Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma

The AQUILA clinical trial tested whether early treatment with daratumumab (brand name: Darzalex), an antibody therapy already approved for active multiple myeloma, could prevent or delay progression to active disease in patients with high-risk smoldering multiple myeloma, a precursor condition for which no treatments are currently approved. The study followed 390 patients for a median of 65.2 months and found that those receiving subcutaneous (under-the-skin) daratumumab injections had a 51% lower risk of disease progression or death compared with those who were simply watched closely. Five years after starting the study, 63.1% of daratumumab-treated patients remained free of progression versus 40.8% of actively monitored patients, and overall survival was also better in the treatment group (93.0% vs. 86.9%). These findings suggest that early intervention with daratumumab may change the natural course of this high-risk precursor condition.

Table of Contents

• Key Points
• Understanding Smoldering Multiple Myeloma
• Why This Research Matters
• Study Design: The AQUILA Trial
• Who Could Participate in the Trial?
• How the Treatment Was Given
• How Success Was Measured
• Key Findings: Delaying or Preventing Active Myeloma
• Survival Results: A Significant Improvement
• Response Rates: How Deep Was the Remission?
• Safety: Side Effects and Risks
• Quality of Life During Treatment
• Clinical Implications: What This Means for Patients
• Limitations: What This Study Couldn't Prove
• Recommendations for Patients and Caregivers
• Frequently Asked Questions
• Source Information

Key Points

• In a 390-patient trial, subcutaneous daratumumab lowered the risk of progression or death by 51% versus active monitoring in high-risk smoldering myeloma.
• At five years, 63.1% of daratumumab patients stayed progression-free versus 40.8% with monitoring; overall survival was 93.0% versus 86.9%.
• Daratumumab was given as under-the-skin injections for up to 36 months; treatment delayed the need for first-line myeloma therapy in most patients.
• Serious infections occurred in 16.1% of treated patients versus 4.6% of monitored patients; quality of life was maintained during treatment.
• The trial was open-label and underrepresented Black patients, so discuss how findings apply to your individual situation with your oncologist.

Understanding Smoldering Multiple Myeloma

Multiple myeloma is a cancer of plasma cells, a type of white blood cell found in the bone marrow that normally helps fight infections. Before this cancer becomes "active" and causes symptoms, many patients go through a quiet, symptom-free phase called smoldering multiple myeloma. Think of it as a warning sign — abnormal plasma cells are multiplying in the bone marrow, but they haven't yet caused the organ damage or classic symptoms that define active myeloma.

The current standard of care for smoldering multiple myeloma has been "watch and wait" — also called active monitoring. This means patients receive regular checkups and blood tests but no disease-specific treatment until the condition progresses to active multiple myeloma.

However, not all smoldering myeloma is the same. Approximately one third of patients have what doctors call high-risk smoldering multiple myeloma, meaning they have certain features that make progression to active disease much more likely. These patients face approximately a 50% risk of progression to active myeloma over time. The challenge has been that no treatments have been approved for this precursor condition, leaving high-risk patients with no options beyond close observation.

Why This Research Matters

There's an important question in myeloma care: Should we treat high-risk smoldering myeloma early, before it turns into active disease, or wait until symptoms develop? Waiting has costs — by the time active myeloma appears, patients may already have kidney damage, bone destruction, or anemia. Some research suggests that close monitoring alone may not prevent the organ damage that can occur when myeloma becomes active.

Daratumumab is a human monoclonal antibody that targets a protein called CD38, which is found in large amounts on myeloma cells. It's already approved for treating active multiple myeloma, both as a single drug and in combination with other treatments. A phase 2 study called CENTAURUS showed that daratumumab had activity in patients with intermediate- or high-risk smoldering myeloma, which supported the design of this larger phase 3 trial.

This study, called AQUILA, was designed to answer a straightforward question: Can giving subcutaneous (under-the-skin) daratumumab early — while patients still feel fine — delay or prevent progression to active multiple myeloma, compared with the traditional approach of active monitoring?

Study Design: The AQUILA Trial

AQUILA was a phase 3, open-label, multicenter, randomized trial. In plain language, this means it was a large, late-stage study designed to definitively test whether the treatment works. The trial was "open-label," meaning both patients and doctors knew which group each patient was in. It was conducted at 124 sites across 23 countries, making it a truly global effort.

Between December 10, 2017, and May 27, 2019, a total of 390 patients were enrolled. They were randomly assigned in a 1:1 ratio — like flipping a coin — to one of two groups:

• Daratumumab group: 194 patients received subcutaneous daratumumab injections
• Active-monitoring group: 196 patients received no treatment, just careful observation

One patient in the daratumumab group was assigned to treatment but never received it, leaving 193 patients who actually started treatment versus 196 who were monitored.

The trial was funded by Janssen Research and Development, the company that makes daratumumab. An independent ethics committee or institutional review board approved the trial at each site, and all patients gave written informed consent before joining.

Who Could Participate in the Trial?

Patients had to be 18 years or older and have a confirmed diagnosis of smoldering multiple myeloma (within the past 5 years) using standard International Myeloma Working Group (IMWG) criteria. They also needed to have "measurable disease" and be generally healthy enough to participate, as measured by an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (on a scale where 0 means no symptoms and 5 means severe disability).

Most importantly, all patients had to be considered high risk for progression to active multiple myeloma. This was defined as having at least 10% clonal plasma cells in the bone marrow and at least one of the following risk factors:

• A serum M-protein level of at least 30 g per liter (M-protein is an abnormal antibody produced by myeloma cells)
• IgA-type smoldering multiple myeloma (a specific subtype associated with higher risk)
• Immunoparesis, meaning reduced levels of two uninvolved (normal) immunoglobulin types
• A serum free light chain ratio (FLC ratio) of 8 to less than 100 — this measures the balance of two types of light chain proteins in the blood
• More than 50% but less than 60% clonal plasma cells in the bone marrow

Patients could have multiple risk factors — in fact, 79.5% of the study population had at least three risk factors. Randomization was stratified (balanced) based on the number of risk factors (fewer than 3 vs. 3 or more) and other specific disease features.

The median age of participants was 64 years (range 31 to 86), and patients had been living with the smoldering myeloma diagnosis for a median of 0.72 years before joining the trial. The median percentage of clonal plasma cells in the bone marrow was 20%. It's worth noting that Black patients were underrepresented, making up only 2.8% of the trial population, while Asian patients made up 7.9%.

How the Treatment Was Given

Patients in the daratumumab group received subcutaneous (under-the-skin) daratumumab at a dose of 1800 mg, coformulated with an enzyme called recombinant human hyaluronidase PH20 to help the medication absorb properly. The treatment followed a specific schedule using 28-day cycles:

1. Cycles 1 and 2: Daratumumab given weekly
2. Cycles 3 through 6: Daratumumab given every 2 weeks
3. After cycle 6: Daratumumab given every 4 weeks

Treatment continued for 39 cycles, 36 months, or until confirmed disease progression — whichever came first. The median number of cycles patients actually received was 38, and the median treatment duration was 35.0 months (range 0 to 36.1). By the study cutoff date (May 1, 2024), 127 patients (65.5%) had completed the full course of 39 cycles or 36 months.

Patients in the active-monitoring group received no disease-specific treatment. They were simply observed for 36 months or until disease progression, whichever came first. The median duration of active monitoring was 25.9 months (range 0.1 to 36.0).

For both groups, disease evaluations were done by a central laboratory every 12 weeks until progression was confirmed.

How Success Was Measured

The primary end point (main outcome) of the trial was progression-free survival — the length of time from randomization until either the disease progressed to active multiple myeloma or the patient died from any cause, whichever happened first.

Progression to active myeloma was judged by an independent review committee using the standard IMWG SLiM–CRAB diagnostic criteria. These criteria define active myeloma as the presence of:

• SLiM: 60% or more clonal plasma cells in bone marrow, a serum free light chain ratio of 100 or more, or more than one MRI-detected bone lesion, or
• CRAB: Elevated calcium levels, kidney dysfunction, anemia, or bone lesions

Secondary outcomes included overall response rate (partial response or better), complete response rate, time to disease progression, time to starting first-line treatment for active myeloma, and overall survival.

The trial was designed to have 85% power to detect a 37.5% lower risk of disease progression or death in the daratumumab group, meaning the study was large enough to reliably find a meaningful difference if one existed. The original plan called for 360 patients and 165 progression or death events.

Key Findings: Delaying or Preventing Active Myeloma

After a median follow-up of 65.2 months (more than 5 years), the results were striking. Disease progression to active multiple myeloma or death occurred in:

• 67 patients (34.5%) in the daratumumab group
• 99 patients (50.5%) in the active-monitoring group

This translates to a 51% lower risk of progression or death with daratumumab (hazard ratio, 0.49; 95% confidence interval, 0.36 to 0.67; P<0.001). The p-value of less than 0.001 means there is less than a 0.1% chance these results happened by random luck — a highly statistically significant finding.

Progression-free survival at 5 years was:

• 63.1% with daratumumab
• 40.8% with active monitoring

In other words, nearly two-thirds of treated patients remained progression-free at 5 years, compared with about four in ten untreated patients. The benefit was consistent across all prespecified patient subgroups, meaning the treatment helped a broad range of patients regardless of age, disease type, or number of risk factors.

Beyond the formal definition of progression, daratumumab also delayed the time to disease progression substantially. The median time to progression (using either IMWG biochemical or SLiM-CRAB criteria) was:

• 44.1 months in the daratumumab group
• 17.8 months in the active-monitoring group

That's a hazard ratio of 0.51 (95% CI, 0.40 to 0.66) — daratumumab more than doubled the time patients lived without their disease advancing.

Treatment with daratumumab also dramatically reduced the need for more intensive treatment later. By the study cutoff, first-line treatment for active multiple myeloma had been initiated in:

• 64 patients (33.2%) in the daratumumab group
• 105 patients (53.6%) in the active-monitoring group

The hazard ratio was 0.46 (95% CI, 0.33 to 0.62), and at 5 years, the estimated chance of needing first-line treatment was 29.7% versus 55.9% — meaning untreated patients were nearly twice as likely to need systemic therapy within 5 years.

Survival Results: A Significant Improvement

Perhaps the most meaningful finding for patients is the difference in overall survival. By the study cutoff, 41 patients had died in total:

• 15 patients (7.7%) in the daratumumab group
• 26 patients (13.3%) in the active-monitoring group

This represents a 48% lower risk of death with daratumumab (hazard ratio, 0.52; 95% confidence interval, 0.27 to 0.98). At 5 years, overall survival was 93.0% with daratumumab and 86.9% with active monitoring. This means that out of 100 patients, about 93 in the treatment group were alive at 5 years compared with about 87 in the monitoring group.

These survival benefits are particularly notable because many patients in the active-monitoring group eventually received treatment when their disease progressed — yet early intervention with daratumumab still provided a survival advantage.

Response Rates: How Deep Was the Remission?

Even though patients started with a symptom-free precursor condition, daratumumab was able to produce meaningful disease responses. The trial measured responses using standard IMWG criteria, assessed by a validated computer algorithm:

• A complete response (CR) or better — meaning no detectable disease — was achieved in 17 patients (8.8%) in the daratumumab group versus 0 patients in the active-monitoring group
• A very good partial response (VGPR) or better was achieved in 58 patients (29.9%) in the daratumumab group versus 2 patients (1.0%) in the monitoring group

These deep responses are clinically important because they suggest daratumumab can actually reduce the burden of abnormal plasma cells, not just hold them in check. The researchers noted that the clinical benefit of daratumumab appeared to be independent of whether a deep response was achieved — meaning even patients who didn't have a dramatic response still benefited from delayed progression.

Safety: Side Effects and Risks

As with any medication, daratumumab comes with potential side effects. The study tracked these carefully, comparing the treatment group to the active-monitoring group. Here's what they found:

Grade 3 or 4 adverse events (serious or life-threatening side effects) occurred in 40.4% of patients in the daratumumab group versus 30.1% in the active-monitoring group. The most common serious side effect in both groups was hypertension (high blood pressure), occurring in 5.7% of treatment patients versus 4.6% of monitored patients.

Serious adverse events (events requiring hospitalization or otherwise medically significant) occurred in 29.0% of daratumumab patients versus 19.4% of monitored patients. The most common serious adverse event was pneumonia, seen in 3.6% of daratumumab patients versus 0.5% of monitored patients.

Key safety points to be aware of:

• Infections: Grade 3 or 4 infections occurred in 16.1% of daratumumab patients versus 4.6% of monitored patients. This is expected, since daratumumab affects the immune system's ability to fight certain infections. COVID-19 events occurred in 8.8% of daratumumab patients versus 5.1% of monitored patients.
• Treatment discontinuation: Adverse events led to stopping treatment in 5.7% of daratumumab patients (11 patients). This is a relatively low rate, suggesting the treatment was generally tolerable.
• Infusion/injection reactions: Systemic (whole-body) reactions related to the injection occurred in 16.6% of patients, with only 1.0% experiencing grade 3 or 4 reactions. Local reactions at the injection site occurred in 27.5% of patients, with none being grade 3 or 4.
• Deaths related to adverse events: Adverse events leading to death occurred in only 2 patients (1.0%) in the daratumumab group — both from COVID-19 or COVID-19 pneumonia — and in 4 patients (2.0%) in the monitoring group, from pulmonary edema, cardiac arrest, pulmonary embolism, and cardiac failure.
• Second primary cancers: These were observed in 18 patients (9.3%) in the daratumumab group and 20 patients (10.2%) in the monitoring group — essentially no difference, which is reassuring.

The researchers concluded that no new safety concerns were identified with subcutaneous daratumumab in this patient population, and side effects were consistent with the drug's known safety profile from its use in active multiple myeloma.

Quality of Life During Treatment

A treatment only makes sense if it doesn't harm the quality of life it's designed to preserve. The study measured patient-reported outcomes using three validated questionnaires:

• The EORTC Quality of Life Questionnaire–Core 30 (a general cancer quality-of-life measure)
• The EORTC Quality of Life Questionnaire–Multiple Myeloma Module (a myeloma-specific measure)
• The EuroQol 5-Dimension 5-Level questionnaire (a general health-status measure)

Results showed that quality-of-life scores at baseline were maintained over the trial duration in both groups, and scores did not differ substantially between the daratumumab and active-monitoring groups. This is good news — it means patients receiving daratumumab didn't experience a meaningful decline in their daily quality of life despite the side effects of treatment.

Clinical Implications: What This Means for Patients

These results could change the standard of care for high-risk smoldering multiple myeloma. Here's what the findings mean for patients:

1. A treatment option now exists where none existed before. For decades, the only approach for smoldering myeloma was to watch and wait. This study shows that a well-tolerated, under-the-skin injection can significantly delay or even prevent progression to active disease.
2. Early treatment may prevent organ damage. The researchers noted that daratumumab "may delay or even prevent end-organ damage and progression to active multiple myeloma." Since active myeloma can cause kidney failure, bone destruction, and severe anemia, preventing these complications is a major win.
3. Survival is improved. A 48% reduction in risk of death, with 93% of treated patients alive at 5 years, is a compelling argument for early intervention in appropriately selected high-risk patients.
4. Patients may avoid or postpone intensive chemotherapy. Only one-third of daratumumab-treated patients needed first-line anti-myeloma therapy within the follow-up period, versus more than half of monitored patients. Avoiding or delaying chemotherapy is a significant quality-of-life benefit.
5. Treatment is time-limited. Patients did not receive daratumumab indefinitely — the protocol capped treatment at 36 months. The fact that the benefits persisted beyond the treatment period suggests a durable effect.

Limitations: What This Study Couldn't Prove

While the AQUILA trial results are impressive, it's important to understand the study's limitations:

• Open-label design: Because patients and doctors knew who was receiving treatment, there's a theoretical risk of bias. However, the primary endpoint was assessed by an independent review committee, and sensitivity analyses using investigator assessments and computer algorithms showed high concordance, which strengthens confidence in the results.
• Limited diversity: Black patients, who have higher rates of multiple myeloma and are diagnosed at younger ages, were underrepresented — only 2.8% of the trial population. This raises questions about how well the results apply to all racial and ethnic groups.
• Progression criteria evolution: The trial used risk criteria based on data available when the trial was designed. When the newer Mayo 2018 risk criteria were applied retrospectively, only 40.5% of patients were classified as high risk, suggesting the trial population included some patients who would not meet today's stricter definition of high-risk disease.
• Long-term follow-up is still ongoing: While median follow-up exceeded 5 years, we need even longer follow-up to understand the full impact on long-term survival and to see whether the benefits persist or wane over time.
• Comparative data are limited: The trial compared daratumumab to observation, not to other potential early treatments. We don't know from this study how daratumumab compares to other strategies that have been explored for high-risk smoldering myeloma.

Recommendations for Patients and Caregivers

If you or a loved one has been diagnosed with high-risk smoldering multiple myeloma, here are some actionable considerations based on this research:

1. Talk to your oncologist about this study. Ask specifically whether you meet the criteria for high-risk smoldering myeloma and whether daratumumab might be an appropriate option for you. The treatment is already FDA-approved for active multiple myeloma, and this study provides strong evidence for its use in high-risk smoldering disease.
2. Know your risk factors. Ask your doctor about your specific risk profile — your M-protein level, IgA status, free light chain ratio, bone marrow plasma cell percentage, and whether you have immunoparesis (reduced normal antibodies). This information determines whether you're considered high risk.
3. Ask about subcutaneous versus intravenous daratumumab. This study used the subcutaneous (under-the-skin) formulation, which is given as an injection and is generally much faster and less burdensome than intravenous (IV) infusions, which can take hours.
4. Understand the side effect profile. Be aware that daratumumab increases the risk of infections, particularly respiratory infections like pneumonia, and can cause injection-site reactions. Ask your doctor about preventive measures, such as vaccination, antiviral medications, or monitoring for infections.
5. Discuss the monitoring plan. If you choose active monitoring, make sure you have a clear plan for regular follow-up — blood tests and bone marrow evaluations at defined intervals — so progression is caught as early as possible.
6. Participate in shared decision-making. The decision to treat early isn't right for everyone. Consider your age, overall health, personal preferences, and tolerance for the inconvenience and potential side effects of treatment versus the risk of progression to active disease.
7. If you're recently diagnosed, ask about clinical trials. While daratumumab is approved for active myeloma, the smoldering myeloma indication may be under regulatory review. Clinical trials may offer access to emerging treatments and contribute to advancing care for future patients.

Frequently Asked Questions

What is high-risk smoldering multiple myeloma?

Smoldering multiple myeloma is a symptom-free precursor condition with abnormal plasma cells in the bone marrow. High-risk means certain features make progression to active myeloma much more likely. In this trial, high-risk patients had at least 10% clonal plasma cells plus one or more risk factors, such as high M-protein or immunoparesis.

What is daratumumab and how does it work?

Daratumumab is a human monoclonal antibody that targets CD38, a protein found on myeloma cells. It is already approved for active multiple myeloma. In this trial, it was given as an under-the-skin injection to patients with high-risk smoldering myeloma to see if early treatment could delay or prevent progression.

What are the side effects of daratumumab?

In the trial, serious infections occurred more often with daratumumab (16.1% had grade 3 or 4 infections) than with monitoring (4.6%). Injection-site reactions were common but not severe. High blood pressure was the most common serious side effect. Two treatment-related deaths occurred, both from COVID-19.

Who could participate in the AQUILA trial?

Patients had to be 18 or older with a confirmed diagnosis of high-risk smoldering multiple myeloma within the past five years. They needed measurable disease and good overall health, and had to meet specific risk criteria, such as having at least 10% clonal plasma cells plus additional risk factors.

What should I ask my doctor about early treatment?

Ask whether you are considered high-risk and meet criteria similar to the trial. Discuss the potential benefits of daratumumab, including delayed progression and improved survival, and its risks, such as infection. Ask about subcutaneous versus intravenous administration and what monitoring plan is right for you.

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

In a phase 3 trial of 390 patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab reduced the risk of progression or death by 51% compared with active monitoring. At 5 years, 63.1% of treated patients were progression-free versus 40.8% monitored, and survival was 93.0% versus 86.9%. However, trial eligibility used older risk criteria, and only 40.5% would meet the newer Mayo 2018 high-risk definition. Side effects included more infections. A second opinion can help clarify your personal risk factors and whether early treatment is right for you. 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 details: The New England Journal of Medicine (NEJM), Volume 392, Issue 18, pages 1777-1788. Published online December 9, 2024, and updated May 8, 2025. DOI: 10.1056/NEJMoa2409029

Funding: The trial was funded by Janssen Research and Development. ClinicalTrials.gov number NCT03301220.

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace professional medical advice. Always consult your healthcare provider about your individual medical situation.