Differential Detection of Clonal Bone Marrow Plasma Cells in IgA Vs. IgG Monoclonal Gammopathy of Undetermined Significance and Its Association with Disease Progression

Introduction: Non-IgM monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM) and related plasma cell disorders. IgG M protein is associated with a lower risk of progression compared to other isotypes, though the biological basis for this difference remains largely unclear.

Aim: To compare the detection rate of clonal plasma cells in bone marrow samples between individuals with IgA and IgG MGUS and its association with clinical features and disease progression.

Methods: This study is part of the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), a population-based screening study for MGUS and a randomized trial of follow-up strategies. A total of 75,422 individuals aged 40 years or older were screened by serum protein electrophoresis and free light-chain (FLC) assay between 2016 and 2020. We included individuals with positive screening for IgA or IgG M protein who were diagnosed with MGUS at the baseline diagnostic work-up and had bone marrow sampling for flow cytometry analysis of plasma cells, performed for a random selection of MGUS individuals at baseline visits. The EuroFlow next-generation flow MM-minimal residual disease method was used to detect and quantify phenotypically aberrant (clonal) plasma cells in bone marrow samples (median limit of detection: 2.4x10^-6; range: 1.2x10^-5-1.4x10^-6). Repeated serum protein electrophoresis and immunofixation measurements were used to evaluate transient M protein, defined by the absence of the M protein type detected at screening, with data censored at myeloma treatment or loss to follow-up. The Wilcoxon and chi-squared tests were used to assess the statistical significance of differences observed between continuous and categorical variables, respectively.

Results: In total, 90 individuals with IgA (n=31) or IgG (n=59) MGUS were included, with a median age of 67 years (range: 45-85), and 53.3% were male. At diagnosis, the median M protein concentration was 0.7 g/L (IQR: 0.2-2.5 g/L, range: not quantifiable-14.0 g/L), and the MGUS risk score distribution was 48.9% low, 33.3% low-intermediate, 17.8% high-intermediate, and 0% high risk. IgA MGUS had a lower median M protein concentration (0.2 g/L vs. 2.0 g/L, p<0.01) and a higher median involved/uninvolved FLC ratio (1.79 vs. 1.38; p<0.05) compared to IgG MGUS.

Overall, clonal plasma cells were found in 77.8% (70/90) of bone marrow samples at a median percentage of 0.20% (range: 0.0077-2.5%) when detected. The detection rate was significantly higher in IgA (93.5%) compared to IgG samples (69.5%; p<0.05) and increased with higher risk scores from 63.6% in low, to 86.7% in low-intermediate, to 100% in high-intermediate risk (p<0.01). Individuals with a detected clonal plasma cell population had higher median M protein concentration (1.5 g/L vs. 0.1 g/L; p<0.001) and median involved/uninvolved FLC ratio (1.77 vs. 1.15; p<0.001), with a higher proportion outside the normal 0.26-1.65 FLC ratio range (42.9% vs. 10.0%; p<0.05).

Over a median follow-up of 62 months (range: 4-84 months), individuals without detected clonal plasma cells (n=20) had a higher rate of transient M protein (45.0% vs. 2.9%; p<0.001) and none progressed to SMM or MM, whereas 8.6% of those with detected clonal plasma cells did progress (n=70; p<0.001), including one to MM.

Conclusion: In this study evaluating the presence of clonal plasma cells in bone marrow samples from IgA and IgG individuals by next-generation flow cytometry, we detected clonal plasma cells more frequently in samples from individuals with IgA MGUS compared to IgG. Additionally, the absence of clonal plasma cells correlated with a higher frequency of transient M protein and an absence of disease progression. These findings provide biological insight into the differences between IgA and IgG MGUS, which may contribute to the lower rate of progression in IgG MGUS. Moreover, they suggest that the use of flow cytometry to investigate plasma cell clonality could enhance risk assessment of non-IgM MGUS by identifying individuals who may not benefit from being monitored for MM progression and could be focused on those with low-risk features.