P171 | REFINING THE 2/20/20 MODEL: THE PROGNOSTIC IMPACT OF LDH AND LONGITUDINAL BIOMARKERS IN SMOLDERING MULTIPLE MYELOMA

Smoldering multiple myeloma (SMM) encompasses a heterogeneous spectrum ranging from indolent forms to pre-malignant stages with high progression risk to multiple myeloma (MM). We retrospectively analyzed 94 patients with SMM who accessed our center over the past five years. The study was approved by the Ethics Committee of Palermo University Hospital (approval numbers 05/2021 and 02/2022). During follow-up, 23 patients progressed to MM, distributed as follows: 50% of high-risk, 31% of intermediate-risk, and 18% of low-risk according to the 2/20/20 model. We assessed 25 baseline laboratory parameters and 6 derived ratios between progressors and non-progressors. Baseline LDH levels emerged as the most significant discriminator (p=0.008), being significantly higher in patients who evolved. The neutrophil-to-LDH ratio (NLDHR) also showed a strong association with progression (p=0.0007), suggesting an interplay between systemic inflammation and metabolic activity in disease evolution. Other markers, such as serum calcium and ferritin, showed trends toward significance, further supporting this point. Incorporating LDH into the 2/20/20 model enhanced risk stratification, identifying three distinct groups with median times to progression of 14 months (high-risk, 15%), 138 months (intermediate-risk, 65%), and not reached (low-risk, 20%). This refined model could allow better tailoring of surveillance intensity and early therapeutic strategies. Among progressors, longitudinal analysis revealed significant increases in bone marrow (BM) plasma cells (PC) (p=0.008), B-2 microglobulin (p=0.012), free light chain ratio (p=0.024), and a decrease in hemoglobin levels (p=0.005), underscoring the dynamic biological shifts preceding active MM. Flow cytometric analysis using FlowCT on diagnostic BM samples from 18 patients (6 progressors and 12 non-progressors) revealed that non-progressors had a higher proportion of granulocytes (p=0.003) and a trend toward lower PC infiltration, suggesting that a more preserved BM microenvironment may protect against disease evolution. Overall, our findings highlight baseline LDH as a potent predictor of progression risk in SMM, complementing the 2/20/20 model. Dynamic monitoring of PC, hemoglobin, free light chains, and beta-2 microglobulin, along with immune profiling, may refine risk assessment and guide personalized surveillance, aiming to focus resources on high-risk patients while minimizing interventions in those at minimal risk.