ASH 2017 | Genetic/genomic studies examine progression from SMM to MM

The 59th American Society of Hematology (ASH) Annual Meeting was held in Atlanta, Georgia, from 9-12 December 2017. On Sunday 10 December, an oral Session was held entitled: Session 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Genomics of The Pathogenesis and Progression of Multiple Myeloma. This session comprised six talks, with the first three focussing on the genetics of progression from Smoldering Myeloma (SMM) to Multiple Myeloma (MM), and which we summarize in this article.

Abstract 391: Whole Exome Sequencing of Paired MGUS/SMM to MM Patients Reveals Novel Subclonal Tumor Evolution Models in Disease Progression of Multiple Myeloma.

The first talk was given by Ankit K. Dutta, from the Myeloma Research laboratory, University of Adelaide and the South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia, and examined subclonal tumor evolution in the progression from Monoclonal Gammopathy of Undetermined Significance (MGUS)/SMM to MM.

This study was performed in order to unravel the genomic complexity, key molecular mechanisms and subclonal tumor evolution which underlie the progression from MGUS/SMM to symptomatic MM.  It involved the genomic analysis of longitudinal MGUS/SMM to MM samples. In this study, bone marrow (BM) samples were isolated from patients following their first diagnosis with MGUS/SMM and subsequently, after developing MM.  Fluorescence-activated cell sorting (FACS) was used to purify CD138⁺CD38⁺⁺ plasma cells and matched CD138^-38^- normal cells, from longitudinal MGUS-MM (n = 5) and SMM-MM (n = 5) BM patient samples. This study involved the generation of exome libraries, bioinformatics analysis to identify somatic variants and custom in-house package for the identification of copy number changes.

Key findings:

• Identification of 4,997 somatic non-synonymous single nucleotide variants (NS-SNVs) in the MGUS/SMM samples (230–796), with a median 456 per patient
• 4127 somatic NS-SNVs (221–609), with a median 344 per patient in the MM samples
• 40% of patients at MGUS/SMM and 70% of patients at MM had KRAS and NRAS mutations
• Two models of tumor evolution were involved in MGUS/SMM to MM transformation:
  • The dominant type (3/8 patients) involving the outgrowth of subclones from MGUS/SMM to MM
  • The maintenance type (5/8 patients) in which subclones present in the MGUS/SMM precursor state are retained at the MM stage
• A decrease in the average number of clones in MGUS vs SMM patients, suggesting a decline in clonal complexity either through dominant clonal outgrowth and/or loss of indolent clones with disease progression
• Clonal fitness (i.e. the acquisition of driver mutations and/or out competing for other subclones) determined survival of subclonal branches
• ICAM5, DUSP27, HERPUD1, NOD2, and TOP2A identified as potential drivers of clonal progression

Ankit Dutta concluded the talk by stating that this study gives new insights into subclonal tumor evolution along with the identification of candidate mutated genes associated with MM transformation. The analysis of subclonal tumor evolution patterns revealed the ‘dominant’ and the ‘maintenance’ models, and multiple subclones at the MGUS/SMM stages were found to be associated with MM progression. Additionally, it was also observed that the subclonal populations involved in MM transformation exist at the time of MGUS/SMM diagnosis. This finding will potentially enable earlier stratification and tailored treatment regimens.

Abstract 392: Next Generation Sequencing Identifies Smoldering Multiple Myeloma Patients with a High Risk of Disease Progression

The second talk was given by Mark Bustoros from the Dana Farber Cancer Institute, Boston, MA, USA, working under the direction of Irene Ghobrial, who presented an oral abstract focused on the use of Next Generation Sequencing (NGS) to identify SMM patients with a high risk of progression to MM. The aim of the study was to identify genomic alterations that occur in patients that progress rapidly from MGUS/SMM to MM and in patients that remain indolent over their lifetime.

Key findings:

• Whole exome sequencing (WES) carried out on 70 tumor-germline matched samples
• Targeted deep sequencing on 116 samples of progressor and non-progressor SMM
• Ultra-low pass whole-genome sequencing (ULP-WGS) of 116 SMM samples
• Detection of tumor fraction in 20 available cell-free DNA (cfDNA) samples before proceeding with targeted sequencing

Data are given as HRSMM vs LRSMM:

• Mutation load (1.44 vs 73)
• Somatic mutations in known signaling pathways (13.8% vs 5%, P <0.015)
• Mutations in MAPK pathway genes (KRAS, NRAS, BRAF) (21.7% vs 0%, P <0.004)
• Mutations in NFĸB pathways (17.4% vs 0%, P <0.018)
• MM somatic copy number aberrations (SCNAs) (78.1% vs9%, P <0.020)
• Tumor fraction of cfDNA (P <0.03)

The talk was finalized with the conclusion that specific genomic alterations are associated with HRSMM and hold the potential to predict the risk to progression in SMM patients.

To listen to Irene Ghobrial talking to the MM Hub about the impact of NGS in the management of MM, listen here.

Abstract 393: MYC Translocations Identified By Sequencing Panel in Smoldering Multiple Myeloma (SMM) Strongly Predict for Rapid Progression to Multiple Myeloma (MM)

The third talk of the session was presented by Niamh Keane, from the Mayo Clinic in Arizona, Scottsdale, AZ and National University of Ireland Galway. Dr. Keane outlined their study to determine markers of high risk of progression to MM, with the goal of identifying patients that may benefit from early treatment through a comprehensive analysis of the genome from SMM and MGUS patients.

Key findings:

• Subgroups of patients (pts) identified in this analysis and verified by clinical FISH:

•  Median SMM time to progression (TTP) = 46 months
• Frequent MYC SV in untreated MM with higher frequency in High-Risk Disease (HRD) vs Non-High Risk Disease (NHRD) MM (53% vs 28%)
• No MYC SV detected in MGUS cohort, SMM non-progressors at >5 years or SMM progressing between 2-5 years
• MYC SV detected in 49% SMM with TPP< 2 years, 55% in high-risk disease (HRD) and 41% non-HRD
• Shorter median TTP in SMM with MYC SV compared to patients without MYC SV (11.5 months vs 61 months; P <0.0001)
• MYC SV confirmed as an independent variable for progression to MM (HR=7, 95% CI 3.6-13.7, P <0.00001)
• Similar frequencies in RAS and NFĸB pathway mutations in MM and SMM (TTP <5 years of diagnosis), lower frequency in MM and SMM (TTP >5 years) and not observed in the MGUS cohort

Niamh Keane concluded that MYC translocations are a genetic marker for the progression to MM, and are not found in MGUS and SMM with TPP >2 years. The identification of MYC translocations at the time of diagnosis of SMM predicts a short TTP to MM.