Smoldering Multiple Myeloma: Early Intervention or Structured Surveillance? A Comprehensive Review of Evidence for...

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by a heterogeneous risk of progression to overt multiple myeloma (MM). Historically managed with active surveillance, advances in risk stratification and the development of novel therapeutics have renewed debate regarding early intervention, particularly in patients with high-risk disease. We conducted a narrative review of clinical trials and observational studies evaluating early treatment versus observation in SMM. Outcomes assessed included progression-free survival (PFS), time to progression (TTP), overall survival (OS), treatment-related toxicity, and quality-of-life measures, alongside evolving diagnostic criteria and risk-stratification models that influence therapeutic decision-making. Early randomized trials using conventional cytotoxic therapy did not demonstrate a survival advantage and supported observation as the standard management approach. However, contemporary studies using novel agents have demonstrated improved disease control in selected high-risk populations. The QuiRedex and ECOG-E3A06 trials showed significant reductions in progression risk with lenalidomide-based therapy, and long-term follow-up suggests a potential overall survival benefit in Qui-Redex. The phase III AQUILA trial further demonstrated delayed progression with daratumumab in high-risk SMM using updated diagnostic criteria. Phase II studies evaluating combination regimens, including KRd-based and daratumumab-containing approaches, have reported high response rates and MRD negativity, although survival data remain immature. Importantly, many benefits reflect delayed biochemical or imaging-defined progression rather than prevention of symptomatic end-organ damage. Current evidence supports selective early intervention in carefully defined high-risk SMM populations; however, uncertainties remain regarding long-term survival benefit, optimal treatment duration, quality-of-life impact, and clonal evolution. Active surveillance with modern monitoring remains appropriate for many patients.