Blood cancers

Two distinct myeloma precursor conditions identified by genome sequencing


Whole genome sequencing (WGS) can potentially be used to recognise two distinct precursor conditions to multiple myeloma (MM), according to new research. Because one of these conditions is clinically stable while the other is progressive, the finding has the potential to significantly alter management of patients.

“After more than 50 years of investigation of the relationship between myeloma precursor conditions and MM, the use of whole-genome analysis provides initial exiting evidence that myeloma precursor conditions with low disease burden at a high-risk of progression can be identified,” wrote study authors led by Prof Bénedith Oben, of Hasselt University in Belgium, in Nature Communications.

MM is consistently preceded by the asymptomatic expansion of clonal plasma cells, in conditions termed either monoclonal gammopathy of undetermined significance (MGUS) or smouldering myeloma (SMM). The two precursor conditions are seen in as many as 3% of the general population over the age of 40.

They are clinically very distinct, with only a small proportion of those with MGUS progressing to MM while about 60% of those with SMM progress within 10 years.

Surrogate markers of disease burden can be used to define a high-risk SMM group, but they fare worse in predicting risk for those with low disease burden.

Using WGS, the researchers examined the mutational landscape of 18 MGUS and 14 SMMs, and compared them with that of 80 MMs. They found distinct genomic signatures for the two precursor conditions, and despite the small numbers included they said the two had “striking differences.”

In one of the two entities described, the precursor condition was characterised by enough myeloma genomic defining events to confer malignant potential associated with progressive disease. In the other, there was a lower burden of genetic events, suggesting a likely prolonged, indolent, and clinically stable course.

“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 authors wrote.

“Going forward, improved and biology-oriented strategies to accurately identify patients with progressive myeloma precursor condition before clonal expansion (i) will allow earlier initiation of therapy before onset of end-organ damage to avoid severe clinical complications, ii) will prevent patients with precursor conditions from being overtreated.”

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