The Questions Are Just Beginning as Smoldering Myeloma Enters a New Era: Peter Voorhees, MD

The management of smoldering multiple myeloma (MM) is undergoing a significant transformation, driven by growing evidence that early intervention can meaningfully delay progression to active disease. On November 6, 2025, the FDA approved daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech Inc) as a subcutaneous monotherapy for high-risk smoldering MM based on results from the phase 3 AQUILA trial (NCT03301220), marking the first regulatory-approved therapy specifically for this population.¹

AQUILA enrolled 390 high-risk patients randomized 1:1 to active monitoring or treatment for up to 36 months. The median progression-free survival (PFS) in the active monitoring arm was 41.5 months and not reached in the daratumumab arm. Patients treated with daratumumab and hyaluronidase-fihj experienced a 51% reduced mortality risk vs active monitoring, and the overall response rate was 60%—double that previously seen in relapsed/refractory MM.¹

Following the approval, The American Journal of Managed Care^® (AJMC^®) spoke with Peter Voorhees, MD, hematologist, Medical Oncology, Atrium Health Levine Cancer Institute. Voorhees spoke to the hope this new regimen offers patients, the importance of risk stratification in treating this hematologic cancer, and the increasing evidence to support early intervention.

Here is his interview in its entirety, along with new insight from Voorhees as he looks beyond this approval to the future of clinical trials and treatment guidance.

This interview has been lightly edited for clarity.

AJMC: For those less familiar with the phase 3 AQUILA trial, can you summarize the key aspects of its design, including the patient population and end points of interests?

Voorhees: We have precursor MM, which is MGUS, or monoclonal gammopathy of undetermined significance, and then we have full-fledged active MM as defined by the International Myeloma Working Group’s [IMWG] SLiM-CRAB Criteria. Then, nestled in the middle you’ve got this group of patients with smoldering MM who have MM but they don’t have any related end-organ damage, nor do they have any SLiM criteria that would suggest that they’re at risk of imminent progression to active MM. It’s in that group of patients, in particular those in the smoldering MM space, who are at increased risk of progression to active MM, where there is an intense amount of interest in developing treatment strategies to potentially change the natural history of this particular entity.

AQUILA was a randomized phase 3 study that took patients with smoldering MM who are considered to be at higher risk of progression to active MM. This included anyone who had at least 10% clonal plasma cells in their bone marrow and met one of the following criteria: either an M spike that was 3 g/dL or higher; if they had an immunoglobulin-A isotype smoldering MM; if they had immunoparesis, as defined by reduction in 2 of the uninvolved immunoglobulin isotypes; if their involved-to- uninvolved free light chain ratio was greater than or equal to 8 but still less than 100; or if they had clonal plasma cells in their marrow representing over 50% but less than 60% of the bone marrow space.

These individuals were randomly assigned to either active monitoring, which to date has been the standard of care, vs the CD38 monoclonal antibody daratumumab administered at the usual dose and scheduled out to 3 years.¹ The primary end point of this study was PFS. This is not PFS in the usual sense of the word, which is simply a biochemical progression of the disease; this is progression to active MM, again defined by the IMWG’s SLiM-CRAB Criteria. Biochemical progression of disease did not constitute PFS in this particular study. Other secondary end points included response, depth of response, overall survival [OS], PFS on first-line treatment for active MM, and time to first-line treatment for active MM.

I think one of the key things that's important to point out here, which is probably a bit unique relative to real-world practice, is that these patients were monitored very intensely, given that they're in a randomized phase 3 registrational study. Each patient received annual imaging, which consisted of both a CT of the whole body, low-dose, or a whole-body PET CT in addition to MRI imaging. They had marrows done every 2 years, and they had serologic assessments of their disease status every 3 cycles or every 12 weeks. These patients were followed very closely through the course of the study.

AJMC: Were there any findings from AQUILA that surprised you, or did the results largely align with what clinicians and investigators were hoping to see in this high-risk smoldering population?

Voorhees: I don't necessarily think that there was anything that was all that surprising, to be honest with you. We know that the CD38 antibodies are very active in MM. We figured that daratumumab monotherapy would perform better in patients with smoldering MM compared with those who have relapsed/refractory disease.

In the original study that led to initial approval of daratumumab back in 2015, the response rates in that relapsed/refractory group of patients was 30%. In the smoldering MM space, it was double that; it was 60%, which is not surprising.² Also not surprising is the fact that the daratumumab arm did better with regard to progression to active MM relative to the active monitoring arm. If you look at the control arm, the active monitoring arm, the median PFS was 41.5 months, and in the daratumumab arm, it was not reached. Also not surprising is the fact that time to first treatment for active MM was longer for patients receiving daratumumab compared with those who underwent active monitoring. When we look at PFS 2, which is progression on their first treatment for active MM, the patients who were assigned to the daratumumab monotherapy arm outperformed the active monitoring arm.

I suppose one thing that perhaps was a bit intriguing—I don't know surprising or not, but certainly intriguing—were the OS data. I want to be clear that the formal analysis for OS has yet to occur. There have not been enough survival events to occur to trigger the formal analysis for OS. That said, OS needed to be looked at at the time of the primary analysis of PFS to ensure that there's no untoward safety signals with daratumumab in this patient population. When you look 5 years out at the 60-month mark, 93% of the patients on the daratumumab arm were alive in contrast to 86.9% for those in the active monitoring arm. The HR there was 0.52, and the 95% CI extended out to 0.98; it did not cross 1.

This is an intriguing signal that there may actually be an OS advantage with the use of daratumumab, but again that requires confirmation at the time of the formal analysis for overall survival.

AJMC: Given the significant improvements in PFS and delayed need for frontline therapy see in AQUILA, how should clinicians balance the potential benefits of early intervention with concerns about overtreatment in an otherwise asymptomatic population?

Voorhees: At the time that this study was initially conducted, we had yet to implement the Mayo 2018 criteria for defining high-risk smoldering MM, which has since been validated by the IMWG and now goes by the IMWG 2020 criteria. We did a post hoc analysis applying modern definitions of high-risk smoldering MM to the patients who were enrolled in this study. IMWG 2020 is commonly known as the 20-2-20 criteria. If you have more than 20% involvement of your bone marrow space with myeloma, that's a point. If you have an M-spike that's greater than 2 g/dL, that gets you a point. If you have an affected-to-unaffected free light chain ratio of greater than 20, that gets you a point. You are considered at higher risk of progression to active MM if you have 2 or more of those risk factors. Approximately 50% of those patients with smoldering MM will go on to develop active disease over a 2-year time frame.

We went and we looked at that particular group of patients, and I think what's really important to recognize there is that the PFS was even more clear in that group of patients than it was in those who were considered at lower risk of progression to active MM and those who were at intermediate risk. Here, the HR for PFS was 0.36, and importantly, in the active monitoring arm, the median PFS was 22.1 months, which is awfully close to 2 years, which is exactly what we would expect based on the risk stratification of IMWG 2020.

I think it's important that you carefully dissect out those who truly have high-risk disease, and using more modern criteria for defining high-risk smoldering MM is important. We certainly have to acknowledge that that will probably continue to evolve over the course of time.

I think the other question that folks have is, if someone is exposed to daratumumab in the smoldering MM space, what impact is that going to have on efficacy of treatment for those who do go on to [be treated] for active MM? We have limited data in that particular space currently. What little data that we have look promising thus far, but I think it's an open question. I think we need to see more events occur. We need to see how patients do on CD38-based triplets and quadruplets who have received daratumumab in the smoldering space, and it's certainly something that we have to discuss with our patients. But certainly, for a patient with significant comorbidities who might make a 3-drug or a 4-drug therapy for active MM difficult, daratumumab monotherapy is a fairly gentle way of trying to reduce or delay time to progression to active MM, and for older patients, potentially obviate the need for any active myeloma therapy at all.

AJMC: How does the FDA’s approval of daratumumab and hyaluronidase-fihj challenge or redefine the traditional shift “watch-and-wait” strategy for high-risk smoldering MM, and how should clinicians approach patient selection for early treatment?

Voorhees: Although active monitoring has historically been the standard of care, we have 2 previous randomized studies that strongly indicated a benefit with early intervention for those with smoldering MM at higher risk of progression to active disease. We have the QuiRedex study from the Spanish Myeloma Group that really paved the way for evaluation of intervention in this patient population, which demonstrated a PFS and OS advantage with the use of lenalidomide and dexamethasone in this patient population.³ We've got the Eastern Cooperative Oncology Group study that was led by Sagar Lonial, MD, FACP, FASCO, [of Winship Cancer Institute of Emory University], which showed a PFS survival advantage with the use of lenalidomide monotherapy for patients at higher risk of progression to active MM.⁴

And now we have a registrational study, a phase 3 study with daratumumab monotherapy, demonstrating an improvement in PFS and an early signal of favorable OS advantage as well. I think this tells us that active monitoring is something that you certainly still need to talk to your patients about, but you also need to let them know that there are treatments available for patients with smoldering MM at higher risk for progression to active MM.

You simply just have to review the advantages and disadvantages to the approaches that are available. Really, it's a shared decision-making model that we have to follow, and we're trying to help patients navigate this complicated space. But this is the first regulatory- approved therapy in smoldering MM, so this changes things, I think, in a fundamental way going forward, and I think as we do additional studies in smoldering MM, there's no possible way that you can have a control arm now that is active monitoring.

I think daratumumab is now a standard of care, and it'll be important to see if we can build on that standard of care. Is multidrug kind of traditional myeloma therapy a better way to go in this group of patients? Is there a role for immunotherapy, T-cell–redirecting therapy in this group of patients? I think that that remains to be determined, but daratumumab now is an important standard of care for this group of patients.

AJMC: Looking ahead, how might this approval shape future clinical trial design or inform updates to treatment guidelines, particularly around risk stratification and timing of intervention?

Voorhees: With regard to the guidelines questions, since these data were initially presented and then published in The New England Journal of Medicine, the National Comprehensive Cancer Network has adopted daratumumab as a standard -of-care choice for smoldering MM at higher risk of progression to active MM, and that was a category 1 recommendation.⁵ I think that the FDA approval further solidifies that decision that the committee made, and we'll certainly see daratumumab monotherapy introduced into other guidelines from myeloma authorities across the world.

In that regard, I think, as far as studies are concerned, I'm going to make a couple of different points here. First off, we are going to see patients opt to receive daratumumab if they have smoldering MM that's at higher risk of progression to active MM. I think as a myeloma community, we have to be absolutely sure that these patients are not barred from participation in clinical trials for frontline therapy in the active MM space. A decision to treat their smoldering MM should not negate their ability to get on a clinical trial subsequently. I think that that's going to be incredibly important.

As I mentioned before, daratumumab now is a standard-of-care treatment for high-risk smoldering MM, and I think any randomized studies going forward are going to need to go head-to-head against daratumumab to show an advantage over it. There's a lot of thoughts in this space. Again, multiagent myeloma therapy, is it better than daratumumab? I think it remains to be seen. Very provocative early data with bispecific antibodies and with chimeric antigen receptor [CAR] T-cell therapy in this group of patients. What does that look like compared with daratumumab? I think a lot of us would expect that the bispecific antibodies and CAR T-cell therapy, as well as the multiagent myeloma regimens, would outperform daratumumab model therapy. But is the adverse effect profile acceptable in this group of patients?

There are a lot of questions that still need to be answered, but this changes the standard of care and the control arms for those studies going forward.

I think with progress always comes new questions. Getting to your point of over treatment, how can we refine the criteria for high-risk smoldering MM such that we do not inadvertently expose a large number of patients to therapy prematurely. Is there a group of patients in this cohort of patients with higher-risk smoldering MM who are biologically active patients and would benefit more from a multidrug combination as opposed to daratumumab monotherapy?

There are all of these questions that now we need to think about going forward as a myeloma community, but I think this really sets the stage for therapeutic trials in smoldering MM. This should remain an area of active investigation for many years ahead.

References

1. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. for the AQUILA Investigators. Daratumumab or active monitoring for high-risk smoldering multiple myeloma. N Engl J Med. 2025;392(18):1777-1788. doi: 10.1056/NEJMoa2409029. Erratum in: N Engl J Med. 2026 Apr 9;394(14):1456. doi: 10.1056/NEJMx250006.
2. Dimopoulos MA, Oriol A, Nahi H, et al for the POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi: 10.1056/NEJMoa1607751
3. 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.
4. 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
5. Kumar SK, Callander NS, Adekola K, et al. NCCN Guidelines® Insights: multiple myeloma, version 1.2025. J Natl Compr Canc Netw. 2025;23(5): 132-140. doi:10.6004/jnccn.2025.0023