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Although the FDA approval of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) offers a treatment option for patients with high-risk smoldering multiple myeloma, the decision to start treatment ahead of active multiple myeloma must happen after an informed discussion with patients, according to Peter Voorhees, MD.

On November 6, 2025, subcutaneous daratumumab was approved by the FDA as a treatment for patients with high-risk smoldering multiple myeloma after results from the phase 3 AQUILA trial (NCT03301220) supported the approval.^1,2 Data from the trial showed patients in the daratumumab arm experienced an improvement in progression-free survival (PFS; HR, 0.49; 95% CI, 0.36-0.67; P < .0001). Patients in the daratumumab monotherapy arm (n = 194) achieved a median PFS that was not reached vs 41.5 months for those who underwent active monitoring.

“This [FDA approval] is a critical first step, but there are a lot of questions that remain. Is there a more aggressive strategy or preferred approach for patients vs daratumumab monotherapy? We are going to have to do randomized studies to show whether that is the case ,” Voorhees, a professor of cancer medicine at the Wake Forest University School of Medicine in Charlotte, North Carolina, and member of the Hematology Department at Atrium Health Levine Cancer Institute, said in an interview with OncLive^®. “It is a really exciting space, and it will be really interesting to see how this evolves in the years ahead.”

In the interview, Voorhees expanded on how the FDA’s approval might change treatment processes for patients with high-risk smoldering multiple myeloma and indicated the significance of the regulatory decision, in addition to addressing the trial itself, along with its common criticisms.

OncLive: What is the significance of the FDA approval of subcutaneous daratumumab in high-risk smoldering multiple myeloma?

Voorhees: There certainly has always been an interest in treating patients with high-risk smoldering multiple myeloma who are at higher risk of progression to active myeloma. [AQUILA] is not the first study that has looked at potential therapeutic interventions in this space, [such as] studies looking at lenalidomide [Revlimid] and dexamethasone vs observation for patients at higher risk for progression to active multiple myeloma.

However, with advances in imaging, study sizes, and other factors, this [topic] has been something that has been of interest for many years. AQUILA is the first larger phase 3 randomized study that was rigorously conducted with advanced imaging techniques to show a benefit regarding PFS of the patient population.

How was the high-risk smoldering multiple myeloma defined for enrollment in the AQUILA trial?

The definition of high-risk smoldering multiple myeloma has evolved over time, and there are several different ways of defining [the term]. In the AQUILA study, the definition of [high-risk smoldering multiple myeloma] was the following; patients had to have at least 10% clonal plasma cells found in bone marrow and 1 of the following: a 30 g/dL or higher, IgA-type smoldering multiple myeloma, evidence of immunoparesis defined as reduction with 2 of the uninvolved immunoglobulin isotypes, affected to unaffected serum free light chain ratio of 8 or higher but less than 100, and clonal plasma cells in bone marrow of more than 50% but less than 60%.

Any one of those things [listed], plus at least 10% involvement of bone marrow space with myeloma, met criteria [in the AQUILA trial] for high-risk smoldering multiple myeloma. Understandably, one of the criticisms of the [AQUILA] study was that the trial had a heterogenous patient population, and that not all patients met the current 2020 International Myeloma Working Group [IMWG] definition of high-risk smoldering multiple myeloma.

A post-hoc analysis as part of the initial presentation and publication looking at the patients [in the AQUILA] trial that specifically met high-risk smoldering multiple myeloma by IMWG 2020 criteria. [The analysis] showed that there was a clear improvement in PFS with daratumumab monotherapy vs active monitoring. In fact, the magnitude of benefit in this patient population was higher than what was observed in the other groups [of the trial], which lends support to the fact that patients with high-risk smoldering multiple myeloma benefit more from intervention as opposed to patients with lower- or intermediate-risk smoldering multiple myeloma.

It should be noted that improvement in PFS was not [defined as] just a change in numbers; patients [in the AQUILA trial] had to meet criteria for active multiple myeloma to be considered to have disease progression. These were patients who met active multiple myeloma criteria by SLiM-CRAB criteria.

What were the key takeaways from the AQUILA trial that helped obtain FDA approval for high-risk smoldering multiple myeloma populations?

The primary end point of the [AQUILA] study was to look at PFS, which was progression to active multiple myeloma by IMWG SLiM-CRAB criteria. When looking at how patients were progressing to active multiple myeloma, daratumumab did reduce the risk of progression. When looking at different subsets of patients, PFS was improved [with daratumumab] regardless of age or renal function. We also saw a reduction in the risk of time to first-line treatment [for active multiple myeloma]. For patients who were assigned to active monitoring, first-line treatment for active myeloma [started in 53.6%] of patients [at 5 years] vs [29.7% of patients in the daratumumab arm], with a HR of 0.46 [95% CI, 0.33-0.62].

We also looked at PFS2, which was time to progression on patient’s first-line therapy for active multiple myeloma, and there was an advantage with regard to PFS2 in the daratumumab arm vs the active monitoring arm. We also looked at OS, but formal analysis of OS has yet to be conducted because there have not been enough events yet to formally flip the switch for the analysis. At the time of the primary analysis for PFS, 93% of patients in the daratumumab were alive [at 5 years] as opposed to 86.9% of patients in the active monitoring arm [HR, 0.52; 95% CI, 0.27-0.98].

Other important data we were really interested in with this patient population was toxicity of therapy, quality of life, and patient-reported outcomes, considering how [patients with] high-risk smoldering multiple myeloma are largely asymptomatic or minimally symptomatic from their underlying disease. We found that there was no degradation in health-related quality of life; in fact, there was numerically improved numbers in the daratumumab arm vs the active monitoring arm. The adverse effects of [daratumumab] were largely restricted to a slightly increased risk of infection and were very manageable without degrading [patient] quality of life in any way.

How are daratumumab treatment decisions being approached in clinic after FDA approval?

The first thing is that the current criteria should be applied for high-risk smoldering multiple myeloma; a discussion should be undertaken with any patient who has high-risk smoldering multiple myeloma as defined by the current IMWG 2020 criteria. [This discussion] is nuanced, as we clearly have data that support daratumumab monotherapy in the [high-risk smoldering multiple myeloma] patient population, in addition to a signal of improved OS, and patients need to know about that. Patients also need to know about the AEs: there is a slight risk of infection, albeit relatively small. In general, the safety of daratumumab monotherapy was quite good, relatively speaking. Patients need to understand the nuances of their decision, and if they pursue daratumumab monotherapy in the high-risk smoldering multiple myeloma space, what implications does that [decision] have if they develop active multiple myeloma? For example, is [developing active multiple myeloma] going to exclude them from a clinical trial?

It is important for industry to acknowledge the fact that we got a regulatory approval of therapy in the high-risk smoldering multiple myeloma space, and they need to allow patients to enroll in studies, even if it means [clinicians] have to stratify in randomized studies based on prior therapies for high-risk smoldering multiple myeloma.

One of the other critiques that has been leveled against the [AQUILA] study, which I think is largely reflective of the time frame in which the study was conducted, was that there are not a lot of patients as of yet who have progressed to active multiple myeloma who have received CD38 antibody-based induction therapies. What are the implications of giving [patients] 3 years of daratumumab monotherapy before a CD38-based regimen for frontline active multiple myeloma therapy? We do not know the full answer to that [question], and patients need to recognize that as they are making their decisions.

While this conversation [about daratumumab] should be had with any patient with high-risk smoldering multiple myeloma, the ideal patient is an older patient with comorbidities that would not be able to tolerate a triplet or quadruplet-based therapy well. [These types of patients] might benefit the most from daratumumab monotherapy and delay that progression to active multiple myeloma, potentially putting them in a space where they never have to discuss triplet or quadruplet induction therapy for their disease.

References

1. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. FDA. November 6, 2025. Accessed November 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-high-risk-smoldering-multiple-myeloma
2. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Phase 3 randomized study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma: primary results of the Aquila study. Blood. 2024;144(supplement 1):773. doi:10.1182/blood-2024-201057