Early daratumumab or immunomodulatory agents in high-risk smoldering multiple myeloma show uncertain benefits versus observation.

Rationale Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and active multiple myeloma. Early identification and intervention for people with high‐risk SMM may prevent or delay progression to symptomatic disease. Current evidence on the optimal timing and choice of intervention remains controversial, necessitating a systematic evaluation. Objectives To evaluate the benefits and harms of different early interventions compared to observation alone or placebo in people with high‐risk smoldering multiple myeloma. Search methods We searched MEDLINE, Embase, CENTRAL, two clinical trial registries, and conference proceedings up to 1 October 2025. Eligibility criteria We included randomized controlled trials (RCTs) comparing early intervention with observation or placebo in adults with high‐risk SMM, defined by validated risk stratification models or International Myeloma Working Group criteria. Eligible interventions included monoclonal antibodies, immunomodulatory agents, alkylating agents, and cytokine inhibitors. Outcomes Our critical outcome was progression‐free survival. Our important outcomes were overall survival, overall adverse events, serious adverse events, and health‐related quality of life. We evaluated outcomes at all reported time points, prioritizing the longest available follow‐up data. Risk of bias We used the original Cochrane risk of bias tool (RoB 1) to assess risk of bias in the included RCTs. Synthesis methods We conducted meta‐analyses using a random‐effects model, applying the Hartung‐Knapp‐Sidik‐Jonkman (HKSJ) method for pooled analyses where appropriate. We used hazard ratios (HRs) for time‐to‐event outcomes, odds ratios (ORs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes. For each effect estimate, we calculated the corresponding 95% confidence interval (CI). We assessed heterogeneity using I² statistics, and we assessed the evidence certainty using GRADE methodology. Included studies We included seven RCTs (1096 participants) evaluating four intervention types: a monoclonal antibody (1 trial, 390 participants), immunomodulatory agents (3 trials, 427 participants), alkylating agents (2 trials, 195 participants), and a cytokine inhibitor (1 trial, 85 participants). Follow‐up ranged from 29.2 months to 150 months. Synthesis of results Monoclonal antibodies versus active monitoring Evidence from one large trial suggests that early intervention with daratumumab compared with active monitoring may reduce the risk of disease progression or death slightly (HR 0.49, 95% CI 0.36 to 0.67; 389 participants; low‐certainty evidence) and may also reduce the risk of death slightly (HR 0.52, 95% CI 0.27 to 0.99; 389 participants; low‐certainty evidence). The drug is associated with an increased risk of overall and serious adverse events, but the evidence for these outcomes is very uncertain. Very low‐certainty evidence suggests little to no difference between daratumumab and active monitoring for health‐related quality of life. Immunomodulatory agents versus observation/active control The evidence for this class of drugs is very uncertain, partly due to substantial heterogeneity and conflicting results between lenalidomide and thalidomide. Pooled analyses suggest little to no difference between immunomodulatory agents and observation/active control for progression‐free survival, overall survival, and health‐related quality of life. We decided not to pool the data for overall and serious adverse events owing to conflicting results. Cytokine inhibitors versus placebo There is very uncertain evidence from one small trial regarding the effect of siltuximab compared with placebo on progression‐free survival, overall adverse effects, and serious adverse effects. The trial provided no data for overall survival or health‐related quality of life. Alkylating agents versus observation There is very uncertain evidence from one older trial regarding the effect of melphalan‐prednisone compared to observation on overall survival. The trial provided no data for progression‐free survival, overall and serious adverse events, or health‐related quality of life. Authors' conclusions Early intervention with daratumumab may reduce the risk of disease progression and mortality in people with high‐risk SMM. The evidence on the risk of adverse events with daratumumab is very uncertain. For immunomodulatory agents, the available evidence is of very low certainty, partly due to conflicting results, so we are unable to draw conclusions about their effects. There is insufficient evidence to support the use of older agents like alkylating agents or cytokine inhibitors. The decision to initiate early treatment in high‐risk SMM requires a careful, individualized risk‐benefit assessment and shared decision‐making. Funding This Cochrane review was supported by the Tri‐Service General Hospital (TSGH‐D‐114168). Registration Protocol (2023) DOI: 10.1002/14651858.CD015494 PICOs PICOs Population Intervention Comparison Outcome