How Has SC Daratumumab Impacted Smoldering Multiple Myeloma Treatment?

In a recent Between the Lines program, a panel of experts in hematologic oncology discussed the current state of high-risk smoldering multiple myeloma treatment following the FDA approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro) based on findings from the phase 3 AQUILA trial (NCT03301220).¹ The experts spoke about how this regulatory milestone may influence clinical decision-making for this high-risk patient population and reviewed logistical considerations for integrating subcutaneous daratumumab into real-life workflows.

The panel was led by Larry Anderson, MD, PhD, FACP, a professor in the Department of Internal Medicine and a member of the Division of Hematology and Oncology at UT Southwestern (UTSW) Medical Center, as well as the director of Myeloma, Waldenström's, and Amyloidosis Program at UTSW’s Harold C. Simmons Comprehensive Cancer Center, where he also leads the Hematologic Malignancies and Cellular Therapy Clinical Research Program. He was joined by Caitlin Costello, MD, a hematologist/medical oncologist and director of the Multiple Myeloma Program at UC San Diego Health’s Moores Cancer Center; and Laahn Foster, MD, a physician and clinical professor in the Clinical Research Division of Fred Hutch, as well as a clinical professor in the Division of Hematology and Oncology at the University of Washington School of Medicine.

What Has the High-Risk Smoldering Multiple Myeloma Landscape Looked Like?

Historically, treating patients with high-risk smoldering multiple myeloma would usually entail monitoring or using other therapies based on clinical trials that were not yet FDA-approved. The approval of subcutaneous daratumumab in November 2025, however, introduced the first commercially available intervention for this high-risk patient population, which has signaled various shifts in practice.

Foster said she has changed her practice to account for the potential use of subcutaneous daratumumab, especially among older patients who present with different comorbidities. “Those are the patients where I'm starting to think [about] using daratumumab because it'll maybe prolong their time to requiring more aggressive therapy, which they might not be eligible for by the time that they need it,” she stated.

Costello, on the other hand, expressed that her practice has yet to change in light of the FDA approval. She partly attributed this attitude to an ever-evolving conversation on how to properly define multiple myeloma. “We keep moving the goal posts a bit in terms of what we call multiple myeloma,” she said. “We have to do a better job of estimating more for our patients and doing the best we can to [identify] who the high-risk patient is. Once we've identified the high-risk patient, then we can talk about the risks and benefits of treatment.”

Although observation has existed as a historical standard in the field, Anderson noted that patients with high early progression risks in high-risk smoldering multiple myeloma may experience an increased likelihood of irreversible organ damage, reflecting the potential necessity of early intervention. Previous trials, including the phase 3 QUIREDEX study (NCT00480363) assessing lenalidomide (Revlimid) and dexamethasone, demonstrated variable efficacy and tolerability outcomes when intervening early against smoldering multiple myeloma.² These data showed that a need persisted for findings from a large, long-term, progression-free survival (PFS)–powered study to demonstrate the utility of early intervention in the field.

How Was AQUILA Designed?

The panel discussed how the high-risk smoldering multiple myeloma paradigm shifted with the phase 3 AQUILA trial, the study that supported the regulatory approval of subcutaneous daratumumab.³

The international phase 3 trial randomly assigned 390 patients with high-risk smoldering multiple myeloma to receive subcutaneous daratumumab in arm A (n = 194) or active monitoring in arm B (n = 196). Patients in Arm A received daratumumab subcutaneously plus hyaluronidase-fihj once weekly for 8 weeks, every 2 weeks for 16 subsequent weeks, and then every 4 weeks for up to 36 months.

Costello highlighted the convenience of offering daratumumab as a fixed-duration therapy. Compared with other indefinite therapies in the multiple myeloma space, she said that fixed-duration daratumumab may interfere less with patients’ lives.

Although fixed-duration therapy appears to be a “nice” option, Foster described how conversations with patients about their goals of care are necessary to determine suitable candidates for daratumumab in this setting. When weighing the risk/benefit profile of early intervention with daratumumab, she pointed to a spectrum of patients with low-risk or intermediate high-risk status who may not clearly benefit from active treatment based on the current data.

“Will this impact [a patient’s] ability to receive aggressive therapy later on? If they relapse on [daratumumab], that's a big difference in relapsing a few years later,” Anderson said. He noted that providers should “discuss with their patients” that they currently lack “long-term data on those implications.”

How Effective and Safe Was Subcutaneous Daratumumab?

Regarding the trial’s primary end point of PFS, subcutaneous daratumumab reduced the risk of progression or death by 51% compared with active monitoring (HR, 0.49; 95% CI, 0.36-0.67). In the daratumumab and monitoring arms, respectively, the 5-year PFS rates were 63.1% vs 40.8%, with early and sustained separations of the Kaplan-Meier curves demonstrating a strong delay in progression to active disease among those who received daratumumab.

The 5-year overall survival (OS) rates were 93.0% with daratumumab vs 86.9% with active monitoring, although these data were not yet mature at the time of analysis (HR, 0.52; 95% CI, 0.27-0.98). The time to first-line therapy was significantly prolonged in the daratumumab arm, as early intervention delayed symptomatic progression.

Despite the efficacy benefits observed with daratumumab in the AQUILA trial, some questions persisted among the panel regarding the agent’s utility in the smoldering multiple myeloma space. For patients who eventually relapse on the agent, choosing subsequent triplets, quadruplets, or transplant regimens may depend on the interval between initiating initial daratumumab therapy and disease progression. “If [progression] starts pretty early, I probably would continue the daratumumab and add other medications on top of it because it's more like they had active disease to begin with,” Foster said. “But if it was later on…it's a different conversation. This is how we have to start thinking about how we're going to treat these patients with prior exposure or treatment for smoldering [multiple myeloma] with daratumumab.”

The question of determining an optimal length for fixed-duration treatment with daratumumab also remained unclear. “Do you really need 3 years vs 2 years of therapy?” asked Anderson. “With this disease, are we aiming for disease control vs disease eradication? I don't think we know [yet].”

The most common grade 3 or higher adverse effects (AEs) in AQUILA included infection, which occurred in 16.1% of patients who received daratumumab vs 4.6% who underwent active monitoring. Other high-grade toxicities included hypertension in 5.7% vs approximately 2%, respectively, and pneumonia in approximately 4% vs less than 1%. Among those who received daratumumab, approximately 2% to 3% experienced grade 3 or higher infusion or injection reactions.

“This trial showed us that we can do fixed-duration [therapy]. Patients will tolerate it,” Costello concluded regarding the trial results. “It will delay the progression of smoldering [disease] to multiple myeloma when compared to doing nothing. This offers [more] opportunities for us and for our patients.”

What Does AQUILA Mean for the Future of Smoldering Multiple Myeloma?

Looking beyond the scope of the AQUILA trial and the subsequent FDA approval of subcutaneous daratumumab, the panel discussed the long-term implications of the agent’s availability in the smoldering multiple myeloma space. Subcutaneous daratumumab may offer the potential for prolonged remission, reduced anxiety surrounding the typically longer “watch-and-wait” periods, and a greater sense of control and planning around the disease’s trajectory. For providers, the new therapy may support a need for standardized high-risk smoldering multiple myeloma assessment, necessitate consistent documentation and monitoring workflows, and facilitate a shift from surveillance-only strategies to risk-benefit discussions.

An upside of the AQUILA trial and other studies assessing active intervention in smoldering multiple myeloma was affirming a “unified approach” regarding the monitoring of patients, said Costello. “There’s been different practices around frequency of monitoring, blood testing, and imaging, so physicians now have a little bit more control or understanding of what the ideal approach is to monitor these patients,” she said. “It does benefit both parties to understand how we can set expectations, how we can monitor, and how we can have the conversation about what is meaningful to the patient.”

Foster stated that daratumumab and active intervention may be fitting for those with baseline comorbidities. It would be a different conversation, however, regarding the treatment of younger patients. “For the younger patients, it's going to be [about] how much they want to do. Do they want to do some sort of treatment? Then, we will talk about the risks vs the benefits of being on some sort of therapy, and the implications down the road for other types of therapy for frontline myeloma,” she stated.

The panelists agreed that managing smoldering multiple myeloma would involve frequent and proactive discussions with patients. Given that smoldering disease is asymptomatic, a definitive decision isn’t immediately needed at a single time point. Diagnosing a patient with smoldering multiple myeloma, Costello said, is like getting “one snapshot in time”. Leading ongoing conversations with patients also affords clinicians time to trend data points.

“The AQUILA trial demonstrated meaningful benefit [with] strong PFS improvement, an emerging OS signal, and a manageable safety profile suitable for an asymptomatic population, potentially supporting a shift towards risk-adaptive early intervention, rather than watching and [waiting], for some of these patients,” Anderson concluded.

References

1. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. FDA. November 6, 2025. Accessed April 30, 2026. https://tinyurl.com/49ks5zkx
2. Mateos M-V, Hernández M-T, Giraldo G, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447. doi:10.1056/NEJMoa1300439
3. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Daratumumab or active monitoring for high-risk smoldering multiple myeloma. N Engl J Med. 2025;392(18):1777-1788. doi:10.1056/NEJMoa2409029