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

Abstract

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.

FIG 1.

The genomic profile of the 214 patients with smoldering multiple myeloma divided into single nucleotide variants (top 6 panels), somatic copy number alterations (CNAs; yellow panel), and translocations (bottom panel). The risk stratification according to the Mayo 2018 risk model (low, intermediate, and high risk colored as red, green, and blue, respectively). The sex of the patient is identified by the colors pink (female) and blue (male). amp, amplification; del, deletion; HRD, hyperdiploidy; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB.

FIG 2.

(A) Correlation matrix of the 214 patients who demonstrated the significant associations and co-occurrence of different multiple myeloma (MM) drivers (adjusted P < .05). The size of the bubble corresponds to the odds ratio. The blue color indicates negative correlations, while the red color depicts positive ones. (B) The clonal proportions of recurrent somatic copy number alterations and (C) single nucleotide variants across the samples. amp, amplification; del, deletion; HRD, hyperdiploidy.

FIG 3.

Fish plots of four samples of smoldering multiple myeloma (SMM) with two serial samples at different time points. (A-C) Time points correspond to time of SMM diagnosis and time of progression to multiple myeloma (MM). (D) Both time points are at the SMM stage because the patient has not progressed to date. amp, amplification; del, deletion.

FIG 4.

Kaplan-Meier curves for analysis of time to progression in patients with (A) mitogen-activated protein kinase (MAPK) pathway mutations (KRAS and NRAS); (B) MYC alterations, including translocation and amplifications; and (C) DNA repair pathway alterations (deletion 17p, TP53, and ATM single nucleotide variants [red] compared to the absence of these alterations [blue]). (D) Forest plots of multivariable Cox regression of the genomic alterations and the clinical risk model with genetic features selected after bootstrap forward/backward variable selection with Mayo 2018 criteria.

FIG 5.

Kaplan-Meier curves for analysis of time to progression of (A) clinically high-risk patients with (red) or without (blue) the high-risk genomic alterations, (B) clinically intermediate-risk patients with or without the high-risk genomic alterations, (C) patients with or without the high-risk genomic alterations in the Dana-Farber multicenter cohort, and (D) patients with or without the high-risk genomic alterations in the Mayo Clinic validation cohort.