Thread by @FrancescoMaura4

Check out our last paper on MGUS and SMM in @NatureComms: "Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities"@SylvesterCancer @UMiamiHealth @sloan_kettering @LaStatale @uhasselt #mmsm disq.us/t/3vrlji0 👇👇(1/18)

In the 1960-1970s two giants, Dr. Waldenström and Dr. Kyle debated the role of serum proteins in asymptomatic individuals, and whether they were linked to myeloma, or not (2/18)

After its first description by Dr Waldenström as “benign monoclonal gammopathy”, in 1978, Dr Kyle proposed the terminology MGUS, which allowed the field to move forward together and to acknowledge the risk of progression to myeloma was undetermined for individual patients (3/18)

Thanks to the advent of NGS our group and others (@Leif_Bergsagel @IreneGhobrial @MarkBustoros @DrGarethMorgan1) have shown that certain myeloma defining genomic events are associated with myeloma precursor progression. PMID: 31439946, 30135448, 32442065, 28550183 (4/18)

However, these studies were characterized by two main limitations: 1) they were mostly based on exome/targeted sequencing and hence not able to fully capture all myeloma defining genomic events; 2) they were focused mostly on smoldering myeloma (SMM) not MGUS. (5/18)

The reason why MGUS has not been included in previous WGS studies is the fact that standard WGS assays require >100,000s abnormal plasma cells to generate valid data (6/18)

To circumvent these limitations together with Peter Campbell and @BenedithOben
we leverage the low input WGS approach developed at the @sangerinstitute: rdcu.be/chslW (7/18)

Interestingly, we did not observe any significant quality difference between low input and standard WGS, suggesting that this new platform can be used in cancer genomic studies designed to characterize low levels of disease (8/18)

WGS allows the characterization of four main features: 1) mutational signatures; 2) driver mutations; 3) aneuploidies; and 4) structural variants/complex events. For each of these, we observed striking differences between stable and progressive myeloma precursor conditions (9/18)

Canonical APOBEC mutational activity (APOBEC3A:3B ~1) was not detected among stable precursors. In contrast, ~80% of multiple myeloma and progressive precursors condition had it. (10/18)

Driver mutations were rarely observed among stable precursors, confirming that the mutational landscape of stable myeloma precursor condition is significantly different in comparison to progressive myeloma precursor condition and multiple myeloma (11/18)

Stable myeloma precursor conditions have a lower prevalence of recurrent aneuploidies such as gain1q, del6q, del8p, gain8q24, and del16q. In contrast, progressive precursors did not show any difference compared to multiple myeloma (12/18)

Stable myeloma precursor conditions rarely have structural variants, chromothripsis, and templated insertions. On the contrary, progressive myeloma precursor conditions and multiple myeloma have the same prevalence (13/18)

Stable myeloma precursor conditions had a significantly different temporal pattern, in which multi-gain events occurred later in the patient’s life (median 53.5 y) compared to progressive myeloma precursor conditions (median 28 y) and multiple myeloma (median 20.5 y) (14/18)

In conclusion, we showed that using myeloma defining genomic events we can easily distinguish stable (or "benign") from progressive myeloma precursor conditions independently from the disease burden (15/18)

Using our novel approach, we are able to identify “myeloma-to-be cases” versus “stable cases” among groups of individuals with a current diagnosis of MGUS or smoldering myeloma (16/18)

This work would have not been possible without an amazing team effort between, multiple institutions @JessaZiekenhuis @policlinicoMI, funding agencies, and people involved: @nickbolli @BenedithOben Guy Froyen Jean-Luc Rummens and Peter Campbell @DrOlaLandgren (17/18)

A special thanks to @DrGarethMorgan1 and @VincentRK for feedback on our drafted manuscript and for providing wise suggestions (18/18)