While observation is the current standard of care for smoldering multiple myeloma (sMM), emerging evidence suggests that early therapeutic intervention may delay progression and improve outcomes especially for high-risk patients. A systematic review and meta-analysis of randomized clinical trials was performed according to the PRISMA guidelines in order to evaluate the effect of treatment compared to observation in outcomes of patients with sMM. Five studies (7 articles) involving 844 patients with intermediate or high risk sMM and comparing treatment to observation or placebo were deemed eligible. All studies reported progression-free survival results, with progression defined as time to active myeloma (without high heterogeneity, I = 42%, p = 0.14). A statistically significant 60% reduced pooled risk for disease progression or death (HR = 0.40, 95%CI:0.29-0.55) was revealed for patients who underwent treatment compared to those who did not. An exploratory sensitivity analysis involving 3 trials with only observation in the control group, revealed a 66% lower risk for disease progression or death (HR = 0.34, 95%CI: 0.21-0.56) for patients in the treatment group compared to the control group. Furthermore, time-to-progression was reported in 3 studies; the pooled effect estimate revealed a statistically significant 58% reduced risk for progression to symptomatic MM (HR = 0.42, 95%CI: 0.29-0.61) for patients who underwent treatment compared to those who did not. Only 2 trials reported mature overall survival outcomes, and the pooled effect estimate showed a 45% lower risk for death (HR = 0.55, 95%CI: 0.37-0.82) for sMM patients who received treatment compared to those on observation. Regarding safety, the odds for serious adverse events for those on treatment was as 3.5 times as high (OR = 3.53, 95%CI: 1.14-10.91) compared to those on observation or placebo. In conclusion, this meta-analysis highlights the significant benefits of early treatment in selected patients with sMM, across key clinical outcomes. However, close monitoring is essential for the management of treatment-related toxicities.