Plasma Cell

Overview of Plasma Cell Dyscrasias

Definition: A group of disorders characterized by the abnormal proliferation of a single clone of plasma cells, leading to the overproduction of a monoclonal immunoglobulin (M protein)
Synonyms: Monoclonal Gammopathies, Plasma Cell Disorders
Key Features:
- Monoclonal Gammopathy: The presence of a monoclonal immunoglobulin (M protein) in the serum or urine. The M protein is produced by the abnormal clone of plasma cells
- Bone Marrow Involvement: The bone marrow is often infiltrated by the clonal plasma cells
- Organ Damage: May lead to organ damage due to M protein deposition, bone lesions, hypercalcemia, renal dysfunction, and increased susceptibility to infections
Spectrum of Disorders: Range from benign to malignant:
- Monoclonal Gammopathy of Undetermined Significance (MGUS): Benign condition with low levels of M protein and no evidence of end-organ damage
- Smoldering Multiple Myeloma (SMM): Intermediate condition with higher levels of M protein but still no end-organ damage
- Multiple Myeloma (MM): Malignant plasma cell disorder with M protein, bone marrow involvement, and end-organ damage
- Waldenström Macroglobulinemia (WM): A lymphoplasmacytic lymphoma that produces IgM M protein (covered in the previous study guide)
- Other Plasma Cell Dyscrasias: Rare disorders such as heavy chain diseases and plasma cell leukemia

Multiple Myeloma (MM)

Definition: A malignant plasma cell disorder characterized by the clonal proliferation of plasma cells in the bone marrow, leading to the overproduction of a monoclonal immunoglobulin (M protein) and associated end-organ damage
Diagnostic Criteria:
- Clonal Bone Marrow Plasma Cells ≥10% or Biopsy-Proven Extramedullary Plasmacytoma
- Presence of M Protein in Serum and/or Urine (except in rare cases of nonsecretory myeloma)
- Evidence of End-Organ Damage (CRAB Criteria):
  - Hypercalcemia: Elevated serum calcium level
  - Renal Insufficiency: Elevated creatinine or decreased glomerular filtration rate (GFR)
  - Anemia: Low hemoglobin level
  - Bone Lesions: Lytic lesions, fractures, or osteopenia on skeletal survey or imaging studies
Pathophysiology:
- Clonal Plasma Cell Proliferation: Abnormal plasma cells accumulate in the bone marrow, disrupting normal hematopoiesis
- M Protein Production: Excessive production of a monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or light chains (kappa or lambda)
- Bone Destruction: Myeloma cells secrete factors that stimulate osteoclast activity, leading to bone resorption and lytic lesions
- Immunosuppression: Myeloma cells suppress the normal immune system, increasing susceptibility to infections
Clinical Features:
- Bone Pain: Most common symptom
- Fatigue and Weakness: Due to anemia
- Pathologic Fractures: Fractures that occur with minimal trauma due to weakened bones
- Recurrent Infections: Due to immunosuppression
- Renal Insufficiency: Due to M protein deposition in the kidneys (myeloma cast nephropathy)
- Hypercalcemia: Can cause confusion, constipation, and kidney damage
- Neurological Symptoms: Due to spinal cord compression or hyperviscosity syndrome
- Amyloidosis: Deposition of light chains in tissues, causing organ damage
Laboratory Findings:
- CBC:
  - Anemia (normocytic or normochromic)
  - Thrombocytopenia
  - Leukopenia (less common)
  - Rouleaux formation: Stacking of RBCs due to increased serum protein
- Peripheral Blood Smear:
  - Normal or abnormal RBC morphology
  - May see plasma cells or circulating myeloma cells (rare)
- Serum Protein Electrophoresis (SPEP):
  - Monoclonal spike (M protein) in the gamma region (usually IgG or IgA)
- Serum Immunofixation Electrophoresis (IFE):
  - Confirms the presence and type of M protein (IgG kappa, IgA lambda, etc.)
- Serum Free Light Chain (FLC) Assay:
  - Measures free kappa and lambda light chains in the serum
  - Increased FLC ratio (kappa/lambda or lambda/kappa) is common
- Urine Protein Electrophoresis (UPEP) and Immunofixation:
  - May detect Bence Jones protein (free light chains) in the urine
- Serum Beta-2 Microglobulin:
  - Elevated levels indicate increased tumor burden
  - Used for staging and prognosis
- Serum Albumin:
  - Decreased levels are associated with poorer prognosis
- Serum Calcium:
  - Elevated in hypercalcemia
- Renal Function Tests:
  - Elevated creatinine and decreased GFR in renal insufficiency
- Skeletal Survey (X-rays):
  - Lytic lesions (“punched-out” lesions) in bones
  - Osteopenia
  - Fractures
- Bone Marrow Aspiration and Biopsy:
  - Increased plasma cells (≥10%)
  - Abnormal plasma cell morphology
  - Immunohistochemistry: To identify plasma cell markers (CD138, CD56)
- Cytogenetic Analysis:
  - Karyotyping and FISH (fluorescence in situ hybridization)
  - Detect chromosomal abnormalities that are used for prognosis and risk stratification (e.g., del(17p), t(4;14), t(14;16))
- Molecular Testing:
  - To detect gene mutations that are used for prognosis (e.g., TP53, BRAF)
Staging:
- Revised International Staging System (R-ISS):
  - Used to determine treatment and outcomes.
  - Serum beta2-microglobulin level
  - Serum albumin level
  - Cytogenetic abnormalities (detected by FISH)
Treatment:
- Treatment depends on risk assessment and patient fitness
- Proteasome Inhibitors:
  - Bortezomib, carfilzomib, ixazomib
- Immunomodulatory Drugs (IMiDs):
  - Lenalidomide, thalidomide, pomalidomide
- Monoclonal Antibodies:
  - Daratumumab (anti-CD38)
  - Elotuzumab (anti-SLAMF7)
- Chemotherapy:
  - Alkylating agents (e.g., melphalan, cyclophosphamide)
- Corticosteroids:
  - Dexamethasone, prednisone
- Autologous Hematopoietic Stem Cell Transplantation (ASCT):
  - A standard treatment for eligible patients
- CAR T-Cell Therapy:
  - Used for relapsed/refractory myeloma
- Bispecific Antibodies:
  - Emerging therapies that bind to both CD3 on T cells and BCMA on myeloma cells, bringing them together to kill the myeloma cells

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Definition: A benign condition characterized by the presence of a monoclonal immunoglobulin (M protein) in the serum or urine, without evidence of end-organ damage or other features of multiple myeloma, Waldenström macroglobulinemia, or other lymphoid disorders
Diagnostic Criteria:
- Serum M protein < 3 g/dL
- Bone marrow plasma cells <10%
- Absence of end-organ damage (CRAB criteria):
  - Hypercalcemia
  - Renal insufficiency
  - Anemia
  - Bone lesions
Epidemiology: Common, especially in older adults
Pathophysiology:
- Unknown cause
- Thought to be a premalignant condition with a low risk of progression to multiple myeloma or other lymphoid malignancies
Clinical Features:
- Typically asymptomatic
- Usually discovered incidentally during routine blood tests
Laboratory Findings:
- Serum Protein Electrophoresis (SPEP): Small monoclonal spike (M protein)
- Serum Immunofixation Electrophoresis (IFE): Confirms the presence and type of M protein (IgG, IgA, IgM, etc.)
- Serum Free Light Chain (FLC) Assay: May be normal or show a slightly elevated kappa/lambda ratio
- CBC, Renal Function Tests, Calcium Level: Normal
- Bone Marrow Aspiration and Biopsy: Not typically required for diagnosis, but may be performed to rule out other disorders
Management:
- No treatment is required
- Periodic monitoring with SPEP, IFE, and serum FLC assay to assess for progression to multiple myeloma or other malignancies
- Risk of Progression: Approximately 1% per year progress to multiple myeloma or other related disorders

Key Terms

Plasma Cell Dyscrasia: A disorder characterized by abnormal proliferation of a single clone of plasma cells
Monoclonal Gammopathy: The presence of a monoclonal immunoglobulin (M protein) in the serum or urine
M Protein: A monoclonal immunoglobulin produced by the abnormal clone of plasma cells
MGUS (Monoclonal Gammopathy of Undetermined Significance): Benign condition with low levels of M protein and no end-organ damage
Multiple Myeloma (MM): Malignant plasma cell disorder with M protein, bone marrow involvement, and end-organ damage
Bence Jones Protein: Free light chains in the urine
Lytic Lesions: “Punched-out” lesions in bones seen on X-ray
CRAB Criteria: Hypercalcemia, Renal insufficiency, Anemia, Bone lesions (used to define end-organ damage in myeloma)
Serum Protein Electrophoresis (SPEP): A test that separates proteins in the serum based on their electrical charge
Immunofixation Electrophoresis (IFE): A test that identifies the type of M protein (IgG, IgA, IgM, etc.)
Autologous Stem Cell Transplant: Stem cells are collected from and transplanted to the same person

Chronic T-Cell

Hereditary