Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression

Mark Bustoros, Romanos Sklavenitis-Pistofidis, Jihye Park, Robert Redd, Benny Zhitomirsky, Andrew J. Dunford, Karma Salem, Yu Tzu Tai, Shankara Anand, Tarek H. Mouhieddine, Selina J. Chavda, Cody Boehner, Liudmila Elagina, Carl Jannes Neuse, Justin Cha, Mahshid Rahmat, Amaro Taylor-Weiner, Eliezer Van Allen, Shaji Kumar, Efstathis KastritisIgnaty Leshchiner, Elizabeth A. Morgan, Jacob Laubach, Tineke Casneuf, Paul Richardson, Nikhil C. Munshi, Kenneth C. Anderson, Lorenzo Trippa, François Aguet, Chip Stewart, Meletios Athanasios Dimopoulos, Kwee Yong, P. Leif Bergsagel, Salomon Manier, Gad Getz, Irene M. Ghobrial

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Purpose: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. Methods: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. Results: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. Conclusion: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

Original languageEnglish (US)
Pages (from-to)2380-2389
Number of pages10
JournalJournal of Clinical Oncology
Issue number21
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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