Genome Sequencing Identifies Myeloma Precursor Disease with Progression Risk

Multiple myeloma (MM) is the second most common hematological malignancy and is consistently preceded by the asymptomatic expansion of clonal plasma cells, termed either monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM).

These two precursor conditions are found in 2%–3% of the general population aged older than 40 years. Only a small fraction of MGUS will ultimately progress to MM, whereas ~60% of persons with SMM will progress within 10 years of initial diagnosis. Currently, the differentiation between MGUS and SMM is based on indirect measures and surrogate markers of disease burden.

Hematologists and Oncologists at the Memorial Sloan Kettering Cancer Center (New York, NY, USA) and their colleagues interrogated genome sequence data for 80 multiple myeloma, 18 MGUS, and 14 SMM cases, including a single SMM case classified as high risk based on an available prognostic model. The team compared genome features in 17 precursor cases that progressed to multiple myeloma within two years and 15 stable precursor cases, uncovering a set of “myeloma-defining genomic events” that included chromothripsis, aneuploidy, driver gene mutations, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational profiles, and templated insertions.

For all samples, bone marrow plasma cells (BMPCs) were isolated from bone marrow aspirates and sorted on a BD FACSAria III instrument (BD Biosciences, San Jose, CA, USA). For matched control DNA from each patient, bone marrow T cells or peripheral blood mononuclear cells were used. The T cells were isolated from the BM aspirates and sorted also using the BD FACSAria III. Standard input whole-genome sequencing were run on a NovaSeq 6000 in a 150 bp/150 bp paired-end run (Illumina, San Diego, CA, USA).

The scientists reported that clinically stable cases of MGUS and SMM are characterized by a different genomic landscape and by differences in the temporal acquisition of myeloma-defining genomic events in comparison to progressive entities. In contrast, the investigators reported, the more clinically stable set of precursor gammopathies were missing such alterations. They also tended to surface in individuals diagnosed with MGUS or SMM somewhat later in life (between around 28 and 65 years old), compared to precursor conditions in those with progressive disease, who were diagnosed between the ages of five and 46 years.

The authors concluded that despite its limited sample size, their study provides proof of principle that whole genome sequencing (WGS) has the potential to accurately differentiate stable and progressive precursor conditions in low disease burden clinical states. The application of this technology in the clinic has the potential to significantly alter the management of individual patients, but will require confirmation in larger studies. The study was published on March 25, 2021 in the journal Nature Communications.

Related Links:
Memorial Sloan Kettering Cancer Center
BD Biosciences
Illumina