Ending the undetermined significance of monoclonal gammopathies (MGUS): First results of the nomoremgus study

Abstract

Abstract Background: MGUS is considered a benign condition despite being associated with shorter survival when compared to matched control populations. Malignant transformation, infections and heart or renal disease account for the increased risk of death. Thus, MGUS will be completely benign in most, of clinical significance in some, and will produce anxiety in all cases that will undergo indefinite Hospital visits and (some invasive) lab tests. Aim: Addmalignant and infection significance into the existing list of monoclonal gammopathies of clinical significance (eg, renal), towards new diagnostic criteria that eliminates the term “undetermined” and classifies monoclonal gammopathies into benign vs clinical significance. Methods: 31 Spanish Hospitalsare participating in theNoMoreMGUS project to generate a nationwide clinical, tumor and immune metadataset of 5,000 MGUS monitored yearly during 5y. Monoclonal gammopathies of malignant significance will be identified with the integration of clinical and laboratory data with the kinetics of circulating tumor (CTC) and immune cells measured with high-sensitive spectral flow cytometry. Immunosuppressive states will be defined to predict risk of severe infection. Here we report the first interim analysis with a focus on the risk of malignant transformation in the first 1,000 cases. Immune biomarkers of infection risk will be presented at the meeting. Results: The first 1,000 cases were enrolled between Feb 2022 and Nov 2023. Median age was 65 (range 30-93) and 49% were male. Isotype distribution was 60.3% IgG, 19.8% IgA, 15.1% IgM, 3.4% biclonal, 1.1% light-chain, and 0.3% IgD/IgE. With a median follow-up of 24.5 months there were 28 progressions: 9 smoldering and 14 active multiple myeloma (MM), 2 light-chain amyloidosis (AL) and 3 asymptomatic Waldenström's macroglobulinemia (WM). CTCs were detected in 466 (47%) cases and the median percentage was 0.0006% (range, 0.0001% - 44%). CTCs were detected in 45% vs 72% of cases with M-protein ≤1.5 vs >1.5 g/dL. Bone marrow aspirates were infrequently performed in the entire cohort (26%), particularly in cases with M-protein ≤1.5 g/dL (24%) but also in those with >1.5 g/dL (43%). Thus, CTC assessment provided minimally invasive information on the percentage and phenotype of tumor cells that was unknow in 74% of cases. Of note, 13 cases with non-IgM MGUS displayed CTCs with a B-cell phenotype and no PC clonality. The median percentage of CTCs was notoriously higher in non-IgM MGUS with B-cell vs PC phenotype (5.0% vs 0.0003%, p<.001) despite similar M-protein levels (median of 0.9 vs 0.7 g/dL, p=.50). CTCs were detected in 67/160 (42%) IgM MGUS and in 399/840 (47.5%) non-IgM MGUS. Despite similar detection rates, the percentage of CTCs was significantly higher in IgM vs non-IgM MGUS (0.31% vs 0.0004%; p<.001). By contrast, M-protein levels were similar between IgM vs non-IgM MGUS (median of 0.6 vs 0.7 g/dL, p=.15). In IgM MGUS, presence of ≥1.5% CTCs at baseline was associated with a 16-fold increased risk of transformation to asymptomatic WM (HR: 16.1, p=.02). M-protein levels did not stratify IgM MGUS at different risk of progression. In cases with non-IgM MGUS, presence of <0.0006% vs ≥0.0006% CTCs at baseline was associated with higher risk of transformation to MM and AL (HR: 7.6, p<.001). Rates of progression at 2y were 0.9% vs 7%. Besides ≥0.0006% CTCs, M-protein >1.5g/dL and an abnormal sFLC ratio were significantly associated with risk of transformation. CTCs (HR: 4.4, p=.008) and M-protein levels (HR: 4.0, p=.015) independently predicted risk of transformation in multivariate analysis. The sFLC ratio was borderline significant (HR: 2.9, p=.10). A minimally invasive model using CTCs, M-protein levels and abnormal sFLC ratio stratified non-IgM MGUS into groups with 0.5%, 1.5%, 6.1% and 16.4% progression rates at 2y based on the presence of 0, 1, 2 or 3 risk factors. The C-statistic of this model (0.87, 95% CI 0.76-0.98; HR: 3.9, p<.001) was superior to that of the Mayo model based on non-IgG isotype, M-protein >1.5g/dL, and abnormal sFLC ratio (0.63, 95% CI 0.42-0.84; HR: 2.00, p=.06). Conclusions: The first interim analysis of NoMoreMGUS defined CTCs as one of the most informative and independent prognostic factors in MGUS. Owing to its minimally-invasive assessment, CTC dynamics together with other clinical and laboratory features hold promise to redefine monoclonal gammopathies into those with none vs malignant significance.