W3L6 - Monoclonal Gammopathies

Question 1

Plasma Cell Disease

Answer 1

Plasma cells are derived from B lymphocytes
Produce and secrete antibodies
- range from 900,000 Da for IgM to 24,000 Da for free light chains
- hence broad and diffuse gamma region
When a plasma cell proliferates (cancerous) it will produce and secrete an antibody of specific type
- monoclonal immunoglobulin (M protein)
- many clones of the cell and so excess amount of the specific Ab
- detection and measurement of the specific Ab is used to diagnose and monitor the disease
- biomarker of disease

Question 2

3 Groups of Monoclonal Gammopathies

Answer 2

Malignant - large tumour burden, must be controlled or eradicated
Premalignant - no clinical symptoms, need only to be monitored, may lead to
malignant disease
Protein/low tumour burden - secreted monoclonal protein causes the disease

Question 3

Immunofixation Electrophoresis (IFE)

Answer 3

An immuno-precipitation assay
Used to detect/characterise paraprotein (monoclonal immunoglobulin – “M” spike) in serum
To test for monoclonal gammopathies
Electrophoresis of serum in agarose gel is followed by over laying with specific antisera (anti- G, M, A, Κ and λ)
Antigen-antibody complex precipitates in gel
Monoclonal Ig has heavy and light chain precipitation, surrounding gamma region is reduced

Question 4

Distribution of Monoclonal Proteins in MM & MGUS Patients

Answer 4

IgG - MM 52%, MGUS 59%
IgA - MM 21%, MGUS 12%
IGM - MM 0.5%, MGUS 18%
IgD - MM 2%, MGUS 0.5%
Biclonal - MM 2%, MGUS 5%
Light chain only - MM 20%, MGUS 6%
None detected - MM 2.8%, MGUS N/A

Question 5

MGUS

Answer 5

Monoclonal gammopathy of undetermined significance
Clinically relevant
The prevalence of MGUS increases with age
The median age at diagnosis is about 70 years, and less than 2% of patients
with MGUS are younger than 40 years of age
The prevalence of MGUS is higher in men than in women
Over a prolonged period of follow-up, a substantial proportion of patients progress to a malignant plasma cell disorder (multiple myeloma, Waldenstrom’s macroglobulinemia, primary amyloidosis, B-cell lymphoma, or chronic lymphocytic leukemia)

Question 6

Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance

Answer 6

Probabilities of transformation into one of the following: multiple myeloma, Waldenstrom’s macroglobulinemia, primary amyloidosis, B-cell lymphoma, or chronic lymphocytic leukemia were:
- 10% at 10 yrs
- 18% at 20 yrs
- 28% at 30 yrs
- 36% at both 35 and 40 yrs
Significant differences were noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS

Question 7

Dealing with MGUS

Answer 7

History and physical examination
Hemoglobin concentration
Serum calcium and creatinine concentrations
Protein studies
Total serum protein concentration and serum electrophoresis
24-hour urine protein excretion and urine electrophoresis
Serum and urine immunofixation
Examination of bone marrow aspirate
Skeletal survey

Question 8

Multiple Myeloma

Answer 8

Five years survival rate of about 49%
Symptoms:
- bone pain
- anemia
- fatigue
- bone fractures
- kidney failure
- increased susceptibility to infections
Diagnosis:
- plasma electrophoresis
- beta 3 micro-globulin levels
- bone marrow biopsy
- skeletal survey

Question 9

Multiple Myeloma Treatment

Answer 9

Autologous stem cell therapy
Proteasome inhibitors (bortezomid, carfilzomid, ixazomid)
Phthalimide derivatives (thalidomide, lenalidomide, pomalidomide)
Abs

Question 10

Waldenstrom’s Macroglobulinemia

Answer 10

IgM monoclonal gammopathy
It is a B cell neoplasm not related to MM
Rare
Slow, indolent nature
Involvement of lymph nodes, hyperviscosity
Diagnosis:
- IFE
- bone marrow biopsy
- flow cytometry
Prognosis : > 10 years usually
Treatment : rituximab (anti CD20 ab), bone marrow transplantation

Question 11

Differences between MGUS, SMM, MM

Answer 11

MGUS
- M protein < 3 g/dL
- bone marrow plasma cells < 10%
- no end organ damage
SMM
- M protein > 3 g/dL
- bone marrow plasma cells > 10%
- no end organ damage
MM
- M protein in serum or urine
- bone marrow clonal plasma cells
- presence of end organ damage

Question 12

Examples of Monoclonal Gammopathies and the Group they Belong To

Answer 12

Malignant - MM, plasma cell leukemia, plasmacytoma
Premalignant - SMM, MGUS, Bence Jones proteinuria
Protein/low tumour burden - Waldenstrom’s macroglobulinemia, primary amyloidosis