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Multiple myeloma clonal evolution in homogeneously treated patients.

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Clonal evolution in multiple myeloma can be driven by pre-existing or newly acquired mutations. Therapeutic pressure in multiple myeloma leads to non-specific clonal selection, impacting cancer relapse.

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Area of Science:

  • Oncology
  • Cancer Genomics
  • Hematology

Background:

  • Clonal evolution is a key driver of tumor progression, chemoresistance, and relapse in cancer.
  • The specific mechanisms of clonal selection induced by therapeutic pressure in multiple myeloma remain poorly understood.

Purpose of the Study:

  • To investigate clonal selection dynamics under therapeutic pressure in multiple myeloma.
  • To identify genetic alterations associated with relapse following intensive treatment.

Main Methods:

  • Large targeted sequencing of bone marrow plasma cells from 43 multiple myeloma patients at diagnosis and relapse.
  • Analysis of mutation frequency, subclonal architecture, and evolutionary patterns.

Main Results:

  • The mutational burden remained unchanged between diagnosis and relapse.
  • Driver mutations were frequently present at subclonal levels at both time points.
  • Observed scenarios included selection of rare subclones, mutation appearance/disappearance, and stability, indicating both pre-existing and newly acquired mutations contribute to relapse.
  • No specific mutation or rearrangement was consistently observed at relapse, suggesting non-specific clonal selection by intensive treatment.

Conclusions:

  • Chemoresistance and relapse in multiple myeloma can be driven by both newly acquired and pre-existing subclonal mutations.
  • Intensive treatment exerts a non-specific effect on clonal selection in multiple myeloma.
  • Biallelic events, including deletion 17p/TP53 mutations, were identified in 22 cases.