Early Versus Delayed Intervention in Smoldering Multiple Myeloma: A Meta-Analysis of Clinical Trials

Introduction Smoldering multiple myeloma (SMM) is a premalignant clinical stage that carries a risk of progression to Multiple Myeloma (MM). The optimal management approach has remained controversial, mostly relying on the risk features of the disease. The current guidelines recommend watchful waiting (WW) in low and intermediate risk SMM and either WW or intervention in high-risk SMM (HR SMM). However, with new methods of risk stratification and emerging therapeutics, the benefits of early intervention (EI) are being debated. We performed a meta-analysis of all the available clinical trials to analyze outcomes with EI. Methods A search was conducted on PubMed, EMBASE, Web of Science, Scopus, Cochrane, clinicaltrials.gov, and publications of ASH, ASCO and ESMO from January 1990 to June 2024. Randomized clinical trials (RCTs) and single-arm trials (SATs) comparing EI with delayed intervention (DI) for SMM were included. (EI- treatment at the time of diagnosis, DI- treatment after progression to MM). The primary outcome was progression to MM. Secondary outcomes were mortality, response to treatment, and adverse events. Trials were categorized by drug class: Melphalan-Prednisone (MP), Bisphosphonates (BP), Immunomodulatory drugs (IMD), Proteosome Inhibitors (PI), Monoclonal antibodies (MAB), PVX-410 multi-peptide vaccine (VC). Further classification was by SMM risk- all SMM stages and HR SMM. Odds ratio (OR) was used for RCT comparisons and proportions for analysis of RCTs and SATs. Results 21 trials were included: 9 RCTs and 12 SATs. 1,541 patients were studied, 1,067 patients in RCTs, and 474 in SATs. 11 trials were exclusive to HR SMM. Number of studies by drug class- MP- 3, BP -2, IMD -3, PI -5, MAB -6, MAB+IMD+PI -1, VC -1. Analysis of RCTs EI resulted in lower odds of progression to MM (OR 0.36, 95% CI 0.17-0.73). Sub-group analysis by drug class showed lower odds of progression to MM with MP (OR 0.14, 95% CI 0.03-0.61), IMM (OR 0.23, 95% CI 0.09-0.64) while BP (OR 1.00, 95% CI 0.65-1.54) and MAB (OR 0.64, 95% CI 0.27-1.56) did not decrease the odds of progression. The odds of mortality with EI compared to DI were not significant (OR 0.80, 95% CI 0.51-1.27), nor were the odds of response (OR 3.42, 95% CI 0.38-30.86). Subgroup analysis by drug class showed no difference in odds of mortality and response rate with EI. Analysis of Treatment arms of RCTs and SATs with EI Progression to MM was seen in 19% (95% CI 11-26) of patients. Sub-group analysis by drug class showed the following proportion of progression- MP 8% (95% CI 3-18), IMD 20% (95% CI 3-38), PI 0.7% (95% CI 0-7), MAB 22% (95% CI 11-32), MAB+IMD+PI 3% (95% CI 0-7), VC 14% (95% CI 1-28). The proportion of mortality was 20% (95% CI 6-34). The overall response rate was 61% (95% CI 47-75). Subgroup analysis by drug class for response rates- MP 40% (95% CI 32-48), IMD 55% (95% CI 31-80), PI 95% (95% CI 90-100), MAB 38% (95% CI 14-61), MAB+IMD+PI 38% (95% CI 14-81), VC 23% (95% CI 5-40). Complete response was seen in 27% (95% CI 7-46), very good partial response was seen in 22% (95% CI 12-31) and partial response was seen in 28% (95% CI 15-42) of the patients. Analysis of HR SMM studies Analysis of RCTs showed significantly lower odds of progression to MM (OR 0.36 95% CI 0.17-0.73) and significantly lower odds of mortality (OR 0.80 95% CI 0.21-0.95) with EI. No significant difference was found in the response rate between EI vs DI. Analysis of all treatment arms overall showed progression of 14% (95 %CI 6-21), mortality of 11% (95% CI 3-18) and a response in 77% (95% CI 59-94). Adverse events The most reported adverse effects were leukopenia in 23.8% (95% CI 5.5- 42), thrombocytopenia in 6.0% (95% CI 1.1-10.8), nausea/vomiting/diarrhea in 24.8% (95% CI 7.8-41.8), constipation in 35.9% (95% CI12.5-59.2), infections in 18.4% (95% CI 6.4-30.4), fatigue/asthenia 33.4% (95% CI 18.6-48.2). Conclusion Our study suggests that EI significantly reduces progression to MM in all SMM patients, and significantly reduces both progression and mortality in HR SMM, with a favorable safety profile. Our study was limited by variability in risk stratification and response assessment methods across trials, and limited reporting of adverse effects. However, considering the overall reduction in progression and mortality, we recommend considering enrollment of patients with SMM into trials to help reinstate new therapeutic guidelines for SMM.