Early intervention in smoldering multiple myeloma: A systematic review of comparative prospective trials

Abstract Introduction: Smoldering multiple myeloma (SMM) or asymptomatic myeloma is a precursor to symptomatic multiple myeloma, and intermediate/high-risk SMM patients have a 50% chance of progression to SMM over two years. Observation remains the current standard for SMM management; however, emerging clinical trial data suggests potential benefits with early intervention in SMM patients. This review aimed to evaluate the outcomes of comparative prospective studies on early SMM treatment. Methods: A systematic review was conducted following PRISMA guidelines, searching Medline, Embase, Cochrane, and ClinicalTrials.gov from inception to July 2025. The search terms included “smoldering multiple myeloma”, “asymptomatic multiple myeloma”, “therapy”, “treatment”, “management”, “clinical trial”, and “prospective study”. A total of 2030 clinical studies were identified, with 435 duplicate studies excluded, and 214 studies assessed for eligibility following title and abstract screening. Of these studies, 118 were excluded due to no comparative treatment arm, 41 due to wrong study design, 27 due to wrong outcome, 19 due to ongoing clinical trials without results published, and four due to less than 10 patients in each treatment arm. The inclusion criteria encompassed prospective studies that compared treatment strategies in adults with intermediate- or high-risk SMM. Eligible studies were required to have at least two treatment arms with >10 patients each and report on efficacy outcomes of progression-free survival (PFS), overall response rate (ORR), stable disease (SD), partial response (PR), very good partial response (VGPR), minimal response (MR), and time to progression (TTP). Safety outcomes included adverse events (AEs) as defined by the Common Terminology Criteria for Adverse Events (CTCAE). Results: One hundred eighty-two patients were included across the five studies that met the inclusion criteria. 4 (80%) of studies were randomized controlled trials (RCTs). Two studies were phase I/II trials, one comparing the use of dose-escalated multipeptide PVX-410 vaccine +/- lenalidomide (R) in SMM patients, and the other comparing dose-escalated anakinra +/-Lenalidomide/dexamethasone (Rd). Comparing the dose-escalated PVX-410 vaccine cohorts with R versus without, 12 (100%) versus 4 (44.4%) had SD, 5 (41.7%) versus 1 (11.1%) had PR, and the median TTP was not reached versus 36 weeks during the 12-month follow-up period. All treatment arms had at least one AE. Comparing the dose-escalated anakinra +/- Rd, the highest dose anakinra group had the best outcomes with 3 (50%) PR, 2 (33.3%) MR, and 1 (16.7%) VPGR, with 1 (16.7%) grade 4 AE. Two studies were phase II RCTs; one compared Rd +/- Carfilzomib (K) in 58 high-risk SMM patients, with statistically significantly higher 3-year PFS in KRd of 94% versus Rd of 40%; p<0.001, across a median follow-up period of 34 months. At least one grade 3+ AE occurred in 74% of KRd versus 53% of Rd-treated patients. The second phase II RCT included 20 intermediate- and high-risk SMM patients treated with Iberdomide (I) +/- d, with ORR of 84.6% versus 80% in the Id versus I group. Most AEs were grade 1-2 in both treatment arms. One phase III RCT compared zoledronic acid +/- thalidomide in a total of 68 SMM patients, with a median TTP of 2.4 versus 1.2 years, 1-year PFS of 85% versus 55%, and 1-year ORR of 37% versus no confirmed response during the median follow-up of 5.9 years. Grade ≥ 2 AE was statistically significantly higher in the combination therapy cohort, 32 (91%) versus 16 (48%), p-value 0.0001. Conclusion: Preliminary evidence from comparative trials suggests that early treatment of intermediate/high-risk SMM with various novel agents may significantly improve efficacy outcomes, including TTP, ORR, and PFS, which supports the potential role of early intervention in delaying progression to symptomatic MM. However, multi-agent treatment options in SMM may be associated with increasing toxicity concerns. Balancing the potential benefits and debilitating side effects is of paramount importance in SMM. Further research is needed to develop an optimal and effective intervention in SMM to prevent disease progression safely.