Smoldering multiple myeloma (SMM) has long been regarded as a middle ground in hematology, biologically aligned with multiple myeloma (MM), yet clinically silent. Patients were monitored until symptoms or end-organ damage signaled progression to active MM.
Over the past decade, however, advances in disease biology, risk stratification, imaging, and immunotherapy have fundamentally reshaped understanding of early plasma cell disorders. These developments challenge long-standing assumptions regarding the traditional “watch-and-wait” approach.
Who Is Considered High-Risk?
The introduction of formal SMM diagnostic criteria in 2003 established a framework for research and clinical care, but it also grouped together patients with markedly different biological risks.
Currently, the Mayo Clinic “20/2/20” model has gained broad acceptance because of its simplicity and clinical applicability. It incorporates three readily available clinical parameters:
- Serum M-protein ≥2 g/dL
- Involved-to-uninvolved free light chain ratio ≥20
- Bone marrow plasma cells ≥20% (high-risk: 2-3 factors)
Despite its utility, this model has important limitations. It is based on conventional clinical and laboratory features and does not capture many of the biological factors now known to influence disease behavior, including genomic alterations, immune microenvironment characteristics, and emerging blood-based biomarkers.
Going forward, risk stratification is likely to become more granular, by integrating:
- Ultra-Sensitive MRD Assessment: sensitivities approaching 10⁻⁷
- Whole-genome and single-cell sequencing: uncover high-risk genetic alterations, clonal evolutionary dynamics
- Advanced Imaging: such as whole-body diffusion-weighted MRI, PET/MRI, and emerging immuno-PET
- Immune Microenvironment Profiling: characterization of immune exhaustion, T-cell dysfunction, and other microenvironmental features
Watch more on OncoDaily TV
A Disease Category in Transition
Rather than representing a single disease entity, SMM may eventually be separated into at least two biologically distinct groups: early MM, characterized by disease biology warranting therapeutic intervention, and benign monoclonal gammopathy, characterized by stable clonal behavior and a low likelihood of ever requiring treatment.
Ultimately, the challenge is not only identifying who will progress. It is determining when biological progression becomes clinically meaningful disease and how early intervention should reshape the boundaries between precursor and active states.
The First FDA-Approved Therapy for SMM
The FDA approval of daratumumab monotherapy for high-risk SMM in 2025 marked a watershed moment. Supported by findings from the phase II CENTAURUS and phase III AQUILA studies, it became the first therapy to receive regulatory approval for patients with SMM, formally establishing early intervention as a therapeutic strategy rather than an investigational concept.
At the same time, the approval raises several important questions. Although daratumumab delayed progression, deep responses remained uncommon, with only a small proportion of patients achieving complete response and very few attaining MRD negativity.
Equally important is avoiding overtreatment. Not all patients with SMM share the same biological risk, and treating individuals with highly indolent disease may expose them to unnecessary toxicity without meaningful benefit.
Combination immunotherapy approaches may achieve deeper responses and sustained MRD negativity, potentially enabling fixed-duration treatment and long-term disease control.
Of Note
Long before the approval of daratumumab, trials such as QuiRedex and E3A06 demonstrated that lenalidomide-based therapy delayed progression to symptomatic MM, establishing proof-of-concept.
The Concept of Relapsed/Refractory SMM
The transition from observation to intervention has solved many longstanding challenges in SMM, but it has also created new ones. Most notably, it has exposed a diagnostic gray zone that current disease classifications were never designed to address. Patients may show evidence of disease progression while receiving or after completing therapy, yet still fail to meet diagnostic criteria for active MM. Conceptually, this creates a scenario that could be described as “relapsed/refractory SMM”, a category that does not formally exist, but increasingly reflects a real clinical dilemma.
How Early Is Too Early?
The prevalence of MGUS and SMM far exceeds that of MM, raising the question of whether earlier detection could improve outcomes. Studies such as the Icelandic iStopMM trial have demonstrated the feasibility of population-based screening, identifying large numbers of previously unrecognized monoclonal gammopathies and enabling earlier recognition of individuals with high-risk disease.
Several concerns continue to limit the adoption of population-wide screening, including:
- Overdiagnosis and medicalization of biologically stable disease
- Psychological burden associated with a precursor cancer diagnosis
- Increased demands on healthcare systems
- The risk of overtreatment as options become more widely available
The Next Wave of Clinical Trials
Current research is focused on how best to deliver early intervention. The phase II ERASMM trial is investigating fixed-duration elranatamab, a BCMA-targeted bispecific antibody in high risk SMM , while REVIVE is evaluating combination approaches incorporating teclistamab plus daratumumab and talquetamab plus daratumumab.
The platform-based IMMUNO-PRISM study is exploring immunotherapy-driven strategies, including teclistamab-containing regimens, in patients with high-risk disease.
Collectively, these trials aim to determine whether deeper responses, sustained MRD negativity, and treatment-free remission can be achieved before the development of symptomatic MM. They may also help answer questions regarding the optimal duration of therapy and how early treatment influences future sequencing choices if MM eventually develops.
Elranatamab in High-Risk Smoldering Myeloma: First Results From the Phase 2 ERASMM Study