What are the diagnostic criteria for an older adult with anemia, bone pain, and recurrent infections suspected of having IgA (Immunoglobulin A) myeloma affecting the kidneys?

Diagnostic Criteria for IgA Myeloma with Renal Involvement

IgA myeloma affecting the kidneys requires ≥10% clonal plasma cells on bone marrow examination PLUS evidence of renal dysfunction (creatinine >2 mg/dL or creatinine clearance <40 mL/min) attributable to the plasma cell disorder, along with demonstration of monoclonal IgA protein in serum or urine. 1, 2

Core Diagnostic Requirements

Bone Marrow Criteria

• ≥10% clonal plasma cells must be documented on bone marrow aspiration and biopsy 1, 2
• CD138 staining should be performed to accurately quantify the plasma cell percentage, as this prevents underestimation 1, 2
• Cytogenetic/FISH studies are mandatory for risk stratification, specifically testing for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, and p53 mutation 2

Critical distinction for IgA specifically: Bone marrow examination is recommended for ALL IgA M-proteins, even in asymptomatic patients, unlike IgG where it may be deferred if M-protein ≤15 g/L without end-organ damage. 3, 1

Renal Involvement (R in CRAB Criteria)

• Serum creatinine >2 mg/dL OR creatinine clearance <40 mL/min defines renal insufficiency 1, 2
• Kidney biopsy is often indicated when significant proteinuria or renal insufficiency is present to demonstrate monoclonal deposits and their pattern of organization 3
• Immunofluorescence and electron microscopic studies are essential on kidney biopsy specimens to demonstrate monoclonal IgA deposits 3
• Non-albumin proteinuria in the setting of acute kidney injury should raise suspicion for IgA myeloma with renal involvement 4

Essential Laboratory Workup

Monoclonal Protein Detection:

• Serum protein electrophoresis with immunofixation to identify and characterize the IgA monoclonal protein 3, 1, 2
• 24-hour urine collection (NOT random sample) for protein electrophoresis with immunofixation 3, 1
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 3, 1, 2
• Serum free light chain (FLC) assay with kappa/lambda ratio measurement 1, 2

Assessment of End-Organ Damage:

• Complete blood count to assess for anemia (hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal) 1, 2
• Serum calcium to detect hypercalcemia (>11.5 mg/dL) 1, 2
• Serum creatinine and creatinine clearance for renal function assessment 1, 2
• β2-microglobulin for prognostic staging 3, 2

Imaging Requirements

• Full skeletal X-ray survey (spine, pelvis, skull, humeri, femurs) to detect lytic bone lesions 3, 2
• MRI of spine and pelvis if skeletal survey is negative but clinical suspicion remains high, or if spinal cord compression is suspected 3, 2
• Low-dose whole-body CT may be superior to conventional radiography and reveals more lesions 3

Complete CRAB Criteria for Symptomatic Myeloma

The presence of ANY ONE of the following attributable to the plasma cell disorder confirms symptomatic myeloma requiring treatment: 1, 2

• C (Calcium): Serum calcium >11.5 mg/dL 1, 2
• R (Renal): Creatinine >2 mg/dL or creatinine clearance <40 mL/min 1, 2
• A (Anemia): Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 1, 2
• B (Bone): Lytic lesions, severe osteopenia, or pathologic fractures on imaging 1, 2

Additional Myeloma-Defining Events (Without CRAB)

Even without CRAB criteria, multiple myeloma is diagnosed if: 2

• ≥60% clonal plasma cells in bone marrow 2
• Involved/uninvolved serum FLC ratio ≥100 (provided involved FLC ≥100 mg/L) 2

• 1 focal lesion ≥5mm on MRI 2

IgA-Specific Diagnostic Considerations

IgA myeloma presents unique diagnostic challenges:

• IgA monoclonal proteins can be difficult to quantify accurately by standard serum protein electrophoresis due to comigration issues 5
• IgA Hevylite (HLC) assays measure IgA kappa and IgA lambda separately, providing more precise quantification than standard electrophoresis and can detect oligosecretory disease 5
• In one study, 8% of IgA myeloma patients presented with oligosecretory disease (<10 g/L M-protein), including some with non-quantifiable SPEP bands 5
• IgA myeloma has a higher probability of bone marrow plasma cell infiltration ≥10% compared to IgG (20.5% vs 4.7% in patients with M-protein ≤15 g/L without bone pain) 3

Renal Pathology Patterns in IgA Myeloma

When kidney biopsy is performed, several patterns may be observed: 3, 4

• Cast nephropathy (myeloma kidney)
• Light chain deposition disease
• AL amyloidosis
• Acute tubular necrosis
• Rarely, coexisting IgA deposition with other immunoglobulin types 6

Critical Pitfalls to Avoid

• Never use random urine samples for protein electrophoresis—only 24-hour concentrated collections are acceptable 2
• Do not defer bone marrow biopsy in IgA cases even if M-protein appears low, as IgA has higher risk of occult myeloma than IgG 3, 1
• Always perform kidney biopsy when renal dysfunction is present with significant proteinuria to characterize the pattern of injury and confirm monoclonal deposits 3
• Ensure CD138 staining is performed on bone marrow specimens to avoid underestimating plasma cell percentage 1, 2
• Do not overlook cytogenetic testing—high-risk features like t(14;16) fundamentally change prognosis and treatment decisions 2, 4
• Consider IgA myeloma even in younger patients (third and fourth decades) presenting with unexplained acute kidney injury and anemia 4

Risk Stratification

International Staging System (ISS): 2

• Stage I: β2-microglobulin <3.5 mg/L AND albumin ≥3.5 g/dL
• Stage II: Neither Stage I nor III
• Stage III: β2-microglobulin ≥5.5 mg/L (worst prognosis)

High-risk cytogenetics include del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 2, 4

Differential Diagnosis

• MGUS: Serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and no CRAB criteria 1, 2
• Smoldering Multiple Myeloma: Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%, with no CRAB criteria 1, 2