MYC Translocations Identified By Sequencing Panel in Smoldering Multiple Myeloma Strongly Predict for Rapid Progression to Multiple Myeloma

Introduction

Smoldering Myeloma (SMM) is a heterogeneous asymptomatic stage between Monoclonal Gammopathy of Unknown Significance (MGUS) and Multiple Myeloma (MM). Risk of progression to MM is 10% in the first 5 years following diagnosis and greatly diminishes thereafter (Kyle et al NEJM 2007). Early intervention in SMM patients at high risk of progression extends survival (Mateos et al NEJM 2013). The IMWG 2014 Updated Criteria establish a subset of SMM patients who are at ultra-high risk for progression to MM within 2 years, and therefore merit treatment (Rajkumar et al Lancet Oncol 2014). Analyses of the genetic and molecular landscape of SMM to date report a near identical picture to MM, however most patients in these studies progress rapidly and are therefore not representative of the entire group. We performed a comprehensive analysis of SMM and MGUS patients to determine markers of high risk of progression that could identify patients to benefit from early treatment

Methods

MGUS not progressing after at least 10 years of follow up and SMM in which follow up data were available were extracted from the Plasma Cell Dyscrasia Biobank. A clinically applicable Custom Capture MM-specific sequencing platform was developed for detection of the most frequently mutated pathways in MM based on analysis of CoMMpass dataset. Coding exons of actionable genes, clinically relevant copy number abnormalities, and regions surrounding IgH (0.5Mb), IgK (0.1Mb), IgL (0.1Mb) and MYC loci (1.6Mb) to identify relevant structural variants (SVs) were included, with combined design 2.2Mb. 12 samples were pre-pooled before capture, and 2 captures were sequenced per lane of Illumina HiSeq4000. Paired-end 150bp reads were mapped to hg19 using BWA-MEM. Single nucleotide variants (SNVs) and small INDELs in capture regions were identified using the GenomeGPS analytic pipeline following Broad GATK variant discovery practices. Copy number variants (CNVs) were identified by patternCNV. SVs of translocations, inversions, large INDELs, and segmental duplications were called by the SnowShoes-SV algorithm developed in-house. False positive SVs, polymorphic SVs, and other artefacts were filtered out using in-house normal SV database.

Results

We identified and sequenced 128 patients including 32 MGUS patients not progressing after 10 years. Of 96 SMM patients included 36 had not progressed to SMM after minimum follow up of 5 years, while 37 and 23 progressed to MM in less than 2 years and between 2-5 years, respectively. The genetic subtype of each patient was determined and verified by clinical FISH. Proportions in each genetic subgroup in MM and SMM/MGUS were similar, indicating that these are primary genetic lesions occurring early in MM pathogenesis. Median SMM time to progression (TTP) was 46 months. As in other series, HRD with IGH translocation, and t(4;14) predicted shorter TTP.

Analysis of CoMMpass dataset found frequent MYC SV (38%) in untreated MM with higher frequency in HRD versus NHRD MM: 53% versus 28% (Misund, ASH 2016). No MYC SV were detected in MGUS cohort, SMM non-progressors at >5 years or SMM progressing between 2-5 years. By contrast, MYC SV were detected in 49% SMM that progressed within 2 years, 55% in HRD and 41% NHRD. SMM with MYC SV had a significantly shorter median TTP compared to patients without MYC SV (11.5 months vs 61 month; p<0.0001). Multivariate analysis with high risk genetic groups and biomarkers for progression (BMPCs >/=60% and FLC ratio 100) confirm MYC SV as an independent variable for progression to MM (hazard ratio=7, 95% confidence interval 3.6-13.7, p=0.00001).

RAS and NFKB pathway mutations were observed with similar frequencies in MM and SMM progressing within 5 years of diagnosis, but with lower frequency in those not progressing by 5 years follow up, and were not observed in the MGUS cohort. A trend toward shorter TTP was observed in patients with RAS pathway mutations but did not reach statistical significance.

Conclusion

In conclusion, we describe MYC translocations as a genetic marker of and likely cause of progression to MM that are absent in MGUS and SMM with TTP >2 years. In contrast MM and SMM early progressors (TTP <2 years) share a similar genetic landscape. Identification of MYC translocations at diagnosis of SMM predicts short TTP to MM, defining a novel ultra-high risk category that merits validation in prospective clinical trials.

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