Daratumumab versus Active Monitoring for High-Risk Smoldering Multiple Myeloma: What the AQUILA Trial Found

Table of Contents

• Key Points
• What Is Smoldering Multiple Myeloma?
• Why This Study Was Needed
• How the Study Was Designed
• Who Could Participate
• How the Treatments Were Given
• Key Findings: Progression-Free Survival
• Response Rates and Time to First Treatment
• Overall Survival
• Safety and Side Effects
• Quality of Life During Treatment
• Limitations of the Study
• What This Means for Patients
• Frequently Asked Questions
• Source Information

Key Points

• In the AQUILA trial, daratumumab reduced the risk of progression or death by 51% versus active monitoring in high-risk smoldering myeloma.
• Five-year progression-free survival was 63.1% with daratumumab versus 40.8% with active monitoring.
• Five-year overall survival was 93.0% with daratumumab versus 86.9% with active monitoring.
• Grade 3 or 4 infections occurred in 16.1% of daratumumab patients versus 4.6% with active monitoring.
• Quality of life was maintained in both groups, with no meaningful decline in daratumumab-treated patients.

What Is Smoldering Multiple Myeloma?

Smoldering multiple myeloma (SMM) is a precancerous condition that sits between a completely benign abnormality and active cancer. Patients have abnormal plasma cells in their bone marrow — the cells that normally produce antibodies — and may have abnormal protein in their blood. But they do not have symptoms. No organ damage has occurred yet.

Plasma cells are a type of white blood cell. In SMM, these cells multiply abnormally and produce a faulty antibody protein called M-protein. The condition is "smoldering" because it can smolder quietly for years. About one third of patients have adverse prognostic factors and are considered to have high-risk disease, with a 50% risk of progressing to active multiple myeloma over time.

Currently, no treatments are approved for SMM. The standard of care has been active monitoring — regular checkups and blood tests to watch for progression. The philosophy has been "watch and wait" because treating early was not thought to change outcomes.

Why This Study Was Needed

Research has shown that patients with high-risk SMM progress to active multiple myeloma faster than other patients. Yet no therapy has been approved to intervene during this window. The question was whether catching the disease earlier could change its trajectory.

Daratumumab (Darzalex) is a monoclonal antibody — a lab-made protein that acts like a guided missile. It targets CD38, a protein found in large amounts on the surface of myeloma cells. When daratumumab binds to CD38, it helps the immune system destroy those cells. The drug is already approved to treat active multiple myeloma, both alone and in combination with other medications.

A phase 2 study called CENTAURUS had already shown that daratumumab worked as a single agent in patients with intermediate-risk or high-risk SMM. That study supported the dosing strategy used in the AQUILA trial and confirmed the drug's side-effect profile in this patient population.

The AQUILA trial was designed to answer a simple question: Can daratumumab given early — before symptoms develop — delay or prevent progression to active multiple myeloma?

How the Study Was Designed

AQUILA was a phase 3, open-label, multicenter, randomized trial. In phase 3 trials, a new treatment is compared to the current standard of care in a large group of patients. "Open-label" means both patients and doctors knew which group each patient was in — a common design in cancer trials when a placebo injection would be impractical.

The trial enrolled patients at 124 sites in 23 countries. Enrollment took place from December 10, 2017, through May 27, 2019. A total of 771 patients with high-risk SMM were assessed for eligibility. Of those, 381 were not eligible. The remaining 390 patients were randomly assigned in a 1:1 ratio: 194 received daratumumab and 196 received active monitoring.

Randomization was handled through an interactive web-based system. It was stratified — meaning balanced — according to several factors that influence risk of progression:

• Number of risk factors for progression (fewer than 3 vs. 3 or more)
• Whether the serum M-protein level was at least 30 g per liter (yes or no)
• Whether the patient had IgA smoldering myeloma (yes or no)
• Degree of immunoparesis — reduced levels of two uninvolved immunoglobulins vs. fewer than two reduced
• Whether the serum free light chain ratio was at least 8 (yes or no)
• Percentage of clonal plasma cells in bone marrow (more than 50% to less than 60% vs. 50% or less)

The primary end point — the main outcome the trial was designed to measure — was progression-free survival (PFS). PFS measures the time from randomization until the disease progresses to active multiple myeloma or the patient dies from any cause, whichever happens first. Progression was assessed by an independent review committee using the International Myeloma Working Group (IMWG) SLiM–CRAB diagnostic criteria, the standard criteria for diagnosing active multiple myeloma.

Secondary end points included overall response (partial response or better), complete response, time to disease progression, time to initiation of first-line treatment for active myeloma, and overall survival (OS). The trial was designed to detect a 37.5% lower risk of disease progression or death, and it had 85% power to do so. The target sample size was 360 patients (180 per group) with 165 events.

All 390 patients were included in the intention-to-treat analysis — meaning everyone who was randomized was counted, whether or not they completed their assigned treatment. This approach gives a realistic picture of how the treatments work in real practice.

Who Could Participate

Patients had to be 18 years or older. They needed a confirmed diagnosis of smoldering multiple myeloma within the past 5 years, according to IMWG criteria. They also had to have measurable disease and an ECOG performance status score of 0 or 1. The ECOG scale runs from 0 to 5, with 0 meaning no symptoms and higher scores indicating greater disability. Scores of 0 or 1 mean a patient is fully active or only slightly limited in physical activity.

Most importantly, patients had to be at high risk for progression. This meant having at least 10% clonal plasma cells in the bone marrow — clonal plasma cells are the abnormal cells that produce M-protein — plus at least one of the following additional risk factors:

• A serum M-protein level of at least 30 g per liter
• IgA smoldering multiple myeloma (a subtype with a higher progression risk)
• Immunoparesis with reduced levels of two uninvolved immunoglobulin isotypes (meaning the normal antibody-producing cells are suppressed)
• A serum free light chain ratio of 8 to less than 100 (free light chains are pieces of antibody protein; an abnormal ratio signals an imbalance)
• More than 50% to less than 60% clonal plasma cells in the bone marrow

The patients in this trial were typical of high-risk SMM patients, with a median age of 64 years (range, 31 to 86). Most had a good performance status: 85.1% of the daratumumab group and 81.6% of the active-monitoring group had ECOG scores of 0, meaning no symptoms at all. The median time from diagnosis of SMM to entering the trial was 0.72 years (range, 0 to 5.0).

The median percentage of clonal plasma cells in the bone marrow was 20%. At least one high-risk cytogenetic abnormality — such as del(17p), t(4;14), or t(14;16), which are specific chromosome changes that make the disease more aggressive — was present in 15.1% of patients overall. The majority of patients (79.5%) had at least three risk factors for progression.

By the Mayo 2018 risk criteria, which were published after the trial was already underway and applied retrospectively, 40.5% of the patients were classified as having high-risk disease. The Mayo 2018 criteria use three factors: a serum M-protein level above 20 g per liter, a serum free light chain ratio above 20, and more than 20% clonal plasma cells in the bone marrow. Having no factors means low risk, one factor means intermediate risk, and two or three factors means high risk.

Black patients were underrepresented in the trial population, making up only 2.8% of participants. Asian patients made up 7.9%. This is important because multiple myeloma is known to affect people of African descent at higher rates and at younger ages.

How the Treatments Were Given

Patients in the daratumumab group received subcutaneous (under-the-skin) injections of daratumumab. Each dose was 1800 mg, coformulated with recombinant human hyaluronidase PH20 at 2000 units per milliliter. Hyaluronidase is an enzyme that helps the medication spread under the skin, allowing the drug to be given as a quick injection instead of a long intravenous infusion.

The treatment schedule was:

1. Weekly injections during cycles 1 and 2
2. Every 2 weeks during cycles 3 through 6
3. Every 4 weeks for cycles 7 through 39

Each cycle lasted 28 days. Treatment continued for 39 cycles, for 36 months, or until confirmed disease progression — whichever came first. The median number of daratumumab cycles actually received was 38 (range, 1 to 39). The median duration of treatment was 35.0 months (range, 0 to 36.1).

Patients in the active-monitoring group received no disease-specific treatment. They were followed with regular checkups for 36 months or until confirmed disease progression. The median duration of active monitoring was 25.9 months (range, 0.1 to 36.0).

By the clinical cutoff date of May 1, 2024, 127 patients (65.5%) in the daratumumab group had completed all 39 cycles or the full 36 months of treatment. In the active-monitoring group, 80 patients (40.8%) had completed 36 months of monitoring.

The most common reason for stopping treatment or monitoring was progressive disease. This occurred in 21.8% of patients in the daratumumab group and 41.8% of patients in the active-monitoring group. A total of 30 patients (15.5%) in the daratumumab group and 51 patients (26.0%) in the active-monitoring group discontinued the trial entirely. The most common reasons for trial discontinuation were death (7.7% vs. 13.3% in the two groups) and patient withdrawal (6.2% vs. 11.7%).

Key Findings: Progression-Free Survival

The results were striking. With a median follow-up of 65.2 months (range, 0 to 76.6), progression to active multiple myeloma or death occurred in 67 patients (34.5%, about 1 in 3) in the daratumumab group. In the active-monitoring group, this occurred in 99 patients (50.5%, about 1 in 2).

The risk of disease progression or death was 51% lower with daratumumab than with active monitoring. The hazard ratio was 0.49, with a 95% confidence interval of 0.36 to 0.67 and a P value of less than 0.001. A hazard ratio below 1 means the treatment reduced the risk. A P value below 0.001 means there is less than a 0.1% chance this result was due to random chance — a highly statistically significant finding.

Put in terms of absolute outcomes: 5-year progression-free survival was 63.1% with daratumumab — meaning about 63 of every 100 patients had not progressed and were alive at 5 years. In the active-monitoring group, progression-free survival at 5 years was 40.8% — about 41 in 100. This is a difference of more than 22 percentage points.

The median time to disease progression (using IMWG biochemical or SLiM–CRAB criteria) was 44.1 months in the daratumumab group and 17.8 months in the active-monitoring group. In other words, half of the patients in the active-monitoring group had progressed by about a year and a half, while half of the daratumumab group had not progressed until nearly 4 years had passed. The hazard ratio for time to progression was 0.51 (95% CI, 0.40 to 0.66).

The results held up when the researchers performed sensitivity analyses. Three different methods of determining disease progression — the independent review committee, the treating investigator, and a computer algorithm — all showed high concordance. This means the finding was robust, not dependent on how progression was measured.

In a prespecified analysis of subgroups — looking at patient groups divided by age, sex, risk factors, and other characteristics — the benefit of daratumumab was consistent across all of them.

Response Rates and Time to First Treatment

The trial also measured whether daratumumab actually shrank the disease burden. A complete response — meaning no detectable signs of the disease — was achieved in 17 patients (8.8%, about 1 in 11) in the daratumumab group. No patients in the active-monitoring group achieved a complete response, which makes sense since they received no treatment.

A very good partial response or better — meaning a near-total reduction in disease — was achieved in 58 patients (29.9%, about 3 in 10) in the daratumumab group and in only 2 patients (1.0%, 1 in 100) in the active-monitoring group.

The clinical significance of early treatment also showed up in how many patients eventually needed treatment for active multiple myeloma. By the clinical cutoff, first-line treatment for active myeloma had been initiated in 64 patients (33.2%) in the daratumumab group, compared to 105 patients (53.6%) in the active-monitoring group. The hazard ratio was 0.46 (95% CI, 0.33 to 0.62).

The 5-year estimate for needing first-line treatment was 29.7% in the daratumumab group compared to 55.9% in the active-monitoring group. In other words, more than half of the monitored patients had started treatment for active myeloma within 5 years, compared to fewer than a third of the daratumumab-treated patients.

Overall Survival

The most important measure for any cancer treatment is whether it helps patients live longer. In this trial, the survival data strongly favored daratumumab.

By the clinical cutoff, 41 patients had died: 15 (7.7%, about 1 in 13) in the daratumumab group and 26 (13.3%, about 1 in 8) in the active-monitoring group. The hazard ratio for death was 0.52 (95% CI, 0.27 to 0.98) — a 48% lower risk of death.

Five-year overall survival was 93.0% with daratumumab — about 93 of every 100 patients were alive at 5 years. In the active-monitoring group, 5-year overall survival was 86.9% — about 87 in 100. That is a 6.1 percentage point difference favoring early treatment.

Trial follow-up is ongoing, with longer-term survival data expected to be reported in the future.

Safety and Side Effects

No unexpected safety concerns were identified in this trial. However, the side-effect profile is important for patients to understand when weighing the benefits of early treatment.

Grade 3 or 4 adverse events — meaning severe or life-threatening side effects — occurred in 40.4% (about 2 in 5) of patients in the daratumumab group and 30.1% (about 3 in 10) in the active-monitoring group. The most common grade 3 or 4 adverse event in both groups was hypertension (high blood pressure), occurring in 5.7% of the daratumumab group and 4.6% of the active-monitoring group.

Serious adverse events — those requiring hospitalization or posing significant medical risk — occurred in 29.0% of daratumumab patients and 19.4% of active-monitoring patients. The most common serious adverse event was pneumonia, occurring in 3.6% of the daratumumab group versus 0.5% of the active-monitoring group.

Eleven patients (5.7%) in the daratumumab group stopped treatment because of adverse events. Two patients (1.0%) in the daratumumab group died from adverse events — one from COVID-19 and one from COVID-19 pneumonia. In the active-monitoring group, 4 patients (2.0%) died from adverse events (pulmonary edema, cardiac arrest, pulmonary embolism, and cardiac failure).

Infections were more common with daratumumab. Grade 3 or 4 infections occurred in 16.1% (about 1 in 6) of the daratumumab group versus 4.6% (about 1 in 22) of the active-monitoring group. COVID-19 adverse events during the reporting period occurred in 8.8% versus 5.1%.

Injection-related reactions were reported in the daratumumab group:

• Systemic reactions (affecting the whole body) related to treatment administration occurred in 32 patients (16.6%), with 2 patients (1.0%) experiencing grade 3 or 4 reactions
• Local reactions at the injection site occurred in 53 patients (27.5%), with none being grade 3 or 4

Second primary cancers — new, different cancers that developed during the trial — occurred in 18 patients (9.3%) in the daratumumab group and 20 patients (10.2%) in the active-monitoring group. This was not a significant difference.

The adverse event data must be viewed in context. The daratumumab group had approximately twice as much time on study treatment as the active-monitoring group (median 35.0 months vs. 25.9 months), and patients in the daratumumab group were also living longer and therefore had more time at risk for events.

Quality of Life During Treatment

A critical question for any early treatment is whether the therapy makes patients feel worse. The trial measured patient-reported outcomes using three validated questionnaires: the EORTC Quality of Life Questionnaire–Core 30 (QLQ-C30), the EORTC Quality of Life Questionnaire–Multiple Myeloma Module (QLQ-MY20), and the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L).

The results were reassuring. Baseline scores on all three questionnaires were maintained over the trial duration in both groups, and the scores did not differ substantially between the daratumumab group and the active-monitoring group. In plain terms: patients receiving daratumumab reported no meaningful decline in their quality of life compared to patients who were simply being watched. The benefit of preventing disease progression did not come at the cost of feeling worse day to day.

Limitations of the Study

Every clinical trial has limitations, and understanding them helps patients interpret the results appropriately.

First, the trial was open-label. Patients and doctors knew which treatment was being given. This design can introduce bias, though the use of an independent review committee to confirm disease progression helps reduce that risk.

Second, Black patients were underrepresented, making up only 2.8% of the trial population. This matters because multiple myeloma has a higher incidence and earlier onset in people of African descent, and treatment effects can sometimes differ across racial and ethnic groups.

Third, the treatment was time-limited: daratumumab was given for up to 39 cycles or 36 months, then stopped. The study does not answer whether longer treatment would provide even greater benefit, or whether retreatment would be needed when progression occurs.

Fourth, the Mayo 2018 risk criteria were published after the trial was initiated. The high-risk classification based on those criteria was therefore applied retrospectively, which could affect how well the results generalize to patients classified as high-risk under current standards.

Fifth, for secondary end points, the confidence intervals were not adjusted for multiple comparisons. This means the results for outcomes other than the primary end point — while strongly suggestive — cannot be used to infer definitive treatment effects in the strict statistical sense.

Finally, although overall survival was significantly longer with daratumumab, the number of recorded deaths is still relatively small (41 total), and follow-up for survival is ongoing. The long-term durability of the survival benefit remains to be confirmed.

What This Means for Patients

For patients with high-risk smoldering multiple myeloma, these results are practice-changing. For decades, the standard answer has been "watch and wait." This study offers a credible alternative: treat early and potentially change the course of the disease.

The magnitude of the benefit is substantial. About 63 in 100 treated patients were alive without progression at 5 years, compared to about 41 in 100 monitored patients. About 93 in 100 treated patients were alive at 5 years, versus about 87 in 100 monitored patients. And less than a third of treated patients needed first-line therapy for active myeloma within 5 years, compared to more than half of monitored patients.

The treatment is not free of side effects. Grade 3 or 4 infections were more common with daratumumab (16.1% vs. 4.6%), and systemic or local injection reactions occurred in 16.6% and 27.5% of treated patients, respectively. However, the fact that quality-of-life scores were maintained in both groups is an important reassurance that the treatment burden is manageable.

Patients with high-risk SMM should discuss these findings with their hematologist or oncologist.

• Ask whether you meet the high-risk criteria used in this trial (at least 10% clonal plasma cells plus one additional risk factor)
• Discuss your personal risk of progression, including your cytogenetic profile and M-protein level
• Review the potential benefits — a 51% lower risk of progression or death — against the side-effect profile
• Consider whether subcutaneous daratumumab is available and covered by your insurance

The AQUILA findings suggest that the window of smoldering disease is not just a waiting period. It may be the best opportunity to intervene. As the study authors note, daratumumab may delay or even prevent end-organ damage and progression to active multiple myeloma, providing clinical benefit independent of achieving a deep response. The 2025 NEJM update confirms that these findings have held with longer follow-up.

This research could pave the way for daratumumab to become the first approved treatment for high-risk smoldering multiple myeloma — a condition for which no treatments have previously been approved.

Frequently Asked Questions

What is smoldering multiple myeloma and why is it called 'smoldering'?

Smoldering multiple myeloma (SMM) is a precancerous condition with abnormal plasma cells in the bone marrow and abnormal protein in the blood, but no symptoms or organ damage. It is called 'smoldering' because it can remain quiet for years. About one third of patients have high-risk disease with a 50% risk of progressing to active multiple myeloma.

Who was eligible to participate in the AQUILA trial?

Patients had to be 18 or older, diagnosed with smoldering multiple myeloma within the past 5 years, and have measurable disease. They needed an ECOG performance status of 0 or 1. Most importantly, they had to be at high risk for progression, meaning at least 10% clonal plasma cells in the bone marrow plus at least one additional risk factor, such as a high M-protein level or IgA subtype.

What treatments were compared in the AQUILA trial?

The trial compared daratumumab (Darzalex) given as a subcutaneous injection to active monitoring (watch and wait). Daratumumab was given weekly for the first two cycles, then every two weeks for cycles 3-6, then every four weeks for cycles 7-39. Each cycle lasted 28 days. Treatment continued for up to 39 cycles or 36 months, whichever came first.

What were the main results of the AQUILA trial regarding progression-free survival?

After a median follow-up of about 65 months, the risk of disease progression or death was 51% lower with daratumumab compared to active monitoring. Five-year progression-free survival was 63.1% with daratumumab versus 40.8% with active monitoring. The median time to progression was 44.1 months with daratumumab versus 17.8 months with active monitoring.

Did daratumumab improve overall survival in the AQUILA trial?

Yes, overall survival was significantly longer with daratumumab. At 5 years, 93.0% of patients in the daratumumab group were alive compared to 86.9% in the active-monitoring group. The hazard ratio for death was 0.52, indicating a 48% lower risk of death. However, the number of deaths was small (41 total), and longer follow-up is ongoing.

What side effects did patients experience with daratumumab?

Grade 3 or 4 adverse events occurred in 40.4% of daratumumab patients versus 30.1% in the active-monitoring group. Infections were more common with daratumumab (16.1% grade 3 or 4 versus 4.6%). Injection-related reactions occurred in 16.6% (systemic) and 27.5% (local). The most common serious adverse event was pneumonia. Quality of life was maintained in both groups.

What does this mean for patients with high-risk smoldering multiple myeloma?

These results are practice-changing. For decades, the standard was 'watch and wait.' Now, early treatment with daratumumab may delay or prevent progression to active multiple myeloma. Patients should discuss with their hematologist whether they meet the high-risk criteria used in the trial, review the potential benefits and side effects, and consider if daratumumab is available and covered by insurance.

Should I get a second opinion before starting daratumumab for high-risk smoldering multiple myeloma?

A second opinion can help you confirm that your smoldering myeloma truly meets the high-risk criteria used in the AQUILA trial, such as at least 10% clonal plasma cells plus an additional risk factor. It can also clarify whether early treatment with daratumumab is appropriate for your specific situation, given the trade-off between a 51% lower risk of progression or death and increased infections and injection reactions. An independent expert review of your diagnosis and treatment plan may provide reassurance and help you make a more informed decision. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma

Authors: M.A. Dimopoulos, P.M. Voorhees, F. Schjesvold, Y.C. Cohen, V. Hungria, I. Sandhu, J. Lindsay, R.I. Baker, K. Suzuki, H. Kosugi, M.-D. Levin, M. Beksac, K. Stockerl-Goldstein, A. Oriol, G. Mikala, G. Garate, K. Theunissen, I. Spicka, A.K. Mylin, S. Bringhen, K. Uttervall, B. Pula, E. Medvedova, A.J. Cowan, P. Moreau, M.-V. Mateos, H. Goldschmidt, T. Ahmadi, L. Sha, A. Cortoos, E.G. Katz, E. Rousseau, L. Li, R.M. Dennis, R. Carson, and S.V. Rajkumar, for the AQUILA Investigators

Publication: The New England Journal of Medicine, May 8, 2025, Vol. 392, No. 18, pages 1777–1788. Originally published December 9, 2024. DOI: 10.1056/NEJMoa2409029

Trial registration: ClinicalTrials.gov number NCT03301220. Funded by Janssen Research and Development.

This patient-friendly article is based on peer-reviewed research published in The New England Journal of Medicine. It is intended for educational purposes and is not a substitute for professional medical advice. Patients should discuss their individual treatment options with their healthcare providers.