Evolving Pattern Improves the IMWG 2/20/20 Classification for Patients with Smoldering Multiple Myeloma

Introduction: Smoldering multiple myeloma (SMM) is a monoclonal gammopathy defined by the presence of an M-protein in serum ≥30 g/L and/or ≥500 mg/24h in urine and/or ≥10% of plasma cells in bone marrow, in the absence of CRAB symptoms or very high-risk criteria (SLiM). Multiple scales are available to stratify the risk of SMM progression. In clinical practice, the most used are the PETHEMA model and the 2/20/20 model established by the Mayo Clinic and validated by the International Myeloma Working Group (IMWG). These scales, in addition to providing prognostic information, allow us to guide patient follow-up and could support the start of treatment in high-risk patients. On the other hand, SMM can develop an evolving pattern, characterized by a progressive increase of the M-protein that is associated with a higher risk of progression to symptomatic multiple myeloma (MM). The objective of this study is to explore whether the incorporation of the evolving pattern to the IMWG score allows for a more accurate identification, particularly of high-risk patients. Materials and methods: Clinical records of patients diagnosed with SMM between 2011 and 2020 in a single hospital center, excluding those who met SLiM criteria, were reviewed. Progression to symptomatic MM was established according to the IMWG criteria. The evolving pattern was defined as the progressive increase of at least 10% or 25% in the M-protein size within the first 12 months from diagnosis when baseline M-protein was ≥30 g/L or <30 g/L, respectively (Ravi et al, Blood Cancer J 2016, Fernandez de Larrea et al, Leukemia 2018). The evolving type was analyzed as a time-dependent covariate. Results: Ninety three patients were initially included in the study; however, 10 patients were finally excluded: 9 for presenting SLiM criteria (1 with >60% bone marrow plasma cells, 9 with a free light chain ratio >100) and 1 for missing data. Median follow-up was 3.2 years (IQR 2-5) with a rate of progression (RP) at 2 and 4 years of 20% (95%CI 12-30) and 33.7% (95%CI 23-46), respectively. Using IMWG risk stratification model, the 2-year RP was 3.3% (95%CI 0.5-21) in low-risk patients, 9.3% (95%CI 2-32) in intermediate-risk patients, and 54 % (95%CI 35-75) in high-risk patients. Regarding the evolving pattern, it was recognized in 25% of patients. Median time from SMM diagnosis and recognition of evolving type was 9 months (IQR 6-12). The RP at 2 and 4 years was 48% (95%CI 29-71) and 65% (95%CI 44-85) for evolving type. After adding the evolving classification to IMWG model, we created a new prognostic classification system that divides patients into three risk groups: low (IMWG low or intermediate risk and non-evolving pattern), intermediate (IMWG low or intermediate risk and evolving pattern, or high risk and non-evolving pattern) and high (IMWG high risk and evolving pattern), with a 2-year RP of 2.4% (95%CI 0.3-15), 20% (95%CI 9-43) and 88.9% (95%CI 61-99), respectively. The cumulative incidence of progression to MM for the three risk groups using the IMWG and the new Evolving-2/20/20 system is represented in Figure 1A, whereas in Figure 1B the reclassification of patients with the new Evolving-2/20/20 system is shown. Regarding the validation of this score, the area under the curve (AUC) of the new score was greater than that of the IMWG and that of the evolving score independently (2y-AUC PETHEMA 0.65, IMWG 0.83, Evolving 0.77, Evolving-2/20/20 0.89; P=0.02). In addition, concordance was superior with the new score Evolving-2/20/20 (C-index 0.93) compared with PETHEMA (0.73), IMWG (0.86) and evolving (0.85) by themselves. The specificity and the positive predictive value for detecting high-risk patients at 2 years with the new model was very high (98% and 88%, respectively) compared to the other risk stratification models (PETHEMA 59% and 27%; IMWG 83 and 52%; Evolving 83% and 49%, respectively). Decision curve analysis indicated that the score was clinically useful. Conclusions: The dynamic addition of the evolving pattern to the IMWG classification (Evolving-2/20/20 system) in patients with SMM, allows more precise risk stratification and the detection of those with very high risk of progression. These patients could benefit from more intensive follow-up and may be eligible for early treatment strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal