Rethinking the Risk: Evolving Strategies for High-Risk Smoldering Myeloma at SOHO 2025

Dr Saad Usmani, chief of the myeloma service at Memorial Sloan Kettering Cancer Center, explores the evolving debate on early intervention for high-risk smoldering multiple myeloma, highlighting pivotal trial data and its potential to reshape clinical practice at SOHO 2025.

Saad Z. Usmani, MD: My name is Saad Usmani. I'm the chief of the myeloma service at Memorial Sloan Kettering Cancer Center.

Can you provide an overview of your SOHO 2025 session?

Dr Usmani: For the longest time, we've had this watch-and-wait approach for smoldering multiple myeloma (SMM). More recently, we've been recognizing that, within the smoldering myeloma subset of patients, there are patients who might be at a higher chance of progressing to active disease requiring intervention. The debate has been whether to go ahead and intervene in those patients.

In our session, we're going to be talking about some of those data, both with a control-the-disease approach as well as the potential for curative intent.

What do you see as the most clinically meaningful developments in the management of high-risk smoldering myeloma, and how close are we to seeing these influence standard practice?

Dr Usmani: We now have 3 randomized phase 3 studies that are showing that intervening in the high-risk smoldering myeloma setting, specifically, can delay the progression to active disease and actually may even show some overall survival benefit.

These 3 clinical trials, which include lenalidomide-based treatment with or without steroids compared to observation, were done in different eras, and there is always going to be a critique around some of the workup that was done during that time. Imaging back in the late 2000s and early 2010s was not as robust as it is now, with the use of PET-CTs and whole-body MRIs. The other critique has been the definition of high-risk smoldering myeloma. The third trial, the AQUILA trial, looked at subcutaneous formulation of daratumumab being given to patients for a fixed duration of time compared to observation.

These trials show that intervening early provides not just delayed progression to active myeloma, but may actually provide overall survival benefits. The debate is becoming more and more heated now on whether to intervene in this subset of patients as we do with active myeloma, or whether a single mechanism of action is the way to go. Nevertheless, I think this is something that we are going to be discussing in our session and see whether these clinical trials lay the foundation to change clinical practice.

Of course, the big elephant in the room is the regulatory approval of this large study of subcutaneous daratumumab compared to observation. We are all waiting to hear from the regulatory authorities around it.

One of the biggest debates in SMM is whether to intervene early or wait for progression. How does the latest evidence help refine that risk–benefit balance?

Dr Usmani: You have to understand that smoldering myeloma is a very heterogeneous group of patients. The way that these clinical trials have been conducted, they've incorporated patients with smoldering myeloma who may be either at an intermediate or high risk of progression.

One key distinction is: which subset of patients benefits the most? It's probably going to be the high-risk smoldering myeloma subset, where 5 to 6 out of 10 patients will be at a high chance of developing active myeloma. Why wait for those patients to develop end organ damage and not treat them early?

The second piece is that risk-benefit balance. Do you treat like they have active myeloma? Do you treat with one drug only and aim to delay progression? What might be the biologic implications of such an intervention? All of those are topics that we are going to touch upon in the SOHO session.

Is there anything else you hope audiences will take away from your session?

Dr Usmani: The key message that the audience will likely take away from the session is that this is an evolving field. However, there is a growing consensus that we probably need to identify that subset where we can intervene and should intervene.

We have better genomic and immunologic tools to hone in on that group. There is good biological evidence in that favor. We are heading in that direction. I think there will be more uniformity in how we define high-risk smoldering myeloma in the new phase of clinical trials that are going to be coming. Eventually, I think there will be a growing consensus around intervening in those groups, even as standard of care.