Clinical trials have sought to determine the benefit of treating the precursors of multiple myeloma, but as the phenotypes and genomics of this entity are becoming better delineated, the wisdom of early intervention has remained confusing for clinicians. At the 2025 Debates and Didactics in Hematology and Oncology Conference, sponsored by Emory University Winship Cancer Institute, Sagar Lonial, MD, FACP, FASCO, clarified some of these issues.¹ Dr. Lonial is Professor and Chair of the Department of Hematology and Medical Oncology, the Anne and Bernard Gray Professor in Cancer, and Chief Medical Officer of the Winship Cancer Institute of Emory University, Atlanta.

Sagar Lonial, MD, FACP, FASCO

‘Somewhat Artificial’ Delineations

The challenge has always been to predict which patient is truly at risk of progressing to myeloma, noted Dr. Lonial. This is a nuanced situation, he added.

Dr. Lonial gave as an example a patient referred to him with 11% plasma cells who had been told he has myeloma based on the standard cutoff of 10%. In Dr. Lonial’s opinion, however, this patient likely has smoldering myeloma or perhaps even monoclonal gammopathy of undetermined significance (MGUS), depending upon the size of the M-spike protein. “It’s hard to be sure,” he said. “These numbers are not absolute numbers and need clinical context to be useful.”

Genomic testing now demonstrates that some patients have a normal B-cell phenotype, regardless of whether they have MGUS or smoldering myeloma, and these patients may have a long trajectory toward developing a plasma cell disorder. This 10% or so of patients “gets thrown into the mix” of the larger group with a myeloma-like phenotype who have a more aggressive natural history. “This really throws things off,” Dr. Lonial pointed out. “Just recognize that these delineations are somewhat artificial.”

“Genetically, smoldering myeloma looks almost identical to myeloma,” Dr. Lonial explained. “What differentiates smoldering myeloma from myeloma is immune control…. What we are trying to determine is among the three categories of smoldering myeloma, how to move a subset of patients out and put them in the symptomatic category.”

For those with transformed B-cell phenotypes, which are relatively indolent, a prevention strategy may be helpful. For patients with MGUS, dietary intervention or microbiome-directed approaches may someday prove to make a difference, because most of the M protein targets are lipid, and the most common source of lipid is the microbiome, he said.

New Guidelines Coming

Meanwhile, it is mandatory to identify the individual risk for each new patient who is put into the “smoldering” category and to inform the patient. To help clinicians accurately do so and to guide appropriate intervention, the International Myeloma Society and the International Myeloma Working Group (IMWG) recently convened to develop new diagnostic criteria; their guidance will be available soon.

“What I think they will come up with is use of the 20/2/20 criteria for risk stratification,” Dr. Lonial stated. As shown in the sidebar, the 20/2/20 criteria are based on the presence of > 20% plasma cells in the bone marrow, M spike protein > 2 g/dL, and free light chain ratio > 20. “It’s not perfect, but it gives you a group of patients at very high risk of progression to myeloma (ie, approximately 80% at 5 years). These patients who would be the focus of clinical trial enrollment, and for clinicians, 20/2/20 is easy to remember.”

He noted that in using the newer biomarker-driven diagnostic criteria, clinicians can easily miss a fine point: a free light chain ratio > 100 must be accompanied by a urine protein > 200 mg/dL to predict a high enough risk of disease progression to warrant intervention. “Those patients have a 70% to 80% risk of developing myeloma within 2 years and have been moved into the myeloma category,” Dr. Lonial noted.

Treating Smoldering Disease With Curative Intent

The concept of treatment with curative intent “is interesting but not currently supported by data,” Dr. Lonial remarked. “The short version of curative intent is that biochemical relapses in these trials are continuing to happen…. Patients are achieving measurable residual disease negativity but are not necessarily cured and are being exposed to considerable treatment toxicity with, in my mind, questionable long-term outcomes.”

The first study evaluating early intervention, the phase III QuiRedex trial,² showed the use of lenalidomide plus dexamethasone was superior to observation in the time to development of myeloma in high-risk smoldering disease. With 10-year follow-up, improvements are continuing to be seen in the time to myeloma, progression-free survival, and overall survival. But lacking the use of modern imaging, the trial has been subject to criticism that many control patients may have actually had myeloma, not its precursor. “The study, therefore, could have been randomizing patients with myeloma to treatment vs observation, and that’s a fair argument,” according to Dr. Lonial.

Subsequently, Dr. Lonial led the phase II/III ECOG3A06 trial of lenalidomide vs observation—without dexamethasone—which found a 90% risk reduction for the early intervention with lenalidomide.³ However, benefit was restricted to patients at highest risk. “My longest patient has been 12 years on single-agent lenalidomide for high-risk smoldering myeloma and has not progressed,” he reported.

The trial that is predicted to change the practice of smoldering myeloma is the randomized phase III AQUILA trial, which evaluated single-agent daratumumab vs observation with active monitoring.⁴ (Daratumumab is a monoclonal antibody that targets CD38.) Use of daratumumab significantly reduced the risk of progression to myeloma or death by 51% (P < .001) for all subsets and risk categories. “It was not just time to a 25% increase in the M protein; patients actually had to develop myeloma. The hazard ratio was quite striking, and overall survival also favored the daratumumab arm. Almost every subgroup and category showed a difference,” Dr. Lonial noted.

The European authorities have already approved daratumumab for treatment of high-risk smoldering disease; in May 2025, the U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee voted favorably on this treatment. “We are expecting a positive review from the FDA any day, so you should have in your pockets the ability to treat patients with high-risk smoldering myeloma,” he said.

Dr. Lonial continued: “To show you the speed of progress, only a decade ago, we had the first data on an anti-CD38 antibody in relapsed or refractory myeloma. It’s pretty much unprecedented to go from approvals in end-stage cancer to indolent precancer within just 10 years.”

Ongoing Studies

Several ongoing studies will be critical in determining the next strategies for smoldering myeloma. The phase III ECOGAA173 DETER-SMM trial is comparing daratumumab plus lenalidomide with lenalidomide plus dexamethasone in high-risk patients. The primary outcomes are overall survival and the Functional Assessment of Cancer–General score from baseline to 24 cycles of treatment. In a phase II trial of the cereblon E3 ligase modulator iberdomide with and without dexamethasone, the focus is on immune enhancement as a means of preventing disease progression; the endpoint is response by IMWG criteria.

Such clinical trials typically have concluded with the disclaimer that “more studies are needed,” but Dr. Lonial maintained that “those days are over. We’ve now got three randomized phase III trials that demonstrate a benefit for either a single agent or a single agent in combination with dexamethasone. And we will likely soon have an FDA approval of a CD38 antibody in high-risk smoldering myeloma.”

At this point, the goal in smoldering myeloma is to identify patients who already have myeloma and whose condition is too advanced for a preventive strategy. Another goal is to find those with indolent disease for whom a low-intensity prevention strategy (such as monthly daratumumab or oral lenalidomide or iberdomide) might prevent the development of CRAB criteria (calcium elevation, renal insufficiency, anemia, and bone lesions)

Meanwhile, Dr. Lonial wants clinical trials to address the question of “prevention vs cure,” but he believes “we should not continue just to wait for more data.” If a clinical trial is not an option, he suggests that patients meeting the 20/2/20 high-risk criteria should be started on treatment with daratumumab or lenalidomide. “For some patients, it’s time to move toward early intervention,” he said.

DISCLOSURE: Dr. Lonial reported financial relationships with Takeda, Amgen, Novartis, BMS, GlaxoSmithKline, AbbVie, Genentech, Pfizer, Regeneron, Janssen, and TG Therapeutics.

REFERENCES

1. Lonial SL: Smoldering multiple myeloma: What we know and where we are going. 2025 Debates and Didactics in Hematology and Oncology Annual Conference. Presented July 26, 2025.
2. Mateos MV, Hernández MT, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.
3. Lonial S, Jacobus S, Fonseca R, et al: Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol 38:1126-1137, 2020.
4. Dimopoulos MA, Voorhees PM, Schjesvold F, et al: Daratumumab or active monitoring for high-risk smoldering multiple myeloma. N Engl J Med 392:1777-1788, 2025.