Mutation landscape of multiple myeloma measurable residual disease: identification of targets for precision medicine

Zátopková, Martina; Ševčíková, Tereza; Fanfani, Viola; Chyra, Zuzana; Říhová, Lucie; Bezděková, Renata; Žihala, David; Growková, Kateřina; Filipova, Jana; Černá, Lucie; Broskevičová, Lucie; Kryukov, Fedor; Minařík, Jiří; Smejkalová, Jana; Maisnar, Vladimír; Harvanova, Lubica; Pour, Luděk; Jungová, Alexandra; Popková, Tereza; Bagó, Juli R.; Sithara, Anjana Anilkumar; Hrdinka, Matouš; Jelı́nek, Tomáš; Šimíček, Michal; Stracquadanio, Giovanni

doi:10.1182/bloodadvances.2020003876

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…This is particularly important as the former can provide additional information about the genetic composition of residual disease that may help optimise subsequent therapeutic interventions, may be a more clinically relevant strategy. 89 Due to the greater sensitivity, MP continue to be detected for longer, particularly for patients with IgG MP. The maximum serological responses will, therefore, be achieved at later time points (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Comparisons should also be made against other peripheral blood‐based techniques for the detection of MRD which are being developed, such as circulating tumour DNA and flow cytometry for the detection of circulating tumour cells. This is particularly important as the former can provide additional information about the genetic composition of residual disease that may help optimise subsequent therapeutic interventions, may be a more clinically relevant strategy 89 …”

Section: Discussionmentioning

confidence: 99%

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The potential role of mass spectrometry for the identification and monitoring of patients with plasma cell disorders: Where are we now and which questions remain unanswered?

2022

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Summary Mass spectrometry (MS) techniques provide a highly sensitive methodology for the assessment and monitoring of paraproteins compared to standard electrophoretic techniques. The International Myeloma Working Group (IMWG) recently approved the use of intact light chain matrix‐assisted laser desorption/ionisation time‐of‐flight mass spectrometry (MALDI‐TOF MS) in lieu of immunofixation in the clinical assessment of patients and the assessment of patients enrolled on clinical trials. The increased sensitivity of these assays may help to detect and monitor monoclonal proteins (MP) in many patients with previously non‐measurable disease, will reduce complete response (CR) rates and increase detection of low‐level MP. The ability to track the unique mass or amino acid sequence of the MP also eliminates interference from therapeutic monoclonal antibodies (tmAbs) in most patients with IgG kappa myeloma. The intact light chain assays also provide structural information about the monoclonal light chain, including the presence of N‐linked glycosylation, which has been shown to be commoner on amyloidogenic light chains and may have prognostic significance in monoclonal gammopathy of undetermined significance (MGUS). In this review, we discuss these issues alongside differences in the analytical and practical aspects related to the different MS assays under development and the challenges for MS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The potential role of mass spectrometry for the identification and monitoring of patients with plasma cell disorders: Where are we now and which questions remain unanswered?

2022

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“…In general terms, MRD testing can show how well patients respond to treatment and it can be used to monitor remission, predict relapse and identify patients in need of alternative therapies. Depending on the specific malignancy, some or all of these potential goals can be met when measuring MRD, but technological considerations and improvements, as well as careful clinical studies in specific disease entities, are warranted for successful clinical implementation [101][102][103][104][105].…”

Section: How To Best Assess Treatment Response and Follow Longitudina...mentioning

confidence: 99%

Application of precision medicine in clinical routine in haematology—Challenges and opportunities

et al. 2022

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Precision medicine is revolutionising patient care in cancer. As more knowledge is gained about the impact of specific genetic lesions on diagnosis, prognosis and treatment response, diagnostic precision and the possibility for optimal individual treatment choice have improved. Identification of hallmark genetic aberrations such as the BCR::ABL1 gene fusion in chronic myeloid leukaemia (CML) led to the rapid development of efficient targeted therapy and molecular follow‐up, vastly improving survival for patients with CML during recent decades. The assessment of translocations, copy number changes and point mutations are crucial for the diagnosis and risk stratification of acute myeloid leukaemia and myelodysplastic syndromes. Still, the often heterogeneous and complex genetic landscape of haematological malignancies presents several challenges for the implementation of precision medicine to guide diagnosis, prognosis and treatment choice. This review provides an introduction and overview of the important molecular characteristics and methods currently applied in clinical practice to guide clinical decision making in haematological malignancies of myeloid and lymphoid origin. Further, experimental ways to guide the choice of targeted therapy for refractory patients are reviewed, such as functional precision medicine using drug profiling. An example of the use of pipeline studies where the treatment is chosen according to the molecular characteristics in rare solid malignancies is also provided. Finally, the future opportunities and remaining challenges of precision medicine in the real world are discussed.

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Single-Nucleotide Variants and Epimutations Induce Proteasome Inhibitor Resistance in Multiple Myeloma

Haertle

Barrio

Munawar

et al. 2022

Clinical Cancer Research

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Purpose: Proteasome inhibitors are the backbone of various treatment regimens in Multiple Myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored. Methods: We performed DNA methylation profiling by Deep Bisulfite Sequencing (DBS) in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunit that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents. Results: We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, NDMM patients, along with PBMCs and CD138+ plasma cells from healthy donors, generally show unmethylated profiles. Conclusion: Under the selective pressure of PI treatment, MM cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell’s proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in Multiple Myeloma.

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Mutation landscape of multiple myeloma measurable residual disease: identification of targets for precision medicine

Cited by 4 publications

References 25 publications

The potential role of mass spectrometry for the identification and monitoring of patients with plasma cell disorders: Where are we now and which questions remain unanswered?

The potential role of mass spectrometry for the identification and monitoring of patients with plasma cell disorders: Where are we now and which questions remain unanswered?

Application of precision medicine in clinical routine in haematology—Challenges and opportunities

Single-Nucleotide Variants and Epimutations Induce Proteasome Inhibitor Resistance in Multiple Myeloma

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