What is the recommended paraprotein screening and subsequent diagnostic workup for an adult with unexplained anemia, hyperviscosity symptoms, peripheral neuropathy, renal insufficiency or proteinuria, bone pain or lytic lesions, recurrent infections, or a family history of plasma‑cell disorders?

Paraprotein Screening in Adults with Concerning Clinical Features

For adults presenting with unexplained anemia, hyperviscosity symptoms, peripheral neuropathy, renal insufficiency/proteinuria, bone pain/lytic lesions, recurrent infections, or family history of plasma-cell disorders, perform serum protein electrophoresis (SPEP) with immunofixation, serum free light chain (FLC) assay with κ/λ ratio, complete blood count, comprehensive metabolic panel (calcium and creatinine), quantitative immunoglobulins (IgG, IgA, IgM), and 24-hour urine protein electrophoresis with immunofixation. 1, 2

Initial Screening Panel

The following tests must be ordered together as a comprehensive panel:

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize monoclonal proteins 1, 2
• Serum free light chain assay with κ/λ ratio to assess clonality through abnormal ratios (<0.26 or >1.65) 1, 3
• Complete blood count to detect anemia (hemoglobin ≥2 g/dL below normal or <10 g/dL) 1, 2
• Serum calcium to identify hypercalcemia (≥11.5 mg/dL) 1, 2
• Serum creatinine to assess renal insufficiency (>2 mg/dL) 1, 2
• Quantitative immunoglobulins (IgG, IgA, IgM) by nephelometry for baseline levels 1, 2
• 24-hour urine protein electrophoresis with immunofixation because approximately 20% of plasma-cell disorders secrete monoclonal proteins only in urine 2

Critical pitfall: Random (spot) urine specimens are insufficient and miss urinary-only monoclonal proteins; always collect 24-hour urine samples. 2

Risk Stratification After Paraprotein Detection

If a monoclonal protein is detected, repeat SPEP at 3-6 months to exclude evolving multiple myeloma or Waldenström's macroglobulinemia. 1, 2

Low-Risk MGUS Criteria

All three must be present:

• Serum M-protein <15 g/L (or <1.5 g/dL)
• IgG type
• Normal FLC ratio 1, 3

For low-risk MGUS: Baseline bone marrow examination and skeletal imaging are NOT routinely indicated if clinical evaluation, CBC, creatinine, and calcium are normal. 1, 3 Follow with SPEP at 6 months, then every 2-3 years if stable. 1

Intermediate/High-Risk MGUS Criteria

Any one of the following:

• Serum M-protein ≥15 g/L (or ≥1.5 g/dL)
• IgA type
• IgM type
• Abnormal FLC ratio 1, 3

For intermediate/high-risk MGUS: Bone marrow aspirate and biopsy are mandatory at baseline to exclude underlying plasma cell malignancy. 1, 3 Perform conventional cytogenetics and FISH on the bone marrow sample. 1 Follow with SPEP and CBC at 6 months, then annually for life. 1

Important consideration: All IgA M-proteins warrant bone marrow examination regardless of size, as the probability of finding ≥10% plasma cell infiltration is significantly higher for IgA compared to IgG. 3

Distinguishing MGUS from Smoldering Multiple Myeloma (SMM) and Multiple Myeloma (MM)

MGUS Diagnostic Criteria

• Serum M-protein <3 g/dL (30 g/L)
• Bone marrow clonal plasma cells <10%
• Absence of end-organ damage (CRAB criteria) 4, 1

Smoldering Multiple Myeloma Criteria

• Serum M-protein ≥3 g/dL (30 g/L) and/or bone marrow clonal plasma cells ≥10%
• Absence of end-organ damage (CRAB criteria) 4

Multiple Myeloma Criteria

• Bone marrow clonal plasma cells ≥10%
• Presence of serum and/or urinary M-protein
• Evidence of end-organ damage (CRAB criteria):
  • Calcium: serum calcium ≥11.5 mg/dL
  • Renal insufficiency: creatinine >2 mg/dL or creatinine clearance <40 mL/min
  • Anemia: hemoglobin >2 g/dL below normal or <10 g/dL
  • Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures 4

Critical distinction: SMM has a 10% per year progression risk over the first 5 years versus 1% per year for MGUS. 4, 1 This difference mandates more intensive monitoring for SMM.

Additional Testing Based on Clinical Presentation

For Peripheral Neuropathy

• Anti-myelin-associated glycoprotein (anti-MAG) antibodies if IgM paraprotein is present 4, 5
• Anti-ganglioside M1 and anti-sulfatide IgM antibodies to support diagnosis of IgM-related neuropathy 4
• Evaluate for AL amyloidosis if abnormal FLC ratio with sensory and autonomic neuropathy 5
• Consider POEMS syndrome if lambda monoclonal protein with CIDP phenotype 5

For Renal Insufficiency or Proteinuria

• Bone marrow examination is always required if unexplained renal insufficiency is present 4, 1
• Evaluate for monoclonal gammopathy of renal significance (MGRS) with renal biopsy if indicated 4

For Hyperviscosity Symptoms

• Serum viscosity measurement may be helpful, though clinical examination (fundoscopy showing retinal vein "sausaging") is more reliable 4
• Coombs test and cold agglutinin testing for IgM-associated coagulopathy and hemolysis 4
• Cryoglobulin testing as cold agglutinins or cryoglobulins may affect IgM level determination 4

For IgM Paraprotein

• CT scan of abdomen to check for asymptomatic retroperitoneal lymph nodes 4, 1
• Bone marrow biopsy with immunophenotyping (flow cytometry and/or immunohistochemistry) showing CD19+, CD20+, CD22+, CD79a+ to confirm lymphoplasmacytic lymphoma for Waldenström's macroglobulinemia diagnosis 4
• MYD88 L265P mutation testing to distinguish WM from other entities 4

Common Pitfalls to Avoid

Failing to order 24-hour urine studies: Relying solely on serum testing misses 20% of patients with urinary-only monoclonal proteins. 2

Discontinuing follow-up after stability: Progression risk continues lifelong; even low-risk MGUS requires periodic monitoring. 1

Missing the diagnosis with negative SPEP: Always perform immunofixation when SPEP is negative or equivocal. 2

Attributing all abnormalities to paraprotein: Elderly patients often have comorbidities that mimic myeloma—mild creatinine elevation may be from diabetes/hypertension, anemia from iron/B12 deficiency or myelodysplastic syndrome, and osteoporosis from aging rather than myeloma. 4

Initiating treatment for MGUS: No treatment is indicated for MGUS outside of clinical trials unless organ damage from the monoclonal protein is documented (monoclonal gammopathy of clinical significance). 1, 3

Using different laboratory methods for serial measurements: Always use the same analytical method and ideally the same laboratory for sequential SPEP measurements to ensure accurate comparison. 2