Reasons for MGUS Progression to Myeloma Remain Unclear

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Studying how MGUS and myeloma clones change over time might yield new insights into myeloma’s molecular heterogeneity.
Studying how MGUS and myeloma clones change over time might yield new insights into myeloma’s molecular heterogeneity.

Monoclonal gammopathy of undetermined significance (MGUS) stems from plasma cells' production of aberrant monoclonal paraprotein. It sometimes progresses to multiple myeloma or lymphoma, and a recent study suggested that individuals with MGUS have a shorter life expectancy than matched controls.1

The epidemiology of MGUS and its progression, however, remains poorly understood.2

The “undetermined significance” part of the term is outdated, noted C. Ola Landgren, MD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, New York. In the 1960s, the link between monoclonal gammopathy and myeloma was a matter of debate: only some researchers felt that monoclonal gammopathy and myeloma were linked. In the 1970s, Robert A. Kyle, MD, of the Mayo Clinic in Rochester, Minnesota, coined “MGUS” as a compromise.

In 2009, Dr Landgren, Dr Kyle, and colleagues reported novel findings from a prospective screening study showing, however, that monoclonal gammopathy is a precursor to myeloma.

“Among more than 77,000 people followed for up to 10 years, there were 71 who developed myeloma,” Dr Landgren told Cancer Therapy Advisor. “All of these people had monoclonal gammopathy in their stored samples from baseline.”

MGUS is frequently asymptomatic and usually goes untreated. It can emerge surprisingly early in life — sometimes decades before progressing to myeloma. Dr Landgren and others showed that MGUS is often already present around age 30 years.4

Even after multiple myeloma develops, some MGUS plasma cell subclones remain premalignant. They also respond differently to anti-myeloma treatment than do myeloma clones, according to a retrospective cohort analysis of patients with biclonal gammopathy multiple myeloma.5

Among 6399 newly diagnosed patients with myeloma who participated in one of several UK-based clinical trials (Myeloma IV, Myeloma XI, or TEAMM) between 2004 and 2015, 44 patients had biclonal gammopathy multiple myeloma with IgG or IgA MGUS clones. The patients were followed throughout treatment and the response rates for the 2 clones were analyzed.

Anti-myeloma therapies in these patients yielded a greater depth of response against the myeloma clones than MGUS clones (93% vs 64%; P = .001), reported the authors, suggesting that only a subset of patients' MGUS cells at the time of diagnosis share the molecular biological factors that render myeloma clones more susceptible to treatment.

While the subclones that did not respond to treatment might explain the etiology of refractory and recurrent disease, Dr Landgren noted that the study was not designed to elucidate the underlying biology of clone persistence through treatment.6

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