Smoldering Multiple Myeloma: Definition, Symptoms, and Treatment
What is Smoldering Multiple Myeloma?
Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma, defined by serum M-protein ≥3 g/dL and/or bone marrow clonal plasma cells ≥10%, but critically without any end-organ damage or myeloma-defining events. 1, 2
Diagnostic Criteria
SMM requires both of the following 1:
- Serum monoclonal protein (IgG or IgA) ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%
- Complete absence of CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) or other myeloma-defining events
Key Distinguishing Features
SMM sits between two other conditions in the disease spectrum 1, 3:
- MGUS (Monoclonal Gammopathy of Undetermined Significance): M-protein <3 g/dL AND bone marrow plasma cells <10%
- Active Multiple Myeloma: Presence of end-organ damage (CRAB criteria) or specific high-risk biomarkers
Natural History and Progression Risk
The progression risk is highly variable and not uniform 1, 2, 4:
- Overall progression rate: 10% per year for the first 5 years, then 3% per year for years 5-10, then 1.5% per year thereafter 1
- Low-risk patients: Median time to progression of 3-8 years 1, 2
- High-risk patients: Often progress within 1-2 years 1, 2
Symptoms
Smoldering multiple myeloma is, by definition, asymptomatic—patients have no symptoms attributable to the disease. 1, 5
This is the critical distinguishing feature from active myeloma. If any of the following symptoms or findings are present, the patient has progressed to active multiple myeloma, not SMM 1, 6:
- Hypercalcemia: Serum calcium >11.5 mg/dL or >0.25 mmol/L above upper limit of normal
- Renal insufficiency: Creatinine >2 mg/dL or creatinine clearance <40 mL/min
- Anemia: Hemoglobin <10 g/dL or >2 g/dL below lower limit of normal
- Bone lesions: Lytic lesions on skeletal imaging, severe osteopenia, or pathologic fractures
Important Clinical Pitfall
When evaluating a patient with suspected SMM, you must exclude other causes of similar laboratory findings 1:
- Anemia from other causes: Iron, B12, or folate deficiency; chronic disease; myelodysplastic syndrome
- Bone disease from other causes: Long-standing osteoporosis (especially in elderly women), benign bone cysts, bone angiomas
- Hypercalcemia from other causes: Hyperparathyroidism (check PTH levels)
- Renal disease from other causes: Diabetes, hypertension, other nephropathies
Treatment Approach
Standard Management: Observation
For most patients with smoldering multiple myeloma, the standard of care is close observation without treatment, with monitoring every 3-6 months. 1, 2, 4
This is a Category 1 recommendation from the NCCN 1. The rationale is that many patients remain stable for years, and early treatment of all SMM patients has not historically shown benefit 4, 5.
Surveillance Protocol
Initial monitoring every 3-6 months should include 1:
Blood tests:
- CBC
- Serum chemistry (creatinine, albumin, calcium)
- Serum quantitative immunoglobulins, SPEP, SIFE
- Serum free light chain (FLC) assay
- LDH and β2-microglobulin (may be useful)
Urine tests:
- 24-hour urine for total protein, UPEP, UIFE
Imaging:
- Bone survey annually or as clinically indicated
- MRI and/or CT and/or PET/CT as clinically indicated
High-Risk SMM: Consider Early Intervention
For high-risk smoldering myeloma patients, early treatment with lenalidomide plus dexamethasone has demonstrated improved time to progression and overall survival in randomized trials. 2, 4, 7, 5
Risk Stratification
High-risk features that predict rapid progression include 1, 4:
Mayo Clinic Model:
- M-protein ≥3 g/dL
- Abnormal serum free light chain ratio (outside 0.125-8.0)
- Bone marrow plasma cells ≥10%
Spanish (PETHEMA) Model:
- ≥95% phenotypically aberrant plasma cells by flow cytometry
- DNA aneuploidy
- Immunoparesis (suppression of uninvolved immunoglobulins)
Additional high-risk markers 1, 4:
- Focal lesions on MRI (30-50% of SMM patients have abnormal MRI)
- IgA M-protein type
- Urinary light chain proteinuria >50 mg/24 hours
- High plasma cell proliferative index
Treatment for High-Risk SMM
When high-risk features are present (particularly those predicting >80% progression risk at 2 years), early intervention should be considered 4, 7, 5:
- Lenalidomide plus dexamethasone for 2 years has shown significant benefit in randomized trials 2, 7
- Enrollment in clinical trials is strongly encouraged 1, 2
Critical Decision Point
The key clinical decision is distinguishing between observation versus early treatment based on risk stratification. Approximately 50% of SMM patients have true premalignancy (MGUS-like behavior) while 50% have already undergone malignant transformation and will progress rapidly 7. The goal is to identify this latter group for early intervention while sparing the former group from unnecessary treatment toxicity.
When to Initiate Active Myeloma Treatment
If progression to symptomatic myeloma occurs (development of CRAB criteria or myeloma-defining events), immediately transition to standard multiple myeloma treatment protocols. 1, 2