Early therapeutic intervention versus observation in high-risk smoldering multiple myeloma: A systematic review and meta-analysis.

e19547 Background: Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma (MM) with heterogeneous risk of progression. High-risk SMM is associated with early transformation and end-organ damage. Although observation has historically been standard of care, advances in risk stratification and novel therapies have challenged the watch-and-wait paradigm. This meta-analysis evaluated the impact of early therapeutic intervention on survival outcomes in high-risk SMM. Methods: PubMed, Embase, Web of Science, Ovid MEDLINE, Scopus, and ClinicalTrials.gov were searched for studies published between 2003 and 2024. Randomized controlled trials and selected prospective studies comparing early systemic therapy with observation or placebo in intermediate- or high-risk SMM were included. Primary outcomes were progression-free survival (PFS), time to progression (TTP) to symptomatic MM, and overall survival (OS). Secondary outcomes included treatment response and toxicity. Time-to-event outcomes were pooled as hazard ratios (HRs) and dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs) using a random-effects meta-analysis (DerSimonian–Laird method). Statistical significance was assessed using the Z-test, and heterogeneity was evaluated using the I² statistic. Results: Nineteen studies involving 1,217 patients were included, comprising eight randomized controlled trials (n=885). Early therapeutic intervention significantly reduced progression to symptomatic MM compared with observation (RR=0.53; 95% CI, 0.33–0.87; P=0.01). Among high-risk SMM patients, early treatment significantly decreased disease progression (RR=0.51; 95% CI, 0.37–0.70; P=0.0001) and mortality (RR=0.53; 95% CI, 0.29–0.96; P=0.04). Lenalidomide-based regimens demonstrated consistent benefit, with hazard ratios for progression ranging from 0.18 to 0.28 and prolongation of median TTP from approximately 2.1 years with observation to up to 9.5 years with early therapy. Pooled 12-month PFS and OS rates were 94% (95% CI, 89%–98%) and 99% (95% CI, 97%–100%) in intervention groups versus 76% and 97% with observation, respectively. The overall response rate was 64% (95% CI, 50%–77%), complete response rate 12% (95% CI, 3%–25%), and minimal residual disease negativity 62% (95% CI, 42%–81%). Grade 3–4 adverse events occurred in 36% (95% CI, 30%–43%). Conclusions: Early therapeutic intervention significantly delays progression to symptomatic multiple myeloma and is associated with improved survival in patients with high-risk SMM. These findings support a risk-adapted treatment approach and reinforce the evolving role of early intervention in biologically aggressive disease.