Thread by @FrancescoMaura4

Can we define stable versus progressive myeloma precursor conditions (ie MGUS and smoldering multiple myeloma)? Check out our last preprint: biorxiv.org/content/10.110… #mmsm. Tweetorial 👇👇👇👇

Multiple myeloma (MM) is consistently preceded by the asymptomatic expansion of clonal plasma cells, (ie MGUS or SMM). These precursor conditions are found in 2-3% of the general population aged older than 40 years. Only a small fraction of these will ultimately progress to MM.

The differentiation between progressive and stable precursor condition (SMM and MGUS) represents one of the most important unmet clinical need in the multiple myeloma community. Recently important studies highlighted distinct genomic drivers associated with SMM progression

However, these studies were characterized by two main limitations: 1) they were based on exome/targeted sequencing approaches and hence not able to fully capture the genomic landscape of myeloma defining events; 2) they were focused mostly on smoldering myeloma not including MGUS

To circumvent these limitations together with Peter Campbell and @BenedithOben we leverage the low input WGS approach developed at the @sangerinstitute to characterize the genomic landscape of normal tissue from a few thousand cells (eg rdcu.be/b976j).

Not surprisingly the low input WGS quality was comparable (if not identical) to standard WGS. This allowed us to interrogate for the first time the WGS profile of 18 MGUS and comparing this with 14 SMMs and 80 MMs. Here we summarize the key innovative findings 👇

Stable myeloma precursor condition revealed a different mutational signature landscape and absence of "canonical" APOBEC activity (APROBEC3A:3B = ~1) compared to progressive myeloma precursor condition and multiple myeloma.

In line with the recent paper from @IreneGhobrial and @MarkBustoros (ascopubs.org/doi/full/10.12…) patients with stable myeloma precursor disease were characterized by a significantly lower prevalence of known recurrent mutations on known myeloma driver genes.

With @AbascalFed we investigated patterns of positive selection across the different stages and we observed signals indicative of positive selection in the known myeloma driver genes in progressive precursors and MM, but this pattern was not seen in the stable precursors

Cases with stable myeloma precursor condition were characterized by a lower prevalence of aneuploidies, structural variants, and complex events, in particular, chromothripsis and templated insertions compared to progressors and to MM (bloodcancerdiscov.aacrjournals.org/content/1/3/258)

Our data also show how known myeloma SV hotspots are rare/absent in stable myeloma precursor condition. We also confirm the absence of MYC translocations among these patients in line with the beautiful paper from @Leif_Bergsagel (rdcu.be/b98iL)

To rule out that the absence of key WGS-MM defining events among stable cases would reflect a sample collection time bias, we leveraged the molecular-clock approach developed by @EHRustad (rdcu.be/b98a3) to time the age in which the first multi-gain event was acquired

Stable myeloma precursor condition demonstrated a significantly different temporal pattern, in which multi-gain events occurred later in life (median 53.5 years) compared to progressive myeloma precursor condition (median 28 years) and MM cases (median 20.5 years)

This data provides evidence that whole genome analysis has provided initial exciting evidence that myeloma precursor conditions with low disease burden at a high-risk of progression can be identified!!!

This paper is the results of a super cool collaboration between @LaStatale @nickbolli @uhasselt @BenedithOben Guy Froyen Jean-Luc Rummens @sangerinstitute Peter Campbell @gjmorgan56 @sloan_kettering @DrOlaLandgren and many other collaborators and friends