Monoclonal Gammopathy Of Undetermined Significance and Risk Of Lymphoid and Myeloid Malignancies: 743 Cases Followed For Up To 30 Years In Sweden

Monoclonal gammopathy of undetermined significance (MGUS) is a non-malignant condition with a prevalence of about 3 % in individuals 50 years or older. It carries a risk of transformation to multiple myeloma (MM) and other lymphoproliferative disorders (LPD) that has been estimated to be 1% per year. However, there is considerable variation in the risk of progression, and differentiating low-risk patients, who may not need further follow-up, from high-risk patients, who may warrant close monitoring or enrolment in early intervention studies, is a challenge. Several risk models for progression have been published. Non-IgG isotype, M-protein concentration >1.5 g/dL, and an abnormal serum free light-chain (FLC) ratio (normal reference: 0.26-1.65) were included in a model developed by the Mayo Clinic, which has not been independently validated with a large number of MGUS cases with long-term follow-up. We therefore assessed established risk score and explored novel risk factors for progression using a large independent cohort of 743 MGUS patients followed for up to 30 years.

We identified 743 MGUS patients in Malmö, Sweden who had serum collected at the date of detection of the M-protein and stored at – 20⁰Celcius. MGUS diagnosis was made according to IMWG criteria: M-protein concentration <3 g/dL, absence of CRAB-criteria or clinical signs of otherLPD, and <10% plasma cells if bone marrow examination was performed. M-protein isotype, M-protein concentration and serum levels of FLC, albumin, creatinine, ß2-microglobulin, C-reactive protein and non-involved immunoglobulins were analysed in stored serum. We obtained the date of diagnosis of incident cancers from three sources: the nationwide Swedish Cancer Registry, the nationwide Patient Registry, and the Patient Registry of Malmö University Hospital. Using Cox regression models, we examined associations of demographic and laboratory factors with progression and determined the discriminatory power of three prediction models for progression.

During 8,240 person-years of follow-up (median 11 years per subject), we observed 92 lymphoid and 10 myeloid malignancies in the study cohort, representing a cumulative risk of 16.0%. MM occurred in 53 patients and the 30-year cumulative risk was 10.8%; an approximate 0.5% annual risk. Three factors were significantly associated with progression: abnormal FLC-ratio (< 0.26 or >1.65), M-protein concentration >1.5g/dL, and depression of non-involved immunoglobulin isotype levels (immunoparesis). A prediction model with separate effects for these three factors and the M-protein isotype had higher discriminatory power than other models, though the differences were not statistically significant. The 30-year cumulative risk for myeloid malignancies was <2%.

In a large cohort of MGUS patients with long-term follow-up, we confirmed that an abnormal FLC-ratio predicts risk for progression of MGUS. This is an important observation as serum FLC assays are commonly used in the clinical setting. Furthermore, our results confirm the predictive value of a high M-protein concentration. A novel observation in our study is that the addition of immunoparesis to a multivariable model that includes independent effects for the factors of the Mayo Clinic risk model increases the discriminatory power to identify high-risk (versus low-risk) MGUS patients.

Turesson: Celgene Corp: Honoraria.