Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

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


J Clin Oncol. 2020;38(21):2380-2389. 

In This Article

Abstract and Introduction


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.


Multiple myeloma (MM) is an incurable plasma cell malignancy with significant inter- and intrapatient heterogeneity. It is almost always preceded by asymptomatic precursor stages, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).[1,2] Patients with SMM have a higher risk of progression to MM (10%/year) compared with MGUS (1%/year).[3] Although some patients progress rapidly, others remain in an MGUS-like state for years.

Current prognostic models do not fully capture SMM progression risk because patients who are considered to be intermediate or low risk by those criteria can still progress. This might be because these models are based mainly on tumor burden markers and may not adequately reflect the underlying biology that could be critical for disease progression. Thus, there is an urgent need for novel prognostic markers that can accurately identify patients with SMM who are at risk for progression and could benefit from early treatment. Herein, we studied 214 samples from patients with SMM to comprehensively characterize the genomic landscape of SMM and identify biomarkers of progression to MM.