Lack of Significant Differences in Somatic Alterations between MGUS, SMM and Symptomatic Multiple Myeloma: A Result from Comprehensive Genomic Profiling Study

Somatic alterations including single nucleotide variants (SNVs), copy number alterations (CNAs) and structural variants (SVs) are an important component and the hallmark of Multiple Myeloma (MM) with certain alterations having clinical implications. Recently, the chronological order of such events was explained in detailed studies however previous study has compared the frequency and clonality of such events in early stage plasma cell disorder (MGUS or SMM) and their comparison with MM.Here we performed whole genome (WGS) and RNA sequencing (RNAseq) on 67 samples (8 Unique paired samples from patients with MGUS and when progressed to MM, 10 paired samples at SMM stage and then progressed to MM, as well as non-progressor SMM (NP-SMM) patients who have not progressed after at least 5 years of follow-up. In addition, we profiled CNAs and their clonality level in 164 MGUS, 147 SMM and 336 newly diagnosed MM patients to construct the clonal structure and frequency of somatic alterations.We did not observe significant difference in overall frequency of mutations at MGUS (median=5662 SNVs, IQR= [5252 - 7864]) and SMM stage (median=5308 SNVs, IQR=[4236 - 6125] ) and at progression to MM (median= 5983 SNVs, IQR=[5097 - 8916]). Overall mutational load increased from precursor stage to MM by only 5% with no recurrent change and the difference was not statistically significant (p > 0.05). Similar trend was also observed for SVs [median=36, IQR= [25.25 -40.75] at MGUS, median=34, IQR= [12-52] at SMM, median=27, IQR= [27-41] at MM]. In fact, some of the samples had lower SNV and SV load in MM compared to precursor stages even though that had increased cancer cell fraction. Copy number analysis on paired samples also showed >90% similarity only with few non-recurrent focal CNAs. We have compared WGS data from non-progressor SMM with progressor SMM and newly-diagnosed MM. The non-progressor SMM patients showed identical CNAs and not significantly different Ig translocation frequencies to both other groups. Except for NRAS mutations, mutation frequency in NP-SMM was similar to others. Finally, by using data from 647 patients at three stages (MGUS, SMM and MM), we compared the frequency of CNAs at each time point. Similar to MM, we observed almost equal frequency of hyperdiploid and non-hyperdiploid SMM cases. In hyperdiploid SMM, clonal copy number gain was observed in 95% of patients involving two of the three chromosomes 9, 15 and 19. Moreover, a similar pattern was observed in other hyperdiploid chromosomes including chromosomes 3,5,7,11 and 21. The observed event frequency and clonality levels in SMM were identical to one observed in MM as well as MGUS. Non-hyperdiploid SMM group had early and clonal events targeting chromosome 13 deletion with gain of 1q, 11 and/or 9 at the same frequency level as in MM. The only significant difference was observed in subclonal deletions targeting some of the infrequent deletion events observed in HMM and NHMM. In conclusion, our data from longitudinal analysis of paired precursor and symptomatic MM samples as well as cross sectional data highlight lack of significant differences in genomic changes between precursor conditions and symptomatic myeloma. This lack of progressive and unique genomic change suggests the need for additional transcriptomic, epigenomic or tumor micro environment changes to accelerate the tumor development.