Real-world survival trends in smoldering versus symptomatic multiple myeloma: A SEER analysis, 2012–2020

Abstract Smoldering multiple myeloma (SMM) represents an asymptomatic intermediate phase between monoclonal gammopathy of undetermined significance and overt, end-organ-damaging myeloma. While modern therapies have improved survival in clinical trials, whether real-world outcomes have improved similarly remains unclear. The Surveillance, Epidemiology, and End Results (SEER) Program began differentiating smoldering and symptomatic cases in 2012. We leveraged this classification to assess incidence and survival trends across these two phases nationally. We conducted a retrospective cohort study of adults diagnosed with multiple myeloma (ICD-O-3 code 9732/3) from 2012–2020 in SEER 18 registries, excluding cases with missing terminology or survival data. Disease phase was defined via the SEER terminology recode. Overall survival (OS) was the primary outcome, measured from diagnosis until death or last follow-up (censored December 2021). Kaplan–Meier curves were generated and compared via log-rank testing. Cox proportional-hazards models adjusted for age, sex, race/ethnicity, and diagnosis year. Interaction terms tested for differential survival trends by phase over time. Among 67,388 evaluable cases, 61,165 (90.7%) were symptomatic and 7,379 (9.3%) smoldering. Median follow-up among survivors was 48 months (IQR 28–72). Baseline age, sex, and race/ethnicity distributions were similar. At 1 year, OS was 92.3% (95% CI 92.1–92.5) in symptomatic vs. 99.1% (98.8–99.3) in smoldering cases; at 3 years, 88.1% vs. 98.2%; and at 5 years, 49.0% vs. 72.4% (log-rank p 2×10⁻¹⁶). In multivariable analysis, SMM was associated with a 59% reduced hazard of death vs. symptomatic myeloma (adjusted HR 0.41, 95% CI 0.39–0.43; p 0.001). Year of diagnosis was associated with a 2.0% annual mortality hazard reduction in symptomatic disease (HR 0.98, 95% CI 0.976–0.984; p 0.001) and a 6.3% annual reduction in smoldering disease (HR 0.937, 95% CI 0.921–0.953), with a significant phase × year interaction (p = 1.6×10⁻⁷). These real-world data confirm a substantial survival advantage for smoldering myeloma, with disproportionately greater gains over time compared to symptomatic disease. Possible contributors include earlier identification of high-risk SMM, more intensive monitoring, and evolving treatment guidelines supporting intervention in ultra–high-risk cases. Nonetheless, 5-year OS remains below 50% in symptomatic disease, underscoring persistent therapeutic gaps. Further refinement of early detection, risk stratification, and intervention strategies is warranted. These findings support ongoing efforts to personalize management across the myeloma continuum through integrated clinical, imaging, and molecular biomarkers.