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Individuals with low-risk or intermediate-risk monoclonal gammopathy of undetermined significance (MGUS) may convert to high-risk MGUS and progress to multiple myeloma within 5 years, researchers reported.

The results could support annual blood tests and risk assessment for those diagnosed with MGUS and its subtype, light-chain MGUS, said C. Ola Landgren, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

Their cross-sectional cohort study, published online in, found that in 23 of 43 participants (53%) with high-risk MGUS before progression, 16 (70%) experienced conversion from low-risk or intermediate-risk MGUS within 5 years. The results were similar for those with light-chain MGUS.

Furthermore, patients' biological features appeared to impact the regulation of stable precursor disease versus progression:

• Immunosuppression (one or more suppressed uninvolved immunoglobulins) was found in 58% of patients with MGUS progression compared with 20% of those without progression

• Among patients with free light-chain (FLC) MGUS, immunosuppression was found in 54% of those with progression vs 12% of those without progression

Among patients in both groups, those with severe immunosuppression (two or more suppressed uninvolved immunoglobulins) had a significantly elevated risk of progression:

• Patients with MGUS: 29% among those with progression versus 3% among those without progression

• Patients with light-chain MGUS: 18% among those with progression versus 2% among those without progression

"In this prospective study, we found that significantly increasing [monoclonal] spike and involved serum FLC concentrations were detectable in patients with disease MGUS progression more than 5 years before multiple myeloma diagnosis," the authors wrote. They said that when they combined individual markers into a risk score for progression, 53% of patients with progressing MGUS but only one of 108 patients with non-progressing MGUS had a high risk score.

The investigators noted that multiple myeloma is one of the few cancers with a defined detectable in peripheral blood that might allow earlier intervention. Usually found incidentally, MGUS is characterized by abnormal immunoglobulins in the peripheral blood and urine and in clonal plasma cells in bone marrow.

Study Details

The study population consisted of 685 adults ages 55 to 74 from the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial diagnosed with progressing MGUS (187 patients) or stable MGUS (498 patients), including light-chain type, from November 1993 through December 2011.

The cohort was 67.3% male, and mean age was 69.1. Data analysis on prediagnostic serum samples took place during April to December 2018.

The following risk factors were associated with progressive MGUS, the researchers found:

• Immunoglobulin A isotype: adjusted odds ratio (aOR) 1.80 (95% CI 1.03-3.13, P=0.04)

• Monoclonal spike of 15 g/L or more: aOR 23.5 (95% CI 8.9-61.9, P<0.001)

• Skewed (less than 0.1 or more than 10) serum FLC ratio: aOR 46.4 (95% CI 18.4-117.0, P<0.001)

• Severe immunoparesis (two or more suppressed uninvolved immunoglobulins): aOR 19.1 (95% CI 7.5-48.3, P<0.001)

Adverse markers associated with progressive light-chain MGUS were skewed serum FLC ratio (aOR 44.0, 95% CI 14.2-136.3, P<0.001) and severe immunoparesis (aOR 48.6, 95% C, 9.5-248.2, P<0.001).

"Future studies should investigate biologic interactions between nontumor and tumor cells in association with progression," Landgren and co-authors wrote.

Study limitations, the team said, included the lack of access to bone marrow biopsy or aspirate material for clinical and biologic characterization.

Writing in an accompanying , Nikhil C. Munshi, MD, of Dana Farber Cancer Center in Boston, and colleagues said the study put forward the biologically relevant concept that risk features are not stagnant. Just as standard-risk multiple myeloma can acquire a new high-risk feature such as 17p deletion, MGUS may develop more aggressive characteristics before proceeding to malignant transformation, the commentators explained.

They said, though, that the findings were actually not surprising, and rather than being predictive, may simply represent slow progression of disease and a change in risk category but not necessarily a change in risk stratification: "The results do not identify those patients who are at an increased risk of progression until they have already shown signs of progression reflected by the change in risk stage. So, a prospective follow-up of patients using the current study may not be feasible," Munshi, et al. wrote.

In addition, they noted that the study also considered four risk stratifiers, including immunoparesis, criteria that do not reflect current of progression. "What this study does suggest is that patients who have low-risk MGUS probably need to be followed for a prolonged period of time," the commentators wrote. "An ongoing question would be: can we identify those patients in each of the risk categories who have extremely low chance of progression?"