SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Multiple Myeloma evolves from a precursor stage called Monoclonal Gammopathy of Unknown Significance (MGUS) to MM.
Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. The risk of MGUS transforming into MM is approximately 1% per year. Smoldering Multiple Myeloma or asymptomatic MM is a precursor to MM and is characterized by at least 10% plasma cells in the bone marrow or M-spike of at least 3 g/dl, or both, but these patients have no evidence of active symptomatic Myeloma with associated end-organ damage such as hypercalcemia, renal insufficiency, anemia or bone lesions. Even though only 10% of patients with SMM progress to MM annually, over 50% of the SMM patients with high risk features will progress to MM in the first 2 years.
The current recommendations for those with SMM are periodic monitoring and treatment intervention only when disease progresses to MM. SMM patients with high risk features include those with at least 10% plasma cells in the bone marrow, a Monoclonal component (IgG monoclonal spike of at least 3 g/dL, IgA M-spike of at least 2 g/dL or a urinary Bence Jones protein level of more than 1 g per 24 hours) or only one of the above two criteria plus at least 95% abnormal plasma cells in the bone marrow, with a reciprocal decrease in one or two uninvolved immunoglobulins of more than 25%, compared to normal values. Immunoparesis describes the reduction of normal/polyclonal immunoglobulin levels and is commonly seen in conditions such as MM, SMM, and MGUS. This phenomenon involves a decline in immunoglobulins not associated with the malignant clone-for instance, in IgG-type myeloma, levels of IgA and IgM are typically decreased. The severity of immunoparesis at diagnosis serves as an independent prognostic indicator in newly diagnosed multiple myeloma. Patients presenting with lower levels of uninvolved immunoglobulins tend to experience shorter Progression-Free Survival (PFS) and Overall Survival (OS).
High-risk SMM has long posed a therapeutic dilemma—patients face a substantial risk of progression to symptomatic disease, yet no standard treatment has been approved. Traditionally, observation has remained the mainstay approach, despite the documented risk of end-organ damage. Daratumumab (DARZALEX®), a CD38-targeting monoclonal antibody already approved for multiple myeloma, has now been evaluated in this pre-malignant population through the pivotal Phase 3 AQUILA trial.
Study Design: The AQUILA Trial
AQUILA was a global, multicenter, open-label, randomized Phase 3 study, evaluating the efficacy of subcutaneous Daratumumab monotherapy versus active monitoring in patients with high-risk SMM. Conducted across 124 sites in 23 countries, the trial enrolled 390 patients, randomized 1:1 to receive either subcutaneous Daratumumab 1800 mg with recombinant Hyaluronidase PH20 weekly during cycles 1–2, biweekly during cycles 3–6, and monthly thereafter for 39 cycles for 36 months, or until disease progression (N=194), or active monitoring (N=196).
Eligibility criteria included:
- 10% or more clonal plasma cells in bone marrow
- At least one high-risk feature, such as:
- Serum M-protein 30 g/L or more
- IgA subtype
- Immunoparesis (2 or more uninvolved Ig isotypes)
- FLC ratio between 8 and 100
- Clonal plasma cells more than 50% but less than 60%
The Primary end point was Progression-Free Survival (PFS) defined as progression to active multiple myeloma as assessed by an Independent Review Committee in accordance with International Myeloma Working Group (IMWG) diagnostic criteria.
Efficacy Outcomes
After a median follow-up of 65.2 months, results demonstrated a clear and significant benefit for Daratumumab over observation:
- Progression-Free Survival (PFS):
- 5-year PFS: 63.1% with Daratumumab vs 40.8% with active monitoring
- Hazard ratio (HR): 0.49 (95% CI: 0.36–0.67; P<0.001)
- Overall Survival (OS):
- 5-year OS: 93.0% with Daratumumab vs 86.9% with active monitoring
- HR for death: 0.52 (95% CI: 0.27–0.98)
These results support a 51% reduction in risk of progression to active multiple myeloma or death with early Daratumumab intervention.
Safety Profile
Daratumumab was well tolerated:
- Grade 3–4 hypertension was the most frequent serious AE (5.7%)
- Treatment discontinuation due to AEs occurred in only 5.7%
- No new safety signals were observed
- Quality of life was maintained throughout treatment and comparable to active monitoring
Clinical Interpretation
The AQUILA trial provides the strongest evidence to date supporting early therapeutic intervention in high-risk SMM. Unlike prior trials (e.g., QuiRedex, ECOG E3A06), which demonstrated benefit with Lenalidomide-based regimens but did not lead to regulatory approval, AQUILA offers compelling long-term survival and disease control data using a well-tolerated, single-agent regimen. Importantly, patient-reported outcomes indicated no decline in quality of life, reinforcing the feasibility of early intervention.
Context & Historical Comparison
- In QuiRedex (Rd vs monitoring), median time to progression was prolonged (9.5 vs 2.1 years), but approval was not pursued
- ECOG E3A06 (Lenalidomide vs monitoring) showed improved PFS but no OS benefit
- AQUILA uniquely demonstrates both PFS and OS advantages with a favorable safety profile, positioning Daratumumab as a potential new standard for early treatment of high-risk SMM
Conclusion
The AQUILA study marks a paradigm shift in the management of high-risk Smoldering Multiple Myeloma. Subcutaneous Daratumumab monotherapy not only halved the risk of progression or death but also preserved quality of life, supporting its consideration as the first active treatment option for this high-risk population. Oncologists should engage in shared decision-making with high-risk SMM patients regarding early therapeutic intervention, particularly in the context of these compelling new data.
Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. for the AQUILA Investigators. N Engl J Med 2025;392:1777-1788
