Risk factors of short-term progression in patients with monoclonal gammopathies

Asymptomatic Monoclonal Gammopathies (AMG), including Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM), are pre-malignant conditions, characterized by a heterogeneous risk of progression to Multiple Myeloma (MM). The identification of risk factors for progression is crucial in the clinical management of patients with AMG, in order to properly stratify patients, plan an adequate follow-up and identify patients with short-term risk of progression, who could potentially benefit from an early treatment. In this study, we retrospectively evaluated possible risk factors of short-term progression to active MM in a cohort of MGUS and SMM patients admitted to our haematological centre between 2010 and 2018. We analysed a total cohort of 220 patients diagnosed with AMG (73 MGUS and 147 SMM) according to the International Myeloma Working Group (IMWG) recently updated diagnostic criteria. All patients analysed underwent to Bone Marrow (BM) examination to confirm diagnosis and quantify the percentage of Bone Marrow Plasma Cells (BMPCs). Median age of the total cohort was 68 years (range 35-93 years), and 58% were male. Light chain was kappa in 70% of patients (77% among the MGUS subgroup and 67% among the SMM subgroup, respectively). Median percentage of BM plasma cells (BMPCs) was 12% (range 2-55%) in the entire population, 7% (range 2-9) in MGUS and 15% (range 8-55) in SMM patients. Median serum M-protein was 1.7 g/dL (range: 0.17-4.5), 1.6 g/dL (range 0.5-3.3) in MGUS and 1.8 g/dL (range 0.17-4.5) in SMM patients. An abnormal serum free light chain (FLC) ratio was found in 68% of AMG patients, among the ones that performed the analysis (134/220 patients). The presence of immunoparesis in one or two of the uninvolved immunoglobulins occurred in 59% of the entire population, in 44% of MGUS and in 63% of SMM patients. Median follow-up time was 34 months (range 3 – 126) for the whole population. Overall 52 patients of the entire cohort progressed to MM (47 SMM and 5 MGUS), with a median TTP of 16 months (range 4-75). By univariate analysis we found that percentage of BMPCs, entity of M-protein and presence of immunoparesis were significantly correlated with progression to active MM (p<0.001 for each variable). On the other hand, presence of an abnormal FLC ratio did not reach a statistical significance between progressed and non-progressed patients, as well as value of the involved serum FLC (p=0.078). Nevertheless, the presence of a FLC ratio < 0.125 or > 8 (as used in Mayo scoring system for SMM) showed a relationship at the limit of statistical significance in this subgroup of patients (p=0.055). Multivariate analysis confirmed percentage of BMPCs and entity of serum M-protein as independent risk factors of progression. We therefore calculated risk of progression on the whole AMG population, showing that the two independent variables, when combined, could stratify patients in different risk groups based on the tumor burden of the gammopathy. Given that evidence, we create a “tumor-burden” score combining the two variables, and stratifying patients in 3 groups. Patients defined as low risk showed a probability of progression of 7% as compared to high risk patients, in which this probability was 70%. Afterwards, we applied Kaplan Meier method on risk factors resulted significant in univariate analysis demonstrating that they also significantly influenced the Time To Progression (TTP) to MM. TTP was significantly different even when applied to the “tumor-burden” score (median TTP in high risk patients: 18 months, not reached in intermediate- and low-risk patients, p<0.001). In conclusion, our work highlights the importance of entity of BMPCs and of serum M-protein, directly related to tumor burden, as risk factor in short-term progression of AMG. The development of a simple, reproducible score based on BMPCs and M-protein could allow to overcome the traditional distinction between MGUS and SMM in the evaluation of the progression of AMG patients to active MM.