FDA Approval of SC Daratumumab: A Turning Point in High-Risk SMM

Smoldering multiple myeloma (SMM) is a heterogeneous precursor disease to active multiple myeloma (MM) in which risks of progression to active MM vary greatly among patients.¹ As such, the treatment approach to SMM has also historically varied among clinicians, with some advocating for earlier intervention and others opting for active monitoring and treatment upon progression to active MM.

Until November 6, 2025, there were no approved therapies for patients with SMM at high risk of progression to active MM (HR-SMM). Earlier this month, the FDA approved subcutaneous (SC) daratumumab and hyaluronidase-fihj (Darzalex Faspro), an anti-CD38 monoclonal antibody, for adults with HR-SMM^2,3—a decision that has begun to shift the SMM treatment paradigm toward earlier therapeutic intervention.

In an interview with Targeted Oncology, Peter Voorhees, MD, Hematology Department at Atrium Health Levine Cancer Institute and professor of Cancer Medicine at Wake Forest University School of Medicine, commented on the clinical significance of the phase 3 AQUILA trial (NCT03301220) that supported FDA approval, offered practical insights for risk stratification and treatment, and closed with thoughts on the evolving SMM treatment landscape.

Targeted Oncology: What gap was the AQUILA trial meant to address in the SMM treatment landscape?

Peter Voorhees, MD: At the time that AQUILA was first developed and activated, there was no clear standard of care for SMM, and there certainly were no regulatory approvals for therapy in the SMM space. We know that there is a cohort of patients with SMM who are at higher risk of progression to active disease, and when we talk about higher-risk patients, we're talking about those that have at least a 50% likelihood of developing active MM over the first 2 years of monitoring. So, there's the unmet need [of], can we intervene on these patients prior to the development of active MM and alter the trajectory of their disease in the long run?

There were 2 important randomized studies done prior to AQUILA that clearly support this path of investigation. There was the [phase 3] QUIREDEX study [NCT00480363] by the Spanish Myeloma Group that demonstrated that combination therapy with lenalidomide [Revlimid] and dexamethasone for 2 years compared [with] active monitoring was associated with a reduction in the risk of progression to active MM and actually conferred an overall survival [OS] advantage. For a number of different reasons—study design issues, lack of advanced imaging, etc—that did not go under regulatory approval, but it set the stage that this can be done in this patient population.

Then, there was the [phase 3] ECOG study [NCT01169337] led by Sagar Lonial [of Emory University], which looked at lenalidomide monotherapy without the steroid vs active monitoring for patients with SMM. [That study also] demonstrated a delay in progression to active MM for those receiving lenalidomide, and it was the patients at higher risk of progression to active MM—the patients [with HR-SMM]—that seemed to derive the most benefit.

Could you briefly summarize the trial’s key efficacy findings?

AQUILA was a study that evaluated the CD38 monoclonal antibody daratumumab [administered subcutaneously] vs active monitoring for patients [with SMM] at higher risk of progression to active MM. The patients that were assigned to the experimental arm received daratumumab monotherapy for a total of 3 years, and then active monitoring patients were monitored per standard protocol. I will point out that myeloma labs were evaluated every 12 weeks on the study until disease progression. Patients had advanced imaging done on a yearly basis with central review, and bone marrow examinations were performed at least every 2 years. So, these patients were followed very closely, regardless of which of the 2 arms they were assigned.

The primary end point of the study was progression-free survival [PFS], and I want to be clear that this is not biochemical PFS; this is PFS to active MM, per International Myeloma Working Group [IMWG] SLiM-CRAB criteria. There [were] other secondary end points like overall response rate, time to first-line treatment for active MM, PFS on first-line treatment for active MM, or PFS2, and OS.

When it comes to the primary end point, importantly, daratumumab monotherapy reduced the risk of progression of SMM to active MM by SLiM-CRAB criteria. The hazard ratio [HR] was 0.49, so you're looking at a 51% reduction in the risk of death or progression to active MM. We looked at the nature of the progressions in the 2 arms of the study—there was a reduction in the rate of progression by CRAB criteria as well as by SLiM criteria, and this was highly statistically significant. When we looked at a variety of different groups—regardless of age, cytogenetics, performance status—there was a clear improvement in PFS for patients assigned to daratumumab monotherapy.

The definition of HR-SMM has changed since the conception of this particular study, and we're now using the IMWG 20/20 criteria, which is essentially the 20/2/20 criteria that people talk about. We've looked at patients who met HR-SMM [criteria] by that more modern metric, and what we saw is that the HR for PFS is 0.36, so more rigorously defined. Patients [with HR-SMM] seem to derive the greatest degree of PFS benefit.

When we looked at time to first-line treatment for MM, for those patients on active monitoring, the median time to treatment start for active myeloma was 50 months, [and] it had not been reached for the daratumumab arm. There's a lot of interest in determining whether application of daratumumab in the smoldering space could potentially impair efficacy in a subsequent line of therapy. So, we wanted to look at [PFS] for patients receiving therapy for active MM. What we showed there is that [PFS2] was better in the daratumumab arm vs the active monitoring arm. Look[ing] 5 years out, 86% of the daratumumab patients are alive and free of progression [vs] 78% for those on active monitoring.

The formal analysis for OS has not been conducted to date because there have not been enough survival events to trigger the formal analysis, thankfully, but to ensure that the daratumumab monotherapy was safe at the time of the primary analysis for PFS, OS was [examined]. Look[ing] 5 years out, 93% of the patients in the daratumumab arm were alive vs 87% for those on active monitoring; that HR was 0.52, so it'll be interesting to see how that plays out over time.

How significant is the logistical advantage of the newly approved SC formulation over the intravenous (IV) formulation of daratumumab (Darzalex)?

I think SC daratumumab has largely replaced IV daratumumab in many parts of the world where there are no logistical barriers to administration of SC dosing. I think here in the United States, the overwhelming majority of daratumumab use in all settings has been SC, which I think has been a significant benefit to patients. So certainly, being able to receive the subcutaneously would lend itself to patient use more readily than the IV version.

Considering that the formulation is indicated for patients with HR-SMM, what steps are necessary to ensure accurate and consistent risk stratification of patients?

As I mentioned previously, the definition of [HR-SMM] has changed over time, and it's certainly likely to change again in the future. Currently, we use the 20/2/20 criteria for determining high-risk disease. If you have more than 20% involvement of your bone marrow space with myeloma, that's a point. If your M-spike is more than 2 grams per deciliter, that's a point. If your affected/unaffected serum free light-chain ratio is greater than 20, that's a point. You’re low-risk if you have 0 points, intermediate-risk if you have 1 point, and high-risk if you have 2 or 3 points, and it's that high-risk group of patients that has approximately a 50% risk of progression to active MM. That has been validated by the IMWG and a more recent retrospective cohort that was published in 2020.

While the criteria for the AQUILA study were broader than that, I think we need to apply what we know about SMM today to the results. I would suggest that anybody who meets HR-SMM by 20/2/20 criteria have a discussion with their hematologist-oncologist about the risk-benefit of receiving daratumumab monotherapy for their smoldering myeloma.

Could you describe how you would use this formulation in a real-world case?

I think that the low-hanging fruit for real-world application of this therapy is perhaps an older, frailer patient, or a patient, regardless of age, with multiple comorbidities, who has HR-SMM and would likely tolerate a triplet or quadruplet induction therapy for MM poorly. In that situation, application of daratumumab monotherapy, which is pretty easy to give from a[n adverse] effect standpoint, may delay the need, or potentially eliminate the need to receive 3- or 4-drug induction therapy for MM. I think that's the group of patients that would benefit the most, but again, I think anybody who meets criteria for HR-SMM these days should have a conversation about daratumumab monotherapy vs active monitoring.

Looking ahead, how do you see the treatment landscape for HR-SMM evolving as a result of this approval?

I think this sets the stage for future studies. There's a lot of interest in more traditional myeloma therapy for this group of patients. The ECOG is looking at lenalidomide and dexamethasone versus daratumumab, lenalidomide, and dexamethasone for HR-SMM patients, for example. T-cell redirecting therapies, both by specific antibodies and CAR T-cell therapy, are being explored in this space.

There's a lot happening at this point, so this is really just the beginning. I think it's going to be important going forward, as more patients receive treatment for HR-SMM, that they're not excluded from participation in clinical trials for active MM. In other words, if a patient who's received therapy for their SMM goes on to develop active disease later, those patients should not be deemed ineligible for participation in a frontline study for active MM.

REFERENCES

1. Abdallah NH, Lakshman A, Kumar SK, et al. Mode of progression in smoldering multiple myeloma: a study of 406 patients. Blood Cancer J. 2024;14(1). doi:10.1038/s41408-024-00980-5

2. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. US FDA. November 6, 2025. Accessed November 25, 2025. https://tinyurl.com/2vb674jn

3. DARZALEX FASPRO^® is the first and only treatment approved by the U.S. FDA for patients with high-risk smoldering multiple myeloma. November 6, 2025. Accessed November 25, 2025. https://tinyurl.com/ys5tunwv