What are the typical peripheral smear findings in a patient with multiple myeloma?

Peripheral Smear Findings in Multiple Myeloma

The most characteristic peripheral smear finding in multiple myeloma is rouleaux formation, where red blood cells stack together like coins due to elevated serum proteins, though circulating plasma cells may also be present in active disease. 1

Primary Red Blood Cell Abnormalities

Rouleaux formation is the hallmark peripheral smear finding in multiple myeloma and should prompt immediate workup for plasma cell disorders. 1, 2 This abnormal distribution of red blood cells occurs due to elevated serum proteins, particularly the monoclonal immunoglobulin produced by malignant plasma cells. 1

Additional red cell morphology changes may include:

• Anisocytosis (variation in red cell size) 3
• Poikilocytosis (variation in red cell shape) 3

Circulating Plasma Cells

Circulating tumor plasma cells (CTPC) are detectable in peripheral blood of virtually all patients with active multiple myeloma (100%) and smoldering myeloma (100%), but only in approximately 59% of MGUS cases. 4

Key points about circulating plasma cells:

• They are present in approximately 60% of newly diagnosed active MM patients when detected by sensitive methods, and over 90% of relapsed or refractory MM patients 5
• Routine Wright-stained blood smears may miss these cells even when present, as they require more sensitive detection methods 5
• Higher numbers of circulating plasma cells correlate with higher bone marrow infiltration, more adverse prognostic features, and shorter time to progression 4
• The presence of ≥20% circulating plasma cells and/or absolute count >2×10⁹/L defines plasma cell leukemia 3

White Blood Cell Findings

The peripheral smear should be examined for:

• Granulocyte abnormalities including nuclear hypolobation (pseudo Pelger-Huet anomaly) and cytoplasmic hypogranulation 1
• A complete differential count of at least 100-200 white blood cells 1, 3

Platelet Abnormalities

Platelet changes may include:

• Platelet anisocytosis (size variation) 1
• Giant platelets 1

Critical Diagnostic Workflow When Rouleaux is Identified

When rouleaux formation is identified on peripheral blood smear, immediately proceed with the following workup: 2

1. Complete blood count with differential to assess for anemia (present in ~73% of MM patients at diagnosis) 6

2. Comprehensive metabolic panel including:

   • Serum calcium (hypercalcemia is a CRAB criterion) 1, 2
   • Serum creatinine and creatinine clearance (renal insufficiency affects ~19% at presentation) 1, 6
   • Albumin and beta-2 microglobulin (for staging) 1
   • Lactate dehydrogenase 1

3. Monoclonal protein evaluation (all four tests required): 1, 2

   • Serum protein electrophoresis (SPEP)
   • Serum immunofixation electrophoresis (SIFE)
   • Quantitative immunoglobulins by nephelometry
   • Serum free light chain assay with ratio

4. Urine studies: 1

   • 24-hour urine collection for total protein
   • Urine protein electrophoresis (UPEP)
   • Urine immunofixation electrophoresis (UIFE)

5. Bone marrow evaluation if monoclonal protein detected: 1

   • Unilateral bone marrow aspirate and biopsy
   • Immunohistochemistry (CD138 staining preferred) and/or flow cytometry to confirm clonality
   • Cytogenetics including FISH for t(4;14), t(14;16), del(17p), del(13q), and chromosome 1 abnormalities 1

6. Skeletal imaging: 1, 2

   • Skeletal survey, whole-body low-dose CT, MRI, or PET-CT to evaluate for lytic bone lesions (present in ~79% at diagnosis) 6

Common Pitfalls to Avoid

Never dismiss rouleaux formation as benign without completing the full plasma cell disorder workup, as it may be the first indication of multiple myeloma requiring urgent intervention. 2

Do not rely solely on routine blood smear examination to exclude circulating plasma cells, as sensitive methods like flow cytometry may be required to detect them. 5 At least 1,000 total events should be analyzed by flow cytometry to achieve adequate sensitivity (0.01%) for detecting abnormal plasma cells. 7

Avoid using random urine samples instead of 24-hour urine collection, as random samples corrected for creatinine concentration are not validated for this purpose. 1

Do not perform bone marrow aspirate alone without biopsy, as the biopsy provides more reliable assessment of plasma cell infiltration and prevents need for repeat procedures if aspirate is inadequate. 1