What are the recommended tests and monitoring for Monoclonal Gammopathy of Undetermined Significance (MGUS)?

MGUS Testing and Monitoring

Risk-stratified monitoring based on the Mayo Clinic model is the cornerstone of MGUS management, with low-risk patients requiring follow-up only every 1-2 years after an initial 6-month check, while intermediate and high-risk patients need annual monitoring. 1, 2

Initial Diagnostic Workup

Essential Laboratory Tests

• Serum protein electrophoresis with immunofixation to detect and characterize the M-protein 1, 2
• Serum free light chain (FLC) analysis to assess the FLC ratio, which is critical for risk stratification 1, 2
• Quantitative immunoglobulins (IgG, IgA, IgM) 1, 2
• Complete blood count to detect cytopenias that might suggest progression 1
• Serum creatinine and calcium to exclude end-organ damage 1
• 24-hour urine collection for protein electrophoresis and immunofixation 1

When to Perform Bone Marrow Biopsy

Bone marrow examination is NOT routinely indicated for low-risk disease (IgG M-protein ≤15 g/L with normal labs and no symptoms) 1. However, bone marrow biopsy should be performed when:

• IgA M-protein is present (regardless of level) 1
• IgM M-protein is present 1
• IgG M-protein >15 g/L 1
• Light-chain MGUS with FLC ratio >10 or <0.10 1
• Any symptoms suggesting progression to myeloma, amyloidosis, or lymphoma 1

When to Perform Imaging

Skeletal imaging is NOT routinely recommended for asymptomatic patients with:

• IgG M-protein ≤15 g/L 1
• IgA M-protein ≤10 g/L 1

Imaging should be performed when:

• IgG M-protein >15 g/L or IgA M-protein >10 g/L 1
• Bone pain is present 1
• For IgG/IgA: skeletal survey (or low-dose whole-body CT as alternative) 1
• For IgM: CT scan of chest, abdomen, and pelvis to detect organomegaly and lymphadenopathy 1

Risk Stratification Using Mayo Clinic Model

All MGUS patients must be risk-stratified using the Mayo Clinic model 1, 2:

Low-Risk MGUS (5% progression at 20 years)

All three criteria must be met:

• IgG isotype 1, 2
• M-protein <15 g/L 1, 2
• Normal FLC ratio 1, 2

Intermediate-Risk MGUS

• Low-intermediate risk (21% progression at 20 years): One risk factor present 1, 2
• High-intermediate risk (37% progression at 20 years): Two risk factors present 1, 2

High-Risk MGUS (58% progression at 20 years)

All three risk factors present (non-IgG isotype, M-protein ≥15 g/L, abnormal FLC ratio) 1, 2

Follow-Up Schedule Based on Risk and Life Expectancy

For Patients with Life Expectancy ≥5 Years

Low-risk MGUS:

• Initial follow-up at 6 months 1, 2
• If stable, follow-up every 1-2 years thereafter 1, 2
• Alternative: No routine follow-up, but investigate only if symptoms develop 1

Intermediate-risk, high-risk, and light-chain MGUS:

• Initial follow-up at 6 months 1, 2
• Then annually thereafter 1, 2

For Patients with Life Expectancy <5 Years

No routine follow-up is recommended for any MGUS subtype; perform additional investigations only if symptoms suggestive of progression develop 1, 2. This applies to elderly patients or those with significant comorbidities who will likely die before MGUS progression 1.

What to Monitor at Each Follow-Up Visit

Clinical Assessment

• Careful history focusing on symptoms of multiple myeloma (bone pain, fatigue, recurrent infections), Waldenström macroglobulinemia, or AL amyloidosis (edema, dyspnea, neuropathy) 1, 2
• Physical examination emphasizing signs of progression 1, 2

Laboratory Studies at Each Visit

• M-protein quantification (serum protein electrophoresis) 1
• Complete blood count 1
• Serum creatinine 1
• Serum calcium 1

Additional Monitoring for Abnormal FLC Ratio

If the patient has an abnormal FLC ratio with elevated involved light chain, also monitor:

• NT-pro-BNP to detect cardiac light-chain deposition 1
• Urinary albumin to detect renal light-chain damage 1

When to Escalate Monitoring

If M-protein increases to ≥30 g/L and meets criteria for smoldering multiple myeloma, increase monitoring frequency to every 3-4 months 1.

Special Considerations

Osteoporosis Screening

DXA scanning should be considered, especially when other osteoporosis risk factors are present, as MGUS increases fracture risk 1. If osteopenia/osteoporosis or fractures are present, treat with bisphosphonates (alendronate or zoledronic acid) plus calcium and vitamin D supplementation 1.

No Preventive Therapy

There are currently no interventions to prevent or delay MGUS progression; any intervention should only occur within clinical trials 1, 2. Therapy should be initiated only when symptomatic disease develops 1.

Thromboprophylaxis Not Indicated

Although venous thromboembolism risk is increased, the absolute risk is low and routine thrombosis prophylaxis is not indicated 1.

Common Pitfalls to Avoid

• Do not over-investigate low-risk MGUS: Bone marrow biopsy and imaging are unnecessary for IgG M-protein ≤15 g/L with normal labs 1
• Do not under-monitor light-chain MGUS: Despite lower M-protein levels, these patients have considerable risk of renal disease and require annual follow-up 1
• Do not forget to educate patients: Instruct patients to contact their physician immediately if symptoms develop between scheduled visits 1
• Do not screen the general population: Population screening for MGUS is not recommended outside research studies 1, 2