Diagnostic Workup and Treatment Approach for Multiple Myeloma vs MGUS
The key distinction between Multiple Myeloma (MM) and Monoclonal Gammopathy of Undetermined Significance (MGUS) lies in the presence of end-organ damage (CRAB criteria) and/or specific biomarkers in MM, while MGUS requires observation only with no immediate treatment. 1
Diagnostic Criteria
MGUS Diagnostic Criteria
- Serum monoclonal protein <3 g/dL 1
- Clonal bone marrow plasma cells <10% 1
- Absence of end-organ damage (CRAB criteria) 1
Multiple Myeloma Diagnostic Criteria
- Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma 1
- Evidence of end-organ damage (CRAB criteria) 1:
- Hypercalcemia: serum calcium >11.5 mg/dL
- Renal insufficiency: serum 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, severe osteopenia, or pathologic fractures
Diagnostic Workup
Initial Laboratory Tests (for both MM and MGUS)
- Serum and urine protein electrophoresis with immunofixation 1, 2
- 24-hour urine collection for protein electrophoresis (not random sample) 2
- Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 1, 2
- Serum free light chain (FLC) assay with kappa/lambda ratio 2
- Complete blood count with differential 1, 3
- Serum chemistry including calcium, creatinine, and albumin 1, 3
- Beta-2 microglobulin and lactate dehydrogenase 3
Bone Marrow Evaluation
- For suspected MM: Bone marrow aspiration and biopsy are essential 1, 2
- For MGUS: Bone marrow examination is not routinely recommended for IgG MGUS if serum M-protein ≤15 g/L without end-organ damage 1
- Bone marrow examination should be performed for all IgA and IgM M-proteins 1
- CD138 staining to accurately determine plasma cell percentage 2
- Cytogenetic/FISH studies for risk stratification 1, 4
Imaging Studies
- For MM: Complete skeletal survey including spine, pelvis, skull, humeri, and femurs 1, 2
- For MGUS: Imaging not routinely recommended for IgG M-protein ≤15 g/L or IgA M-protein ≤10 g/L without bone pain 1
- Low-dose whole-body CT is a reasonable alternative to conventional X-rays 1, 5
- MRI is recommended when spinal cord compression is suspected or for symptomatic sites with negative skeletal survey 1, 2
- PET/CT is useful for evaluating treatment response but not recommended for routine initial diagnosis 2, 5
Treatment Approach
MGUS Management
- No immediate treatment is required 1
- Lifelong follow-up is generally advised to monitor for progression 1
- Follow-up can be optimized based on risk stratification using the Mayo Clinic model 1
- For patients with osteopenia/osteoporosis, bisphosphonates may improve bone mineral density 1
- No indication for standard thrombosis prophylaxis despite slightly increased risk 1
Multiple Myeloma Treatment
- Treatment should be initiated in all patients with active myeloma fulfilling CRAB criteria 1
- For elderly patients (non-transplant setting), oral combinations of melphalan and prednisone plus novel agents are standard of care 1
- Recommended regimens include melphalan/prednisone/thalidomide (MPT) or bortezomib/melphalan/prednisone (VMP) 1
- For younger patients, high-dose chemotherapy with autologous stem cell transplantation is standard 6, 7
- Supportive care includes bisphosphonates, thromboprophylaxis, and infection prophylaxis 3, 6
Important Distinctions and Pitfalls
- Smoldering Multiple Myeloma (SMM) represents an intermediate stage between MGUS and MM with higher risk of progression (10% per year for first 5 years) 1
- SMM criteria: Serum M-protein ≥3 g/dL and/or bone marrow plasma cells ≥10%, but no end-organ damage 1
- SMM requires closer monitoring than MGUS but immediate treatment is not currently recommended 1
- Failure to recognize progression from MGUS to MM can lead to preventable end-organ damage 4
- Unnecessary bone marrow biopsies and imaging in low-risk MGUS patients should be avoided 1
- Updated MM diagnostic criteria now include specific biomarkers even without CRAB features: bone marrow plasma cells ≥60%, serum FLC ratio ≥100 with involved FLC ≥100 mg/L, or >1 focal lesion on MRI 4