Plasma Cell Dysrasias

Question 1

Paraproteinemias

Answer 1

Family of disorders characterized by:

Monoclonal proliferation and accumulation of plasma cells

or

B lymphocytes which produce a paraprotein

Question 2

Paraprotein

Answer 2

• Monoclonal immunoglobulin or immunoglobulin light chain in the blood or urine resulting from clonal proliferation of plasma cells or B lymphocytes
• Paraprotein is referred to by many different names including:
  
  • M band
  • Monoclonal band
  • Monoclonal spike
  • Monoclonal protein

Question 3

Paraprotein Diseases

Answer 3

• There are many diseases that have paraproteins
• Some are malignant:
  
  • Multiple myeloma
  • Waldenström’s macroglobulinemia ⇒ IgM production
  • Malignant lymphoma
  • Primary amyloidosis
  • Heavy chain disease ⇒ production of isolated heavy chain
• Some are benign:
  
  • Benign monoclonal gammopathy
  • Chronic cold hemagglutinin disease
  • Transient M-proteins
• Ass. w/ a variety of cancers, SLE, RA, other connective tissue disorders, chronic hepatitis, and HIV
• Majority of paraproteins due to MGUS (64%)
• Multiple Myeloma makes up ~14%

Question 4

Multiple Myeloma

Pathogenesis

Answer 4

Uncontrolled proliferation of cells that secrete immunoglobulins which may be:

• Intact immunoglobulin ⇒ both a light and heavy chain
• Only light chains ⇒ called Bence Jones proteins in the urine
• IgM listed as “rarely” b/c it usually presents as a clinically separate condition called Waldenström’s macroglobulinemia

Question 5

Multiple Myeloma

Epidemiology

Answer 5

• 2:1 men to women
• 2:1 Black individuals to White Individual
• Represents 1% of all cancers
• Thought to be incurable
• Median survival is 3 years

Question 6

Multiple Myeloma

Clinical Features

Answer 6

• Bone pain often w/ loss of height
• Elevated serum protein (can be asymptomatic)
• Hypercalcemia
• Plasma cells secrete osteoclast activating factor (OAFs)
  
  • IL-1, TNF, and lymphotoxin
  • Bone breakdown ⇒ calcium release
• Constitutional symptoms ⇒ weakness, fatigue, weight loss
• Anemia ⇒ normochromic, normocytic, often see rouleaux formation on smear
• Renal disease
  
  • Plasma cells secrete proteins which can collect in renal tubules and cause dysfunction
  • Hypercalcemia ⇒ dehydration ⇒ renal insufficiency
  • Calcium deposition ⇒ ± renal failure
  • ± Amyloid deposition in the kidneys ⇒ renal failure
• Susceptibility to infections
  
  • Multiple myeloma suppresses normal plasma cells ⇒ ⊗ functional Ab production
  • As abnl plasma cells infiltrate the bone marrow ⇒ low overall white count
• Hyperviscosity syndrome
  
  • Mostly seen in IgM gammopathies but can see w/ myeloma, particularly IgA subtypes because it forms a dimer
• Hemorrhagic tendency
  
  • Proteins tend to interfere w/ the normal clotting cascade
  • Paraproteins will often coat the phospholipid surfaces and proteins involved in coagulation
• Neurologic dysfunction
  
  • Plasma cell infiltration of the vertebrae ⇒ spinal cord compression
  • Some paraproteins cause direct nerve damage

Question 7

Multiple Myeloma

Diagnosis

Answer 7

Newer, more simplified criteria:

• ≥ 10% plasma cells in marrow or a plasmacytoma, plus
• A monoclonal protein (urine or serum)
• Some forms of myeloma do not secret a paraprotein ⇒ called non-secretory
• Need to have > 30% plasma cells of the cellular elements of the marrow
  
  • Normal marrow ~ 50% fat and 50% cells
  • Normally plasma cells make up 1-2% of the cellular component

Question 8

Monoclonal Gammopathy of Undetermined Significance

(MGUS)

Answer 8

• Much more common than multiple myeloma
• Paraprotein is usually IgG and its level is < 3 g/dl
• No other features of myeloma
  
  • Must have preserved levels of uninvolved immunoglobulins
• On longitudinal study over 22 years:
  
  • ~19% remained stable
  • 10% had a gradual increase in paraprotein levels but no manifestations of disease
  • 50% died of unrelated causes
  • ~25% developed multiple myeloma or one of the other known conditions that make paraproteins
• Risk of transformation to myeloma is 1%/year
• Greater if IgG > 1.5 g/dl or a non-IgG paraprotein

Question 9

Multiple Myeloma

Pathology

Answer 9

• Rouleaux formation (stacking) of RBCs
• Myeloma cells
  
  • Eccentric nucleus, perinuclear clear zone w/ Golgi apparatus (site of paraprotein production)
  • ± Multinucleated
  • ± Intranuclear inclusions (Dutcher bodies)
  • ± Cytoplasmic inclusions (Russell bodies)
• Bone marrow appearance
  
  • Very hypercellular marrow
  • Normal cellular elements are absent (e.g. megakaryotes, WBC precursors, RBC precursors, etc.)

Question 10

Multiple Myeloma

Radiologic Changes

Answer 10

• Lytic lesions of the skull and vertebrae
• Caused by osteoclast activating factor
• Combination of cytokines produced by the plasma cells
• Include TNF-alpha, IL-1, and lymphotoxin

Question 11

Multiple Myeloma

Staging

Answer 11

Uses level of β2 microglobulin and serum albumin
Also looks at serum creatinine

Stage and Survival

People w/ the lowest level (i.e. Stage I) disease live about 5 years or more

Prognosis for multiple myeloma has been improving over recent years