What is the appropriate diagnostic workup and treatment approach for a patient presenting with symptoms suggestive of multiple myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS)?

Diagnostic Workup and Symptom Assessment for Multiple Myeloma and MGUS

For patients with suspected plasma cell disorders, immediately order serum protein electrophoresis with immunofixation, serum free light chain assay, complete blood count, comprehensive metabolic panel (including calcium and creatinine), and quantitative immunoglobulins (IgG, IgA, IgM) as the initial screening battery. 1, 2

Initial Clinical Presentation and Symptoms to Assess

Key Symptoms Requiring Immediate Evaluation

• Bone pain that worsens at night or with movement, particularly in the back, ribs, or long bones 3, 2
• Unexplained anemia (present in 73% of MM patients at diagnosis) manifesting as fatigue, weakness, or malaise 2, 3
• Renal dysfunction (19% have acute kidney injury at diagnosis) 2
• Recurrent infections due to immunoparesis 3
• Hypercalcemia symptoms including nausea, vomiting, confusion, or polyuria 3
• Weight loss and general constitutional symptoms 3

Critical Physical Examination Findings

• Assess for focal bone tenderness over spine, ribs, sternum, or long bones 1
• Evaluate for signs of spinal cord compression (weakness, sensory changes, bowel/bladder dysfunction) requiring immediate intervention 4
• Check for signs of hyperviscosity if IgM paraprotein present (visual changes, bleeding, neurologic symptoms) 1
• Look for peripheral neuropathy (numbness, tingling) which may indicate AL amyloidosis 1

Diagnostic Laboratory Workup Algorithm

Mandatory Initial Blood Tests

• Serum protein electrophoresis with immunofixation to identify and characterize monoclonal protein 1, 2
• Serum free light chain (FLC) assay with kappa/lambda ratio (abnormal ratio suggests clonal process) 1, 2
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 1, 2
• Complete blood count to assess for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal) 1, 2
• Comprehensive metabolic panel including:
  • Serum calcium (>11.5 mg/dL indicates hypercalcemia) 2
  • Serum creatinine (>2 mg/dL or clearance <40 mL/min indicates renal insufficiency) 2
  • Albumin and total protein 1
• Beta-2 microglobulin for prognostic stratification 1, 2

Mandatory Initial Urine Tests

• 24-hour urine collection (not random sample) for protein electrophoresis and immunofixation to detect Bence Jones protein 1, 2
• 24-hour urine total protein quantification 1

Bone Marrow Examination Decision Algorithm

When Bone Marrow Biopsy is MANDATORY

• Any patient with M-protein present AND any CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) 1, 2
• IgA M-protein at any level 2
• IgM M-protein at any level 2
• IgG M-protein >15 g/L 1
• Abnormal free light chain ratio >10 or <0.10 even without other symptoms 1

When Bone Marrow Biopsy Can Be DEFERRED

• IgG M-protein ≤15 g/L with ALL of the following: 1
  • Normal history and physical examination
  • Normal calcium, creatinine, and complete blood count
  • No symptoms suggesting myeloma, AL amyloidosis, or lymphoma
• Patients with limited life expectancy due to advanced age or severe comorbidities 1

Bone Marrow Examination Components When Performed

• Aspiration and biopsy for plasma cell percentage (≥10% required for MM diagnosis) 1, 2
• CD138 staining to accurately quantify plasma cell percentage 1, 2
• FISH cytogenetics for risk stratification: del(17p), t(4;14), t(14;16), del(13q), del(1p21), ampl(1q21), t(11;14) 1, 2
• Immunophenotyping to confirm clonality 1

Imaging Studies Algorithm

For IgG and IgA Paraproteins

• Skeletal survey (skull, spine, pelvis, ribs, humeri, femurs) as initial imaging 1
• Low-dose whole-body CT is preferred over plain radiographs (detects 25.5% more lesions) 2, 5
• MRI of spine and pelvis if skeletal survey negative but clinical suspicion remains high, or if spinal cord compression suspected 1, 2
• FDG-PET/CT can detect active myeloma and is more sensitive than plain radiographs 2

For IgM Paraproteins

• CT scan of chest, abdomen, and pelvis to detect organomegaly and lymphadenopathy (concern for Waldenström macroglobulinemia or lymphoma) 1

Imaging NOT Routinely Required

• IgG M-protein ≤15 g/L without symptoms or laboratory abnormalities 1
• IgA M-protein ≤10 g/L in asymptomatic patients 1

Diagnostic Criteria: Distinguishing MGUS, SMM, and MM

MGUS Diagnostic Criteria

• Serum M-protein <3 g/dL (IgG or IgA) 2, 6
• Clonal bone marrow plasma cells <10% 2, 6
• NO CRAB criteria (no hypercalcemia, renal insufficiency, anemia, or bone lesions) 2
• Stability of M-protein over time 6

Smoldering Multiple Myeloma (SMM) Diagnostic Criteria

• Serum M-protein ≥3 g/dL OR clonal bone marrow plasma cells ≥10% 2, 7
• NO CRAB criteria and no myeloma-defining biomarkers 2
• Higher risk: progresses at 10% per year for first 5 years, then 3% per year for next 5 years, then 1.5% per year thereafter 1

Multiple Myeloma Diagnostic Criteria

Requires BOTH:

• ≥10% clonal plasma cells on bone marrow examination OR biopsy-proven plasmacytoma 1, 2

AND EITHER:

• Evidence of end-organ damage (CRAB criteria): 1, 2
  • Calcium >11.5 mg/dL
  • Renal insufficiency (creatinine >2 mg/dL or clearance <40 mL/min)
  • Anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal)
  • Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures)

OR Myeloma-Defining Biomarkers (even without CRAB): 7

• Bone marrow plasma cells ≥60%
• Free light chain ratio ≥100 or ≤0.01

• 1 focal lesion on MRI (≥5 mm)

Risk Stratification and Follow-Up Protocol

MGUS Risk Stratification (Mayo Clinic Model)

Low-risk MGUS (5% progression risk at 20 years): 1

• IgG isotype
• M-protein <15 g/L
• Normal FLC ratio
• Follow-up: At 6 months, then every 1-2 years, OR no further follow-up with investigations only if symptoms develop 1

Intermediate-risk MGUS (21-37% progression risk at 20 years): 1

• One or two risk factors present
• Follow-up: At 6 months, then annually thereafter 1

High-risk MGUS (58% progression risk at 20 years): 1

• All three risk factors present (non-IgG, M-protein ≥15 g/L, abnormal FLC ratio)
• Follow-up: At 6 months, then annually thereafter 1

Light-chain MGUS: 1

• Follow-up: At 6 months, then annually thereafter (considerable risk of renal disease despite low progression rate) 1

Follow-Up Components at Each Visit

• Careful history for symptoms of progression (bone pain, fatigue, infections, neurologic symptoms) 1
• Physical examination emphasizing signs of MM, Waldenström macroglobulinemia, AL amyloidosis, or M-protein related disorders 1
• Laboratory studies: 1
  • Quantification of M-protein
  • Complete blood count
  • Creatinine and calcium
  • If abnormal FLC ratio with elevated involved light chain: NT-pro-BNP and urinary albumin to detect light chain organ damage 1

When to Escalate to SMM Follow-Up

• If M-protein evolves to ≥30 g/L and fulfills SMM criteria, follow every 3-4 months 1

Additional Investigations for Specific Clinical Scenarios

If Peripheral Neuropathy Present

• IgM anti-myelin-associated glycoprotein (MAG) activity testing 1
• Consider AL amyloidosis workup 1

If Hyperviscosity Symptoms Present

• Serum viscosity measurement 1
• Fundoscopy to assess for retinal changes 1

If Cryoglobulinemia Suspected

• Cryoglobulin testing 1
• Hepatitis C serology (associated with type II cryoglobulinemia) 1

If AL Amyloidosis Suspected

• NT-pro-BNP (cardiac involvement) 1
• Urinary albumin (renal involvement) 1
• Tissue biopsy with Congo red staining from affected organ 1

If Bleeding Diathesis Present

• Bleeding time, APTT, PT 1
• Coombs test for cold autoantibody 1

Critical Pitfalls to Avoid

Do NOT Confuse Severe Osteoporosis with Myeloma

• Always check for M-protein before assuming osteoporosis in patients with multiple vertebral fractures 5
• Myeloma shows focal lytic "punched-out" lesions on imaging, particularly in skull, spine, ribs, pelvis 5
• Osteoporosis shows diffuse decreased bone density without focal lesions 5

Do NOT Miss Early Myeloma in MGUS Patients

• Follow MGUS patients according to risk stratification—high-risk patients need annual monitoring 1
• Light-chain MGUS requires annual follow-up despite low progression rate due to renal disease risk 1

Do NOT Order Unnecessary Bone Marrow Biopsies

• Bone marrow biopsy is NOT needed for low-risk IgG MGUS (M-protein ≤15 g/L) without symptoms or laboratory abnormalities 1

Do NOT Delay Evaluation of Spinal Cord Compression

• Initiate dexamethasone immediately if spinal cord compression suspected to prevent paraplegia 4
• Obtain urgent MRI of the symptomatic spinal region 1

Do NOT Forget to Assess Life Expectancy

• Elderly patients or those with severe comorbidities and life expectancy <5 years may not require routine follow-up, only investigations if symptoms develop 1

Treatment Approach Based on Diagnosis

MGUS Management

• No immediate treatment required 2
• Lifelong follow-up to monitor for progression according to risk stratification 2
• No preventive interventions outside of clinical trials 1

SMM Management

• No immediate treatment currently recommended 2
• Closer monitoring than MGUS (every 3-4 months initially) 1, 2
• Treatment only if progression to active MM or development of myeloma-defining biomarkers 2

Multiple Myeloma Management

• Treatment should be initiated in all patients with active myeloma fulfilling CRAB criteria 2
• Immediate referral to hematology/oncology for chemotherapy and assessment of autologous stem cell transplantation eligibility 3
• Supportive care includes: 3
  • Bisphosphonates or denosumab for bone disease
  • Thromboprophylaxis
  • Infection prophylaxis
  • Aggressive hydration (>3 L/24h) for hypercalcemia and renal protection 2