Smoldering multiple myeloma (SMM) is an asymptomatic precursor of multiple myeloma, with high-risk patients facing a substantial likelihood of progression to symptomatic disease.^1,2 Until now, there have been no approved treatment options for this patient population, and standard care has been limited to close monitoring.^1,2 The recent European Commission (EC) approval of subcutaneous daratumumab, based on phase 3 AQUILA trial results, introduces the first licensed treatment for high-risk SMM and provides a new opportunity to delay or prevent progression to symptomatic disease.¹

SMM represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and overt multiple myeloma.³ It is defined by serum monoclonal protein ≥30g/L or urinary monoclonal protein ≥500mg/24h and/or 10%-60% clonal bone marrow plasma cells, in the absence of myeloma-defining events or amyloidosis.³ Within this group, patients with high-risk SMM carry a substantially higher likelihood of progression, with up to half advancing to symptomatic myeloma within two years.² Daratumumab is a human IgG1κ monoclonal antibody that targets CD38.⁴ Building on its established role in multiple myeloma, both as monotherapy and in combination regimens, daratumumab demonstrated significant efficacy and a favorable safety profile in the phase 3 AQUILA trial, culminating in a landmark approval.^1,4

The phase 3 AQUILA trial was a global, open-label, multicenter, randomized study that enrolled 390 adults with SMM diagnosed within the previous five years.¹ Eligible patients had measurable disease, good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1), and high-risk features, defined as ≥10% clonal bone marrow plasma cells plus at least one factor such as elevated serum M-protein (≥30g/L), immunoglobulin A (IgA) subtype, immunoparesis, free light chain ratio (8 to <100), or >50% to <60% clonal plasma cells in bone marrow.¹ Participants were randomized 1:1 to receive fixed-duration subcutaneous daratumumab (n=194) or active monitoring (n=196).¹ Patients in the treatment arm received daratumumab 1,800 mg coformulated with recombinant human hyaluronidase PH200 weekly during cycles 1-2, every two weeks during cycles 3-6, and every four weeks thereafter, for up to 36 months or until progression.¹ The primary endpoint was progression-free survival (PFS),  and secondary endpoints included overall and complete response (per International Myeloma Working Group [IMWG] criteria), as well as time-to-event outcomes such as disease progression, initiation of first-line multiple myeloma therapy, and death from any cause.¹

Baseline characteristics were well-balanced between groups.¹ Patients had a median age of 64 years and a median time from diagnosis of 0.72 years; the median bone marrow clonal plasma cell percentage was 20%.¹ At least one high-risk cytogenetic abnormality was present in 15.1% of patients, and 79.5% had at least three risk factors for progression to multiple myeloma.¹ At a median follow-up of 65.2 months, daratumumab reduced the risk of progression or death by 51% compared with active monitoring (HR=0.49; 95% CI: 0.36-0.67; p<0.001).¹ Five-year PFS was 63.1% with daratumumab vs. 40.8% with monitoring.¹ Median time to disease progression was 44.1 months with daratumumab vs. 17.8 months with active monitoring (HR=0.51; 95% CI: 0.40-0.66).¹ Response rates were higher with daratumumab, with complete responses in 8.8% and very good partial responses or better in 29.9%, compared with none and 1.0% in the monitoring group.¹ Fewer patients in the daratumumab arm required first-line therapy for active multiple myeloma (33.2% vs 53.6%; HR=0.46; 95% CI: 0.33-0.62), with 5-year estimates of 29.7% vs. 55.9%, respectively.¹

Safety outcomes were consistent with the established profile of daratumumab.¹ Grade 3/4 treatment-emergent adverse events occurred in 40.4% of patients treated with daratumumab and 30.1% of those in the active-monitoring group, with hypertension the most common event (5.7% vs 4.6%).¹ Treatment discontinuation due to adverse events was infrequent (5.7%), and fatal events were rare (1.0% vs 2.0%).¹ Grade 3 or 4 infections were more frequent in the daratumumab arm (16.1% vs 4.6%).¹ Lastly, in the daratumumab group, treatment-related systemic reactions occurred in 16.6% of patients (1.0% grade 3/4), while local injection-site reactions were reported in 27.5%, all grade 1/2.¹ No new safety concerns were observed.¹

In summary, supported by evidence from the AQUILA trial, the approval of subcutaneous daratumumab establishes a new paradigm of early intervention, enabling clinicians to intercept disease earlier, delay progression, and improve long-term outcomes.¹