Classification of Smoldering Multiple Myeloma and Low-Risk MDS
Smoldering multiple myeloma is classified as a pre-malignant condition, while low-risk myelodysplastic syndromes are considered malignancies.
Smoldering Multiple Myeloma: A Pre-Malignant Disorder
Smoldering multiple myeloma (SMM) is definitively characterized as a pre-malignant disorder with higher tumor burden and higher risk of progression compared to MGUS 1. The NCCN explicitly describes SMM as "a precursor to MM" and states it represents "a stage of disease with no symptoms and no related organ or tissue impairment" 1.
Key Distinguishing Features of SMM as Pre-Malignancy:
SMM represents a heterogeneous condition where approximately 50-67% of patients have pre-malignancy (essentially MGUS biology), while the remaining 33-50% have already undergone malignant transformation but remain asymptomatic 2, 3.
The condition is defined by ≥10% bone marrow plasma cells and/or serum M-protein ≥3 g/dL without end-organ damage (no CRAB criteria: hypercalcemia, renal insufficiency, anemia, bone lesions) 4.
Progression to active multiple myeloma occurs at varying rates (months to several years) based on risk features, with high-risk SMM progressing at approximately 10% per year in the first 5 years 1.
Clinical Implications:
The Mayo Clinic consensus explicitly states that SMM "requires only observation" and that "it is important to distinguish this presymptomatic phase from symptomatic myeloma that requires therapy" 1.
Historic management has been close observation, though high-risk SMM patients may now be candidates for early intervention 1.
Myelodysplastic Syndromes: Malignant Disorders
Low-risk MDS is classified as a malignancy, not a pre-malignancy, despite its indolent clinical course.
Evidence for MDS as Malignancy:
The WHO 2008 classification system categorizes MDS as a distinct myeloid neoplasm, placing it within the spectrum of "acute myeloid leukemia and related precursor neoplasms" 1.
MDS is characterized by clonal hematopoiesis with dysplastic changes and cytopenia, representing established malignant transformation 1.
The European LeukemiaNet explicitly refers to MDS as a "hematologic malignancy" when discussing performance status and treatment eligibility 1.
Risk Stratification Does Not Change Malignant Status:
Low-risk MDS patients (low IPSS risk with asymptomatic cytopenia) do not require immediate treatment and can be followed with watchful waiting, but this observation strategy does not reclassify the condition as pre-malignant 1.
The NCCN distinguishes MDS from pre-malignant conditions like CHIP (clonal hematopoiesis of indeterminate potential) and CCUS (clonal cytopenia of unknown significance), which lack the dysplastic morphology that defines MDS 1.
Critical Distinctions to Avoid Confusion:
The key difference is that SMM lacks end-organ damage and represents a transitional state where malignant transformation may or may not have occurred biologically, while MDS represents established clonal malignancy with dysplastic morphology, regardless of risk category 1.
In SMM, the absence of CRAB criteria is definitional and distinguishes it from active myeloma 4.
In MDS, the presence of dysplasia in ≥10% of cells in one or more lineages confirms malignant transformation, even in low-risk disease 1.
Treatment decisions in both conditions are based on risk stratification and symptom burden, but this does not alter their fundamental classification as pre-malignancy (SMM) versus malignancy (MDS) 1, 2.