What is smoldering myeloma?

Smoldering Myeloma: Definition and Clinical Characteristics

Smoldering myeloma (SMM) is an asymptomatic precursor stage to multiple myeloma characterized 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 (no CRAB criteria: hypercalcemia, renal insufficiency, anemia, or bone lesions). 1

Diagnostic Criteria

The International Myeloma Working Group (IMWG) established consensus criteria in 2003 that define SMM based on specific laboratory thresholds without clinical manifestations 1:

Laboratory Requirements:

• Serum M-protein ≥3 g/dL (must be IgG or IgA subtype) and/or 1
• Bone marrow clonal plasma cells ≥10% 1

Critical Exclusion Criteria:

• No hypercalcemia (serum calcium must be ≤11.5 mg/dL) 2
• No renal insufficiency (creatinine must be <2 mg/dL or creatinine clearance >40 mL/min) 2
• No anemia (hemoglobin must be ≥10 g/dL or within 2 g/dL of normal) 2
• No bone lesions (no lytic lesions, severe osteopenia, or pathologic fractures) 2

Distinguishing SMM from Related Conditions

SMM occupies an intermediate position between MGUS and symptomatic multiple myeloma 1:

• MGUS: M-protein <3 g/dL AND bone marrow plasma cells <10% AND no end-organ damage 1, 2
• SMM: M-protein ≥3 g/dL and/or bone marrow plasma cells ≥10% BUT no end-organ damage 1, 2
• Symptomatic Multiple Myeloma: M-protein ≥3 g/dL and/or bone marrow plasma cells ≥10% WITH end-organ damage present 1

Clinical Significance and Natural History

SMM represents a heterogeneous condition with variable progression risk—patients may remain stable for years or progress to symptomatic myeloma within months 1. The median age at diagnosis ranges from 65-70 years, and SMM accounts for 10-15% of all multiple myeloma cases 1.

The risk of progression to active myeloma is lifelong but varies dramatically based on risk stratification 1:

• Low-risk patients may have median time to progression of 3-8 years 1
• High-risk patients often progress within 1-2 years 1

Important Diagnostic Caveats

Clinicians must carefully distinguish true end-organ damage from unrelated comorbidities in elderly patients 1:

• Mild creatinine elevation may be due to diabetes or hypertension, not myeloma 1
• Anemia may result from iron deficiency, B12/folate deficiency, chronic disease, or myelodysplastic syndrome 1
• Longstanding progressive osteoporosis argues against symptomatic myeloma, while sudden onset suggests active disease 1
• Hypercalcemia with stable levels may indicate hyperparathyroidism rather than myeloma 1

Management Approach

The standard of care for most SMM patients is close observation without treatment 1. Patients should be monitored every 3-6 months initially 1.

However, high-risk SMM patients may benefit from early intervention with lenalidomide and dexamethasone 1. The NCCN guidelines note that early treatment in high-risk patients has demonstrated improved time to progression and overall survival in randomized trials 1.

The key clinical challenge is identifying which patients are truly high-risk and warrant early treatment versus observation 1. Risk stratification tools include serum free light chain ratio, percentage of bone marrow plasma cells, M-protein level, and advanced imaging findings 1.