A New Tool to Evaluate the Risk of Multiple Myeloma

Before fully manifesting itself, multiple myeloma - a malignant tumour affecting a particular type of bone marrow cell known as plasma cell - is preceded by the development of an asymptomatic precursor state. By analysing the genome of more than a thousand patients, an international team of scientists has succeeded in developing a tool to assess danger signals and the risk of developing the tumour. The results were published in Nature Genetics.

"Until now, we did not have a reliable, easy-to-use genomic tool to understand, right from the start, who among those with the asymptomatic precursor state of the disease really runs the risk of developing multiple myeloma," explains Andrea Poletti, assistant professor at the Department of Medical and Surgical Sciences at the University of Bologna, and one of the authors of the study. "This analysis fills that gap: it offers a genetic compass capable of guiding doctors from the earliest stages of the disease and possibly providing a clear clinical warning signal."

There are two silent precursor states of multiple myeloma: one is called 'monoclonal gammopathy of undetermined significance' (MGUS) and the other 'smouldering multiple myeloma' (SMM). However, only a fraction of patients with these early forms actually develops the disease. The researchers focused, therefore, on finding genetic factors that could signal the risk of this malignant progression.

To do this, they analysed the DNA of 1,030 tumour samples taken from patients with multiple myeloma, sequencing the entire genome and highlighting not only the best-known mutations, but also several other types of molecular alterations. To ensure the results were reliable, the analysis was performed on two independent cohorts of patients and on several samples taken from the same patients over a period of more than four years.

From 17 key genomic alterations, the researchers devised a new score with a scale from 0 to 12, called the 'MM like score'. With this new tool, it is possible to clearly define whether a patient has one of the precursor forms or multiple myeloma.

"We have seen that patients with a score of 1 of above double, or in some cases even triple the risk of a smouldering multiple myeloma becoming multiple myeloma, thus offering a clear clinical warning sign," says Elena Zamagni, professor at the Department of Medical and Surgical Sciences, who participated in the study. "Furthermore, our investigation revealed a 'step' progression of the disease, in which late genetic events such as alterations of specific genes, chromosome deletions or pathway mutations, act as accelerators of malignant disease progression."

The results also showed that the disease’s development pathway can be very long, with the first 'genetic spark' of myeloma occurring on average 20 to 30 years before diagnosis.

The new evaluation system could therefore make it possible to select patients with smouldering multiple myeloma who are at high risk, with the advantage of being able to repeat the test several times without the need to take bone marrow samples. Added to this is the identification of new genetic elements and key mutations that can be used to develop targeted therapies, to be tested already in patients with early and asymptomatic forms of multiple myeloma.

The study was published in Nature Genetics with the title “Genomic landscape of multiple myeloma and its precursor conditions”. Andrea Poletti, Carolina Terragna and Elena Zamagni from the Department of Medical and Surgical Sciences contributed on behalf of the University of Bologna.