Risk Patterns Prior to Progression From MGUS to Myeloma Call for Annual Assessments

C. Ola Landgren, MD, PhD

Serial assessment of blood-based immune markers showed that the risk of progression from monoclonal gammopathy of undetermined significance (MGUS), the precursor disease to multiple myeloma is fluctuating rather than determinate, and these patients can experience progression to myeloma within 5 years, according to results of a study published in JAMA Oncology.¹

Results showed that, among patients' serial samples prior to progression, 23 (53%) of 43 patients had high-risk MGUS prior to developing multiple myeloma. Sixteen (70%) of these 23 patients with low-risk or intermediate-risk MGUS developed high-risk MGUS within 5 years. These findings were consistent among patients with light-chain MGUS and were indicated by changes in monoclonal proteins (P = .06 for linear term and P = .02 for quadratic term), serum-free light chains (P = .01), and immunosuppression (P <.001).

“Previously reported annual risk of progression from MGUS to multiple myeloma of 0.5% to 1% reflected the average risk among all MGUS cases, but were not applicable to individual patients,” lead study author C. Ola Landgren, MD, PhD, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, stated in a press release.²

Typically, the risk of progression from MGUS to multiple myeloma is approximated from a single assessment, most often during a patient's initial workup.

“In the current study, we found that the risk of progression is not constant. Our data indicates that individuals with low-risk or intermediate-risk MGUS can convert to high-risk MGUS and progress to multiple myeloma within a 5-year window,” Landgren stated in the press release.

The study population drew from patients between the ages of 55 and 74 years who were enrolled in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial and had a diagnosis of progressive MGUS (n = 187) or stable MGUS (n = 498) from November 1993 through December 2011. The majority of the study population were men (n = 461; 67.3%) and the median age was 69.1 years.

Subsequently, investigators identified patients who had been diagnosed with multiple myeloma in the PLCO Screening Trial with ≥1 prediagnostic serum sample (n = 208). Of these cases, 159 had nonimmunoglobulin (Ig)M MGUS and 28 had light-chain MGUS prior to their diagnosis. Investigators also accounted for patients with non-IgM MGUS (n = 281) and light-chain MGUS (n = 217) who did not develop multiple myeloma during the study period to serve as controls. Patients were matched in a 1:1 case-to-control ratio according to their age, sex, race, and ethnicity.

Data analysis was performed on all patients' prediagnostic serum samples (n = 3266) from April 2018 to December 2018. The analysis assessed serum protein and monoclonal Ig levels, serum free light chains, and serum light chains within each immunoglobulin class, each of which was associated with a point value.

Patients with a total score of 0 to 1, 2, or ≥3 were categorized as low-risk, intermediate-risk, and high-risk, respectively.

The risk factors that correlated with progressive MGUS were the IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P = .04), ≥15 g/L monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P <.001), skewed (<0.1 or >10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P <.001), and severe immunoparesis (≥2 suppressed uninvolved immunoglobulins IgG, IgA and/or IgM; adjusted OR, 19.1; 95% Cl, 7.5-48.3; P <.001).

Results also showed that skewed serum free light chains ratio (adjusted OR, 44.0; 95% CI, 14.2-136.3; P <.001) and severe immunoparesis (adjusted OR, 48.6; 95% CI, 9.5-248.2; P <.001) carried a greater risk of progressive light-chain MGUS to multiple myeloma.

“This finding has direct clinical relevance and supports annual blood tests for all individuals diagnosed with MGUS or light-chain MGUS, and, importantly, yearly reassessment of a patient's clinical-risk status,” said Landgren. “Based on our new data, we have already expanded our research program on multiple myeloma and its precursor disease to focus on genomic evolution and characterization of the bone marrow microenvironment. This will help us further understand biological mechanisms of the development of multiple myeloma.”

References

1. Landgren O, Hofmann J, McShane C, et al. Association of immune marker changes with progression of monoclonal gammopathy of undetermined significance to multiple myeloma. JAMA Oncol. 2019;5(9):1293-1301. doi:10.1001/jamaoncol.2019.1568.
2. Cracking a Code: Landmark Prospective Study Helps Researchers Better Understand Which MGUS Patients Will Progress to a Multiple Myeloma Diagnosis. Memorial Sloan Kettering Cancer Center. Published July 18, 2019. https://bit.ly/2kwFDyC. Accessed 3 Aug. 2019