The Smoldering Debate: Treat or Monitor Early Myeloma Risk?

Is it time to treat smoldering multiple myeloma as a disease in its own right? Once considered merely a precursor to multiple myeloma, this asymptomatic condition is now under fresh scrutiny. With advances in risk stratification and growing evidence supporting early intervention, experts like Binod Dhakal, MD, MS, associate professor of Medicine at the Medical College of Wisconsin, believe it’s time to reconsider the golden standard.

At the 2nd Annual HemOnc Pulse Live!, held May 2–3, 2025, in Austin, Texas, Dr. Binod Dhakal presented on smoldering myeloma, describing it as a “heterogeneous entity” and noting its relatively recent identification as a clinical category in the 1980s.

“You would argue that most of the progression might happen in the first ten years”, he explained, observing a 2007 study by Robert A Kyle, viewing the probability of SMM’s progression into MM, which potentially merited its treatment early before progression into true [MM].

The research from 2007 remains a working theory, and the choice of whether to treat or pursue the watch and wait approach is an ongoing area of contention in the field.

Rethinking “Smoldering”

Because of its heterogeneity, SMM has enough variance to merit further study. Highlighting phase 2 and 3 clinical trials, he demonstrated that the immune system is less dysfunctional in SMM, warranting comparative research between SMM and relapsed or refractory MM.

Dr.Binod Dhakal giving his presentation at the 2nd Annual HemOnc Pulse Live.

In the phase 3 QuiRedex trial of lenalidomide in combination with dexamethasone versus observation, the treatment arm showed a survival advantage. There was a significant decrease in the risk of disease progression or death (Hazard ratio [HR], 0.24, 95% CI, 0.14-0.41; P <.0001). Moreover, the over survival benefit was shown with an HR of 0.43 (95% CI, 0.21-0.92; P =.024).²

Other trials like the phase 3 AQUILA study, which assessed the use of daratumumab vs active monitoring in high-risk SMM, also shown a survival benefit.³ According to D. Dhakal, the existing research signals that there is rationale for treating SMM. In criticism, Dr. Dhaklal explained that studies on the watch and wait approach are not considering all the factors.

“They’re relying on the disease factors that [are] possibly changing over time and not the true biological risk that we cannot identify with these models,” he said.

Proactive treatment of may be the next step forward in clinical care. According to Dr. Dhakal, the potential benefit is significant: “If you go big, you could potentially cure this, and the patients won’t progress into multiple myeloma.”

Reference:

1. Dhakal Binod, et al. Smoldering Multiple Myeloma: To Treat or Not To Treat? Presented at the 2nd Annual HemOnc Pulse in Austin, TX.
2. Mateos M, Hernandez M, 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
3. Dimopoulos M, Voorhees, Schjesvold F, et al. Daratumumab or active monitoring for high-risk smoldering multiple myeloma. N Engl J Med. 2025;392:1777-1788. doi: 10.1056/NEJMoa2409029