Exploring a New Era of Treatment for Smoldering Myeloma

In November of 2025, the FDA approved daratumumab and hyaluronidase (Darzalex Faspro) as treatment for high-risk smoldering myeloma.¹ This marked the first approved therapy for the condition that can progress to multiple myeloma. The choice between treatment and active surveillance is still dependent on the recognition of patients at high risk of progression, but making this option available is changing how smoldering myeloma is seen by hematologists.

During a Case-Based Roundtable event in La Jolla, California, moderator Caitlin Costello, MD, hematologist and professor of medicine at UC San Diego Health, reviewed the supporting data for the phase 3 AQUILA trial (NCT03301220) of daratumumab with participating physicians, examining how it accounted for risk stratification and balanced the adverse event (AE) profile of daratumumab with the observed survival benefit of treatment.

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Targeted Oncology: How did the AQUILA study investigate treatment for smoldering myeloma?

Caitlin Costello, MD: The AQUILA study was the third trial that was done for the treatment of smoldering myeloma, where originally…[investigators were] looking at lenalidomide [Revlimid], then [another group] added dexamethasone.^2-4 Now we're saying, what about daratumumab? The goals of all these studies have always been, how do we delay the progression? With this theoretical high likelihood of progression, is there some way we can prevent it from happening?

These patients had confirmed smoldering myeloma and they have to have been diagnosed within 5 years, which, in my mind, incorporates a variety of different patients—those patients who are on the cusp of developing something, or those [observed for] 5 years already and have proven that maybe they're not moving all that fast, and it may not ever do anything.² They looked at some different risk factors, typical for smoldering myeloma, and randomized them to daratumumab or no daratumumab. They looked at these patients after 3 years, and the primary end point was all those patients who had progression-free survival [PFS], and that was by SLiM CRAB [International Myeloma Working Group (IMWG) criteria]…but also looking at overall response rates, complete response rates, time to first-line treatment for myeloma, disease progression and death.

So we now have a trial that's looking at using daratumumab, which we previously have not had one. When you look at the patients who were treated on the trial, they're pretty typical patients of ours.¹ They have reasonably good performance status. It's the typical distribution of the types of myeloma, although the majority of them had 10% to 20% clonal plasma cells. There was another 30% or so who had 20% or more. Looking at those risk factors, the majority of them had fewer than 3 risk factors [for] progression to [multiple] myeloma. When you looked at the risk abnormalities, there were some patients who had some high-risk features, in line with what we think about for multiple myeloma, at least about 15% or so. When they looked at the different risk models in terms of thinking about if patients are low, high, intermediate risk, it was broadly even, so we had a reasonable distribution across both arms in the trial.

What were the outcomes of the trial?

When you give a disease-altering treatment to patients, it makes their—I don't even want to call it a disease—their abnormality better. Looking at these patients, their [risk of] progression or death was considerably improved after 5 years with those patients who had received active treatment vs active monitoring [HR, 0.49; 95% CI, 0.36-0.67; P <.001], and particularly in terms of the overall survival [OS], although it was not a primary end point and it was not statistically significant, there is a trend towards some difference here [HR, 0.52; 95% CI, 0.27-0.98]. But I think some of the things that were pretty impressive to a lot of people was the HR and P-values here, looking at a pretty substantial difference that was statistically meaningful for those patients who received treatment with daratumumab.

We have 5 years of follow-up, which is pretty good follow-up for us to understand how this is going to impact our patients, but if it's going to impact our patients, how is it going to do that? When you look at patients in the treatment arm, 96.9% had an AE, not surprisingly, and many of those were fatigue or upper respiratory infections—things that we commonly see with patients getting daratumumab vs those patients with active monitoring. There were still some AEs [82.7%], not to the same degree as those getting treatment. Forty percent of patients in the daratumumab group had grade 3 or 4 AEs vs with about 30% in active monitoring, and the most common serious AE was pneumonia in those patients.

How does risk stratification show which patients benefit most from daratumumab?

They looked at this because if you take asymptomatic people and you give them a treatment, you want to make sure that you are improving PFS and OS, as long as you understand what the cost of it is. This was telling us that there are AEs associated with daratumumab. The question is, are they clinically meaningful enough to help us guide our decision-making with our patients?

When this was further dug into, because, as I mentioned, patients who had 5 years of smoldering myeloma were included, and we're really trying to parse out a bit to say, can we really understand if there is a group of patients with smoldering myeloma who may benefit more from being treated than others? They tried to pull out these patients based on their IMWG risk stratification criteria and see, can we lump patients into high, intermediate, or low risk and get a better idea of if there's a group that benefits?

When you look at HRs across these different risk groups, you can see a nice HR that improves, with that high-risk group in particular [HR for PFS, 0.36].⁵ There were more data at the American Society of Hematology Annual Meeting this year that came out that said, if we are trying to think hard about who might be the right person to treat with daratumumab for smoldering myeloma, it's likely going to be those high-risk patients, particularly where we didn't see a huge improvement in patients with lower or intermediate risk.

What other treatment options could be appropriate?

The question is, would I use anything else besides daratumumab, and daratumumab technically is the only approval. Lenalidomide has been well studied but does not have that same label indication. But NCCN has them both as possibilities. There are studies to support it if lenalidomide was considered to be an option. In my opinion, I think daratumumab is probably better tolerated than lenalidomide when you're talking about 36 cycles of it.

I think if you're trying to choose one, I talk through the patients in terms of AEs of each, lifestyle, quality of life, and put that into the context of what is expected for their smoldering myeloma in terms of progression and what is expected in terms of saying that their risks are of some benefit to them in particular.

Now people are starting to say, “If one's good, why not both?” There is a lot of interest to say, what else can we do, as we do in myeloma. A [study; NCT04270409] is now looking at combining the CD38, this time with isatuximab [Sarclisa], using it in combination with lenalidomide, specifically for the high-risk group of smoldering myeloma. We're really pulling out the people we think are going to benefit the most from it. These patients received isatuximab with lenalidomide and with some steroids before then for [6] cycles, where they were treated up to 30 cycles.⁶

When they looked at these patients after 3 years, 94% of them respond when they look at the 4-year PFS, which I actually have a small problem with. PFS, I don't love that idea, because it's really time to diagnosis, which is a very different data point to me than it is time to relapse, what we're trying to compare it with. I personally would prefer to see a different kind of nomenclature at a minimum. But when you're looking at these, we know these drugs work. We know that these drugs, and particularly these drugs together, can have AEs that are hematologic in nature, where you're seeing patients get thrombocytopenia, anemia, some neutropenia; [there are] some non-hematologic [AEs], things that we're pretty well used to in terms of GI, rash, fatigue, and although there was no grade 5, there was a grade 4 neutropenia. A majority of these AEs are hematologic in nature.

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_{DISCLOSURES: Costello previously reported receiving research funding to her institution from AstraZeneca, Bristol Myers Squibb, Janssen, Takeda, Kite, Poseida, and Pfizer; and honoraria from AstraZeneca, Bristol Myers Squibb, Janssen, and Pfizer.}

REFERENCES

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

2. 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

3. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2020;38(11):1126-1137. doi:10.1200/JCO.19.01740

4. Mateos MV, Hernández MT, Salvador C, et al. Lenalidomide-dexamethasone versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A randomized, open-label study. Eur J Cancer. 2022;174:243-250. doi:10.1016/j.ejca.2022.07.030

5. Voorhees PM, Dimopoulos MA, Cohen YC, et al. Daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma: AQUILA outcomes based on Mayo 2018/IMWG 2020 risk stratification, IMWG scoring, and age. Blood. 2025;146(suppl 1):372. doi: 10.1182/blood-2025-372

6. Thomas S, Manasanch E, Jagannath S, et al. Final results of a multi-center phase 2 trial of isatuximab-lenalidomide in patients with high risk smoldering multiple myeloma (HRSMM). Blood. 2025;146(suppl 1):5834. doi:10.1182/blood-2025-5834