.13. - DOI - PubMed
    1. Weinhold N., Ashby C., Rasche L., Chavan S.S., Stein C., Stephens O.W., Tytarenko R., Bauer M.A., Meissner T., Deshpande S., et al. Clonal Selection and Double-Hit Events Involving Tumor Suppressor Genes Underlie Relapse in Myeloma. Blood. 2016;128:1735–1744. doi: 10.1182/blood-2016-06-723007. - DOI - PMC - PubMed
    1. Walker B.A., Boyle E.M., Wardell C.P., Murison A., Begum D.B., Dahir N.M., Proszek P.Z., Johnson D.C., Kaiser M.F., Melchor L., et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients with Newly Diagnosed Myeloma. J. Clin. Oncol. 2015;33:3911–3920. doi: 10.1200/JCO.2014.59.1503. - DOI - PMC - PubMed

LinkOut - more resources