The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma

Nat Commun. 2021 Jan 12;12(1):293. doi: 10.1038/s41467-020-20524-2.


Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC Deaminases / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Biomarkers, Tumor / metabolism
  • Clone Cells
  • DNA Copy Number Variations / genetics
  • Disease Progression
  • Evolution, Molecular*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Genome, Human
  • Humans
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Mutation / genetics
  • Mutation Rate
  • Progression-Free Survival
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Smoldering Multiple Myeloma / diagnosis
  • Smoldering Multiple Myeloma / genetics*
  • Time Factors
  • Translocation, Genetic


  • Biomarkers, Tumor
  • KRAS protein, human
  • APOBEC Deaminases
  • Proto-Oncogene Proteins p21(ras)