Risk and Patterns of Progression Among Smoldering Myeloma Patients after the Implementation of New Criteria and Modern Imaging

In 2014, IMWG redefined symptomatic multiple myeloma (MM), to include biomarkers (SLiM) in addition to CRAB criteria. IMWG also redefined smoldering/asymptomatic (SMM) and its risk stratification and proposed a model based on three independent factors predicting 2-year progression risk (serum FLC ratio>20, monoclonal spike>2 gr/dl and bone marrow infiltration > 20% clonal plasma cells - 20-2-20). In addition, a more detailed scoring tool was also proposed. However, the diagnosis and follow up of early lesions (MGUS and SMM) has also evolved since 2014, with the widespread use of advanced imaging: some patients initially diagnosed as SMM may now be identified as symptomatic MM and start therapy. As a result, progression rates, patterns of disease progression and risk of MM complications may have also changed. The aim of our study was to describe risk and patterns of progression among patients with SMM, diagnosed after 2014. The analysis included 427 SMM patients diagnosed and followed in the Department of Clinical Therapeutics, Athens, between 2014 and 2023, according to the contemporary practices, that include advanced imaging (ldWBCT, WBMRI or PET/CT) at the time of diagnosis and during follow up. During the same period 486 patients were diagnosed with non-IgM MGUS. The median age of SMM patients was 65 years (vs 67 for MGUS patients), median hemoglobin was 12.9 gr/dl, median M-spike was 1.31 gr/dl; median eGFR was 82 ml/min/1.73 m2, with 6% of patients having <40 ml/min/1.73; in all cases the cause of renal dysfunction was unrelated to the monoclonal gammopathy. According to 20-2-20, 50% of patients were low risk (score of 0), 31% intermediate risk (score of 1) and 19% as high risk (score 2-3). According to IMWG scoring tool, which assigns different scores to the levels of the prognostic variables, 63% were low, 31% low-intermediate, 5% intermediate and <1% high risk. The median follow-up of the cohort was 36 months (IQR 17-64). At last follow up, 42 SMM patients (10.1%) had progressed to symptomatic MM (vs 6 (1.2%) patients originally diagnosed with MGUS). The 1-, 2- and 3- year cumulative progression rate was 4%, 9% and 13% respectively. For MGUS patients the cumulative 1-, 2- and 3-year progression rate was 1%, 2% and 2%, respectively. Per IMWG's 20-2-20, the 1-, 2- and 3-year progression rate was 0%, 1% and 2% for low risk and was 2%, 3.5% and 6% for intermediate risk SMM; thus, the 1-, 2- and 3- years progression risk among low and intermediate risk SMM was 1%, 2% and 3%. However, among high risk SMM, the 1-, 2- and 3-year progression rate was 18%, 28% and 43% (p<0.001). According to the IMWG scoring tool, 3-year progression was 0% for low risk, for low-intermediate the 1-, 2- and 3-year progression rate was 6%, 15% and 24% respectively, and for intermediate and high was 33%, 53% and 66%. Among SMM patients that progressed to symptomatic MM, one (2.5%) progressed by developing a soft tissue plasmacytoma, one (2.5%) with acute renal dysfunction, 13 (31%) with anemia (hemoglobin<10 gr/dl), 14 (33%) with lytic bone disease detected with ldWBCT imaging, and 13 (31%) based on SLiM criteria. Among patients with bone disease, lytic lesions were detected mostly during follow up imaging, and only in one patient were associated with symptoms (fracture). Among patients with MGUS, progression events included lytic bone disease detected during routine imaging in two patients, acute renal dysfunction in two and SLiM criteria in 2 patients. In conclusion, in patients with SMM diagnosed by 2014 IMWG criteria and followed with contemporary imaging, the progression events mostly include anemia, SLiM criteria or asymptomatic bone disease detected during routine imaging. The risk of imminent progression among those with low or intermediate risk per 20-2-20 score or low risk according to scoring tool is low and is similar to that of MGUS. Among those at high risk per 20-2-20, the progression risk seems to be lower than in the original cohorts, probably due to the use of advanced imaging at the time of diagnosis. IMWG scoring tool may be more accurate, but only a small group is rated as intermediate/high risk. Our data point to the need for careful assessment of patients with SMM at the time of diagnosis, with the use of advanced imaging to ensure those at low/intermediate risk about their prognosis. For high-risk patients, clinical trials if available should be considered, but overtreating these patients should be avoided based only on current prognostic tools.