What is the appropriate diagnostic workup and treatment for a patient with an interstitial increase in plasma cells in the bone marrow?

Diagnostic Workup for Interstitial Increase in Bone Marrow Plasma Cells

When bone marrow shows an interstitial increase in plasma cells, you must immediately initiate a comprehensive plasma cell dyscrasia workup to distinguish between monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, and symptomatic multiple myeloma, as the presence of elevated plasma cells (particularly if ≥10%) requires systematic evaluation for end-organ damage and myeloma-defining events. 1, 2

Immediate Laboratory Workup Required

Plasma Cell Quantification and Characterization

• Determine the exact percentage of plasma cells using both bone marrow aspirate and trephine biopsy, with CD138 immunostaining to accurately quantify plasma cell infiltration—when both procedures are performed, record the highest percentage obtained by either method for diagnostic purposes 1
• Establish clonality through immunoperoxidase staining or immunofluorescence to identify monoclonal immunoglobulin in plasma cell cytoplasm, focusing on light chain restriction (kappa/lambda ratio) 1, 2
• Perform flow cytometry immunophenotyping to assess for abnormal plasma cell markers (CD19-, CD56+, CD38+, CD138+, CD45-), which helps confirm monoclonality 2

Monoclonal Protein Detection

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize any M-protein 1
• Quantitative immunoglobulin measurement by nephelometry (IgG, IgA, IgM) to assess for suppression of uninvolved immunoglobulins 1
• Serum free light chain assay with kappa/lambda ratio calculation—this is essential for detecting light chain-only disease and risk stratification 1, 2
• 24-hour urine collection for total protein, urine protein electrophoresis, and urine immunofixation to detect Bence Jones proteinuria 1

Assessment for End-Organ Damage (CRAB Criteria)

• Complete blood count with differential to evaluate for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal) and assess for rouleaux formation on peripheral smear 1, 3
• Comprehensive metabolic panel including:
  • Serum calcium (corrected for albumin) to detect hypercalcemia 1
  • Creatinine and calculated creatinine clearance to assess renal function 1
  • Albumin level for staging purposes 1
  • Liver function tests 1

Prognostic Markers

• Serum β2-microglobulin for International Staging System classification 1
• Serum lactate dehydrogenase (LDH) which has independent prognostic significance 1

Cytogenetic Studies

• Standard metaphase cytogenetics to identify chromosomal abnormalities and distinguish hyperdiploid from non-hyperdiploid disease—despite only 20% yield, this captures important prognostic information 1
• Fluorescence in situ hybridization (FISH) on CD138-sorted plasma cells with probes for high-risk abnormalities: del(17p13), t(4;14), and t(14;16) 1, 2

Imaging Studies

• Complete skeletal survey including posteroanterior chest, anteroposterior and lateral views of cervical/thoracic/lumbar spine, humeri, femora, skull (anteroposterior and lateral), and anteroposterior pelvis to detect lytic bone lesions 1, 2
• MRI of spine and pelvis should be strongly considered if smoldering myeloma is suspected, as it detects occult lesions that predict more rapid progression to symptomatic disease 1, 2

Diagnostic Algorithm Based on Results

If Plasma Cells <10% with M-Protein Present

• Diagnosis: MGUS 2
• Risk stratify based on M-protein level, immunoglobulin type, and free light chain ratio 2
• Follow every 6-12 months with SPEP, CBC, calcium, and creatinine 2

If Plasma Cells ≥10% Without End-Organ Damage

• Diagnosis: Smoldering Multiple Myeloma 2
• Increase monitoring frequency to every 3-4 months initially 2
• MRI findings of focal lesions predict rapid progression and may warrant closer surveillance or clinical trial enrollment 1, 2

If Plasma Cells ≥10% WITH End-Organ Damage (CRAB Criteria)

• Diagnosis: Symptomatic Multiple Myeloma requiring immediate treatment 2, 4
• Immediate referral to hematology/oncology for therapy initiation 2
• Treatment typically involves combination regimens with proteasome inhibitors, immunomodulatory drugs, and corticosteroids 5, 4

Critical Pitfalls to Avoid

• Never rely on random urine samples—a complete 24-hour urine collection is mandatory for proper evaluation of urinary monoclonal protein 3
• Do not skip bone marrow examination even if serum M-protein is detected, as it is essential for confirming diagnosis, quantifying plasma cell burden, and obtaining material for cytogenetic studies 3
• Avoid using bone marrow aspirate alone—trephine biopsy provides more reliable assessment of plasma cell infiltration and prevents need for repeat procedures if aspirate is inadequate 1
• Do not order routine hyperviscosity testing—funduscopic examination is more clinically useful, and numerical hyperviscosity values correlate poorly with symptoms 1
• Remember that plasma cell percentage alone does not establish diagnosis—you must demonstrate clonality and assess for end-organ damage 1, 2