What is a clonal plasma cell?

What is a Clonal Plasma Cell?

A clonal plasma cell is a neoplastic plasma cell derived from a single abnormal progenitor cell, characterized by monoclonal immunoglobulin production and specific immunophenotypic abnormalities including CD19 negativity and often CD56 positivity, which can be detected through multiparametric flow cytometry and is the hallmark cellular component of plasma cell disorders such as multiple myeloma. 1, 2

Characteristics of Clonal Plasma Cells

Immunophenotypic Features

• Clonal plasma cells typically show CD19 negativity (found in 95% of myeloma cases), which contrasts with normal plasma cells that are CD19 positive 1, 2
• Strong CD56 expression is present in approximately 75% of myeloma cases but is found in <15% of normal plasma cells 1
• CD38 and CD138 are expressed on both normal and clonal plasma cells and are used for plasma cell identification 2, 3
• Other common aberrant markers include CD117 positivity (30% of cases), CD20 positivity (30% of cases), and CD27 weak/negative expression (40-50% of cases) 1, 2

Clonality Assessment

• Clonality is definitively established by demonstrating restricted kappa or lambda light chain expression within the cytoplasm of plasma cells 1, 2
• An abnormal kappa/lambda ratio (>4:1 or <1:2) indicates the presence of a clonal plasma cell population 4
• Assessment of cytoplasmic κ/λ expression is critical at diagnosis and for evaluation of stringent complete remission according to International Myeloma Working Group criteria 1, 4

Detection Methods

Multiparametric Flow Cytometry

• Flow cytometry is the established and preferred method for detecting and quantifying clonal plasma cells 3
• The primary gating strategy should be based on CD38 vs. CD138 expression 2, 3
• A minimal panel for detection of abnormal plasma cells should include CD19 and CD56 1, 2
• Extended panels should include CD20, CD117, CD28, CD27, CD81, and CD200 1, 2
• At least 100 neoplastic plasma cell events should be acquired for accurate enumeration 1, 3

Technical Considerations

• Bone marrow samples should be washed twice in buffered saline solution prior to assessment of cytoplasmic immunoglobulin expression to remove cytophilic immunoglobulin 1, 3
• Flow cytometry can detect neoplastic plasma cells even when they represent as little as 0.01% of leukocytes 1, 3
• The sample is suitable for quantitative analysis if normal plasma cells (CD19+CD56- and/or polyclonal) are detectable 2

Clinical Significance

Diagnostic Applications

• The presence of clonal plasma cells is essential for diagnosing plasma cell disorders including multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), and solitary plasmacytoma 1, 5
• The ratio of abnormal to normal plasma cells in bone marrow is a significant prognostic factor in MGUS and asymptomatic myeloma 1
• A predominance of abnormal plasma cells (>97% of total bone marrow plasma cells) is typically seen in myeloma, while the presence of normal plasma cells (>3% of total bone marrow plasma cells) is more consistent with MGUS 1

Prognostic Value

• The detection of circulating clonal plasma cells in peripheral blood is associated with higher-risk disease in all stages of monoclonal gammopathies 6
• The presence of ≥400 circulating clonal plasma cells is associated with higher plasma cell proliferation, adverse cytogenetics, and shorter overall survival 6
• Minimal bone marrow infiltration by clonal plasma cells detected by flow cytometry is of major prognostic importance for solitary plasmacytoma of bone 5

Genetic Features

• Clonal plasma cells in multiple myeloma can be subdivided into cytogenetic groups based on recurrent genetic abnormalities 5
• These include MM with CCND family translocations, MM with MAF family translocations, MM with NSD2 translocation, and MM with hyperdiploidy 5
• Recurrent lymphoid clonal hematopoietic mutations (in FAT1, KMT2D, MGA, and SYNE1) and myeloma driver gene mutations (in ZFHX3 and DIS3) are found in clonal plasma cell populations 7

Pitfalls in Identification

• No single marker can systematically differentiate neoplastic plasma cells from their normal counterparts, necessitating a panel approach 2
• Relying solely on morphological examination without flow cytometry confirmation may miss cases with low levels of circulating plasma cells 3
• Using inadequate antibody panels that fail to distinguish between normal and neoplastic plasma cells can lead to misdiagnosis 3
• The demonstration of phenotypically abnormal plasma cells is more sensitive and specific for detecting residual disease than clonality assessment alone 2