Smoldering myeloma (SMM) is an asymptomatic condition that represents an intermediate stage between a benign precursor state, Monoclonal Gammopathy of Undetermined Significance (MGUS), and the active blood cancer, Multiple Myeloma (MM). SMM is part of a spectrum of diseases called plasma cell dyscrasias. Patients experience no organ damage or symptoms, even though abnormal plasma cells are present. The significance of this diagnosis lies in its elevated risk of progression to active, symptomatic Multiple Myeloma, a rate substantially higher than that associated with MGUS.
The Definition of Smoldering Myeloma
Smoldering myeloma arises from the abnormal proliferation of a single clone of plasma cells within the bone marrow. Normally, plasma cells produce antibodies to fight infection, but in SMM, the clonal cells produce a large quantity of a single, non-functional antibody, known as a monoclonal protein (M-protein). This M-protein circulates in the blood or is excreted in the urine.
The defining feature of SMM is a significant tumor burden without any evidence of organ damage. Active Multiple Myeloma is diagnosed when abnormal plasma cells cause complications, known as the CRAB criteria: high Calcium levels, Renal dysfunction, Anemia, or Bone lesions. Since SMM patients lack these complications, their condition is considered pre-malignant, requiring close observation rather than immediate treatment. The annual risk of progression to active MM for a patient with SMM is estimated to be about 10%.
Specific Diagnostic Thresholds
The diagnosis of Smoldering Myeloma relies on specific laboratory thresholds. This includes a serum M-protein level of at least 3.0 grams per deciliter (g/dL) or a monoclonal protein level in the urine of at least 500 milligrams per 24 hours (mg/24h).
The percentage of clonal plasma cells found during a bone marrow biopsy is the second component. For an SMM diagnosis, the bone marrow must contain between 10% and 60% clonal plasma cells. If the percentage is less than 10%, the diagnosis is MGUS. If the percentage reaches 60% or more, the condition is immediately reclassified as active Multiple Myeloma, even without CRAB symptoms.
Assessing the Likelihood of Progression
Clinicians use risk stratification models that incorporate clinical measurements and genetic markers to categorize patients into low, intermediate, or high-risk groups based on the likelihood of progression.
A commonly used tool is the Mayo Clinic 20/2/20 model, which uses three factors to estimate risk:
- Bone marrow plasma cell percentage greater than 20% (>20%).
- Serum M-protein concentration greater than 2.0 g/dL (>2.0 g/dL).
- Involved-to-uninvolved serum free light chain ratio greater than 20 (>20).
Patients with two or more of these factors are categorized as high-risk, facing a significantly higher chance of progression within two years.
Genetic abnormalities also play a significant role in predicting progression. High-risk cytogenetic markers, such as the deletion of chromosome 17p or the translocation t(4;14), indicate an increased risk of progression. Integrating these genetic findings with clinical models creates a more precise forecast for a patient’s long-term outlook.
Strategies for Monitoring and Management
The standard approach for managing Smoldering Myeloma is “active surveillance.” This involves monitoring the patient closely to initiate treatment immediately upon progression to active Multiple Myeloma.
The frequency of monitoring depends on the patient’s risk category, as determined by stratification models. Low- or intermediate-risk patients may have monitoring intervals of four to six months for the first year, which may then be extended. High-risk patients are monitored more intensively, often every three to four months.
Monitoring involves a comprehensive set of tests:
- Serum protein electrophoresis and serum free light chain assays to track M-protein levels.
- Regular blood tests to monitor for signs of end-organ damage, such as anemia or renal insufficiency.
- Annual imaging, such as whole-body computed tomography (CT) or magnetic resonance imaging (MRI), to detect new bone lesions.
While standard care reserves treatment for progression to active myeloma, very high-risk SMM patients may be eligible for clinical trials exploring early therapeutic intervention to delay or prevent the onset of symptomatic disease.