Clinical trialPhase 3Multiple myeloma

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma

N Engl J Med · 2025390 patients (194 daratumumab, 196 active monitoring)

Dimopoulos MA, Voorhees PM, Schjesvold F, et al. N Engl J Med. 2025. 392:1777-1788

Study type: Clinical trial
Study name: AQUILA
Phase: Phase 3
Design: Randomised, open-label, multicentre trial
Sample size: 390 patients (194 daratumumab, 196 active monitoring)
Source: N Engl J Med · 2025
Trial registration: NCT03301220

In plain words

"Smouldering myeloma" is a condition in which tests show myeloma cells but there is not yet any damage to the bones, kidneys or blood, and the person has no symptoms. Until now, the standard approach was just "watch and wait". This study showed that in people at high risk of progressing to active myeloma, daratumumab injections under the skin for up to 3 years roughly halve this progression and even lengthen life. Its side effects were mild. The decision to treat should be made with a specialist, based on an accurate assessment of whether the person is truly "high risk".

Key results

63.1% vs 40.8%

5-year progression-free survival

HR 0.49 (95% CI 0.36–0.67); P<0.001; median follow-up 65.2 months

93.0% vs 86.9%

5-year overall survival

HR for death 0.52 (95% CI 0.27–0.98); 15 (7.7%) vs 26 (13.3%) deaths

Drugs in this study:Lenalidomide (Revlimid)Daratumumab (Darzalex)

Dose and schedule cards

High-risk smoldering myeloma: subcutaneous daratumumab (AQUILA) or lenalidomide (E3A06)

High-risk smoldering myeloma (early treatment can be considered; EHA-EMN guideline)On the page “Multiple myeloma” · High-risk smoldering myeloma: early treatment

High-risk smoldering myeloma (early treatment can be considered; EHA-EMN guideline)

Drug	Dose	Route	Schedule
Daratumumab (AQUILA)
Subcutaneous daratumumab	1,800 mg	SC	Weekly in Weeks 1–8, every 2 weeks in Weeks 9–24, every 4 weeks from Week 25
Lenalidomide (E3A06)
Lenalidomide	25 mg once daily	Oral	Days 1–21 every 28 days

Cycle length: Daratumumab per schedule; lenalidomide every 28 days
Duration: Daratumumab: up to 39 cycles or 36 months or until progression to myeloma; lenalidomide: until progression or toxicity

Daratumumab dosing from the FDA label (AQUILA) and results from AQUILA; lenalidomide dosing from E3A06, in which thromboprophylaxis with at least aspirin, at a suggested dose of 325 mg daily, was recommended. Systemic injection-related reactions occurred in 17% of patients in AQUILA. In this setting, daratumumab is given as monotherapy, and the corticosteroid premedication differs from that used with combination regimens: methylprednisolone 100 mg or equivalent 1–3 hours before each dose (a reduction to 60 mg may be considered after the second dose) and oral methylprednisolone 20 mg for 2 days, starting the day after the injection.

On the page “Multiple myeloma” · High-risk smoldering myeloma: early treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Subcutaneous daratumumab

Daratumumab 1800 mg (co-formulated with recombinant hyaluronidase) subcutaneously: weekly in cycles 1 and 2, every 2 weeks in cycles 3 to 6, then every 4 weeks (28-day cycles), for up to 39 cycles, 36 months or confirmed disease progression, whichever occurs first.

2Active monitoring

No drug; disease assessments at the same intervals as the daratumumab group.

Source of the regimen details: ClinicalTrials.gov NCT03301220; FDA approval status from the FDA announcement (November 2025)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with high-risk smouldering multiple myeloma — the asymptomatic precursor stage of active myeloma — according to the study criteria.

Endpoints

Primary endpoint: progression-free survival; progression to active myeloma was assessed by an independent review committee according to IMWG diagnostic criteria.

Secondary endpoints: overall survival, response, time to first-line treatment and safety.

Safety and side effects

The most common grade 3 or 4 adverse event was hypertension (5.7% in the daratumumab group versus 4.6% in the monitoring group). Discontinuation due to adverse events in 5.7%; no new safety concerns were seen.

Clinical significance and place in guidelines

The first phase 3 trial to show an overall survival benefit with early treatment of high-risk smouldering myeloma. On the basis of this study, on 6 November 2025 the FDA approved subcutaneous daratumumab (Darzalex Faspro) as the first approved treatment for adults with high-risk smouldering myeloma. In guidelines, treatment of high-risk smouldering myeloma or participation in a clinical trial now replaces "watch and wait alone" for selected patients.

Limitations

The study was open-label. The definition of "high risk" in this study is not entirely the same as the models commonly used today (such as the Mayo Clinic 2/20/20 model), and some patients might be considered to have active myeloma by current criteria. The impact of early treatment on response to later treatments and its cost-effectiveness are still debated.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.