It is a neoplasm of B-cell lineage; proliferation of the cells forms a monoclonal population of plasma cells and produces a single type of Ig/Ig fragment.

1. By Mojgan Talebian

2. From a single cell of B cell lineage
Proliferation of monoclonal population of
plasma cells
Production of a single type of
immunoglobulin/immunoglobulin fragment
Homogenous M protein in serum protein
electrophoresis

3. Multiple Myeloma
Macroglobulinemia
Heavy chain disease

4.  A Trial of:
• An abnormal proliferation of plasma cells in the bone
marrow
• Overproduction of monoclonal immunoglobulin
• Related tissue/organ impairment; lytic bone disease,
increased calcium ,renal insufficiency, anemia,
 Classification is according to the type of Ig
 Mostly produce IgG or IgA, a few IgD and IgE
 IgM production is rare, usually in Waldenström's
macroglobulinemia
 MM variants:
• IgM myeloma; with the presence of osteolytic lesions
• Bence-Jones myeloma; production of excess light
chains, dimers form of either κ or λ, in serum and urine

5.  Chronic progressive disorder, fatal
 the median age at the time of diagnosis 65;
prevalence increase with aging process
 More in men
 genetics; more common in primary relatives
of the patient
 Other potential risk factors:
• Exposure to large doses of radiation, chemicals
• Chronic antigenic exposures
• Arthritis
• Osteomyelitis

6.  Production of multiple tumors in the bone
• Secretion of osteoclast activating factor by solid tumors in the bone results in osteoporosis:
 Bone fractures, lytic bone lesions:
 hypercalcemia
 Reduction in normal hemopoiesis; anemia, neutropenia, and thrombocytopenia
 Production of paraproteins; hyperviscosity, dilutional anemia, hyponatremia, high ESR,
and rouleaux formation
 Reduction of normal Ig level; rise of the total serum globulin and reduction of serum albumin
 Easy bruising and bleeding due to interference with platelet function
 Amyloidosis; deposition of glycoprotein, amyloid in tissues and organs
 Proteinuria, renal tubular dysfunction, renal failure due to excess light chain and
paraprotein precipitation
• Light chains filtered and reabsorbed by the renal tubules; damaging the tubules
• Increase loss of amino acids, glucose and electrolytes
• Granular or waxy casts
 Plasma cell leukemia: if plasma cells presence in large number in the peripheral blood

7.  Seen in 30% to 40% of patients
 Translocations; t(11;14) and t(4;14), t(14;16),
(q13;q32)
 Trisomy 3, 5, 7, 9 and 11
 The worst prognosis: monosomy 13, 13q14
deletion, and hypodiploidy
 The most frequent abnormality: translocations
involving 14q32 (the site of heavy chain
locus)
 Hyperdiploidy and aneuploidy; plasma cells
are bi- and multi-nucleated

8. Bone pain, bone fractures, skeletal
deformity
CNS involvement
Amyloidosis
Hypercalcemia: anorexia, nausea,
vomiting, constipation and dehydration
Renal dysfunction, edema
Hyperviscosity syndrome; purpura,
bruises, nose bleeding, headaches, and
blurred vision

9.  Mild to moderate reduction in Hemoglobin
 Normochromic normocytic anemia
 Rouleaux formation, blue background stain
 High ESR over 100 mm/hr, (in light chain
disease it is normal or moderately increased)
 Decreased leukocyte number, neutropenia
 Mild decrease in platelets number
 Few number of plasma cell in peripheral
blood
 Hypercalcemia

10.  BM examinations: aspirate and biopsy
 Diffuse or localized marrow infiltration, hypercellularity
 BM plasma cell labeling index (% of dividing plasma cells),
differentiate between benign and malignant plasma cell, a
major prognosis factor
 Plasmacytosis; ranging from 10% to 100%
 Malignant plasma cells: small and mature to large and
immature and atypical
 Flaming plasma cells, red areas in the cytoplasm, associated
with IgA myeloma
 Grey gelatinous bone marrow in advanced form of the disease

11.  Two variants:
 Mature:
• Eccentric nucleus with coarse chromatin pattern,
typical cartwheel appearance is not apparent
• Very blue cytoplasm with perinuclear halo
 Immature:
• Finer nucleus with prominent nucleoli
• Multinucleated cells; in the advanced form of the
disease and presence of hyperdiploidy and aneuploidy
• More cytoplasm but lighter with perinuclear halo,
vacuoles and Russell bodies 
(Mott cell)

12.  Increase of plasma volume and serum viscosity
 Serum calcium, indicator of hypercalcemia
 Serum creatinine, indicator of renal function
 Increased total protein
 Decreased albumin
 Serum protein electrophoresis
• Single homogeneous M-band, mostly in gamma or
occasionally in beta region
 No noticeable M-band in patients with light chain myeloma,
presence of light chain in Ig electrophoresis
 In rare cases of non-secretory myeloma: no M-band and no light
chains fragments in Pr or Ig electrophoresis
• Decreased gamma globulin

13.  http://www.thrombocyte.com/causes-of-multiple-myeloma-cancer

14.  Immunoelectrophoresis
• The type of monoclonal Ig
• The class of heavy chain
• The monoclonality confirmation, single light chain
• On concentrated urine sample to identify Bence-Jones
Proteinuria
• The heat precipitation of B-J protein: solubility of B-J protein
by slowly heating urine to 50 to 60° C, and reappearance of
the Protein when the urine temperature cools to below 60°C
• The test of choice is immunoelectrophoresis
 Serum immunofixation test, to clarify if the
monoclonal pattern is masked by normal
proteins

15.  http://pleiad.umdnj.edu/~dweiss/pc/pcSerum_img.html

16.  New International Staging System
• Stage I:
 Serum β2 microglobulin <3.5 mg/L
 Serum albumin > 3.5 g/dl
• Stage II: not stage I or III
 Serum β2 microglobulin <3.5 mg/L but Serum albumin < 3.5 g/dl
 Serum β2 microglobulin 3.5 mg/L to < 5.5 mg/L irrespective of the serum albumin level
• Stage III: serum β2 microglobulin >5.5 mg/L
Grippe PR et all : international staging system for multiple myeloma J Clin Oncol 23: 3412, 2005
Hemoglobin Corrected
serum
Calcium
Lytic bone
lesions
M-Spike Medial
survival
Stage I >100 g/L <12 mg/dL (0.67
mmol/L)
Fewer than 2 lytic
bone lesions
Small
IgG < 50 g/L
IgA <30 g/L
Urine light chain < 4
g / 24 hrs
> 60 months -
Stage II Dose not meet all
stage I criteria/ any
stage III criteria
- - - 41 months -
Stage III <85 g/L >12 mg/dL (0.67
mmol/L)
2 or more lytic bone
lesions
Large
IgG >70 g/L
IgA >50 g/L
Urine light chain >
12 g / 24 hrs
23 months Type A. Serum creatinine < 2.0 mg/dL (0.18
mmol/L)
Type B. Serum creatinine > 2.0 mg/dL (0.18
mmol/L)

17. Sign and Symptoms Laboratory findings Radiographic Features Bone Marrow
 Bone pain
 Fatigue
 Weight loss
 Recurrent infection
 Renal failure
 Spinal cord compression
 Back pain
 Paresthesia
 Elevated paraproteins-M
peak
 Low hemoglobin
 Hypercalcemia
 Low albumin
 High β2 microglobulin
 High serum creatinine
 High c-reactive protein
 Lytic lesions
 Osteoporosis
 fractures
•High in plasma cells

18.  An Incurable hematological malignancy
 Chemotherapy; Dexamethasone, thalidomide
and/or lemalidomite
 Radiotherapy, reducing bone pain
 Plasmapheresis, reducing hyperviscosity
 Blood transfusion
 IV fluids and diuretics, increasing urinary
excretion of calcium
 Bisphophonates, preventing of bone loss and
repairing of bone lesions and control of
hypercalcemia

19.  Involve small lymphocytes with the exhibition of plasma cell
differentiation; plasmacytoid lymphocytes
• Cells exhibit Pan-B lymphocyte surface antigens: CD19, CD20,
CD24, with light chain restriction mostly ƙ
 IgM-secreting lymphoplasmacytoid cells express both cytoplasmic
and surface IgM
 Accumulation of monoclonal IgM paraproteins (macroglobulin) in the
blood
 The IgM acts like cryoglobulin with anti-i specificity; cold autoimmune
hemolytic anemia

20.  IgM monoclonal gammapathy of
undetermined significance (MGUS), the most
common
 Waldenström's macroglobulinemia, the next
most common
 malignant lymphoma
 IgM MM
 chronic lymphocytic leukemia (CLL),
 primary systemic Amyloidosis, the least
common

21.  http://imagebank.hematology.org/AssetDetail.aspx?AssetID=1178&AssetType=Asset

22.  WM
• Bone marrow infiltration by small lymphocytes
• Surface Ig+, CD5-, CD10-, CD19+, CD20+, CD22+, CD23-
 IgM MM
• Is extremely rare, account for <0.5% of all MM
• ≥10% plasma cells on bone marrow biopsy
• lytic bone lesions and/or translocation t (11;14) (absent in 20% of
cases)
• loss of CD19, CD27, CD45
• aberrant expression of CD56, CD20, CD117 and cyclin D1, CD38
and cytoplasmic immunoglobulin
* Differentiation between WM and IgM MM by using
immunophenotyping features have limitations.

23.  Age between 50 to 70, mostly in men
 Anemia, weakness and fatigue
 Hepatosplenomegaly
 Lymph node enlargement
 Bone pain and osteoporosis is rare
 Nose bleeding, gastrointestinal bleeding, purpura as a
result of platelet dysfunction and inhibition of coagulation
factors
 Cold intolerance, cold agglutinins
 Hyperviscosity: neurologic symptoms, ocular changes,
headaches, problem in concentrating, mucous
membrane bleeding, and congestive heart failure

24.  Blood
• Normochromic, normocytic anemia
• Marked rouleaux formation
• High ESR
• Normal/slightly decreased leukocyte
• Lymphocytosis + , Plasmacytoid lymphocytes
• Normal/ slightly decreased platelet count
 Bone marrow
• Increased lymphocytes, plasmacytoid lymphocytes and plasma cells
• Intranuclear vacuoles containing IgM monoclonal protein (Dutcher bodies)
• Decrease of normal cellular elements
• Prominent feature of Mast cells
 Blood and Urine chemistry
• High total pr
• M-band in Protein electrophoresis
• Serum Immunoglobulins are not as low as the one in Multiple Myeloma
• Monoclonal IgM paraprotein in immunoelectrophoresis, Kappa light chain in most cases
• Bence- Jones Proteinuria
• Cryoglobulin

25.  An indolent disease, Prognosis Factors:
hemoglobin, age, weight loss, cryoglobulin
 Reduction of the tumor size
 In symptomatic patients:
• Plasmapheresis
• Chemotherapy, alkylating agents like
chlorambucil and fludarabine

26.  Rare neoplastic disorders
 Production of paraprotein consists of only
heavy chain
 The probable inability to attach the heavy
chains to light chains, or there is no light
chain synthesis
 Four types, based on the monoclonal heavy
chain:
• γ Heavy chain disease
• µ Heavy chain disease
• α Heavy chain disease
• δ Heavy chain disease

27.  The most common type of heavy chain disease
 Younger patients, Mediterranean area
 Serum electrophoresis: a broad band in the α2-β region
 Hypogammaglobulinemia and decreased level of
albumin
 Immunoelectrophoresis: alpha chains but no light
chains
 No BJ protein
 Peripheral blood: normal
 BM: slight/moderate increase in plasma cells
 Respiratory lymphoplasmacytosis
 Lymphoma of the small intestine, severe malabsorption
syndrome

28.  The second most common type
 Lymphadenopathy
 Hepatosplenomegaly in some cases
 Often normal pr electrophoresis: in serum
electrophoresis: the M-band in the gamma or beta
regions, M-band reveals more in
immunoelectrophoresis
 Urine electrophoresis mimics the serum
immunoelectrophoresis
 IgA and IgM are not decreased
 Probability of: lymphocytosis, pancytopenia, atypical
lymphocytes, eosinophilia, and plasma cells
 BM: lymphoplasmacytosis, eosinophils goes up
 The disease may end up to lymphoma

29.  Parallel with CLL
 Pr electrophoresis: normal or small spike in the
beta region
 Immunoelectrophoresis: monoclonal M-band
 BJ Proteinuria, Kappa light chain
 BM: mimic CLL: 70 to 80% lymphocytes, few
plasma cells
 Amyloidosis and osteoporosis

30. Very rare disease
Similar to Multiple myeloma
In serum electrophoresis:
• M band in the β-γ region
• No BJ protein
• BM: plasmacytosis, osteolytic lesions

31.  1. What malignancy is common to occur in patients with MGUS
a. CLL
b. Non-Hodgkin’s lymphoma
c. Multiple Myeloma
d. All of the above
 2. What are the major criteria in diagnosis of Multiple Myeloma:
a. More than 30% plasma cell in bone marrow
b. IgG ƙ M- spike
c. Low normal immunoglobulin
d. Both a and b
 3. The most common plasma cell dyscrasia:
a. Multiple Myeloma
b. Waldenström's Macroglobulinemia
c. chain Heavy chain disease
d. MGUS
 4. The most devastating feature of Myeloma:
a. Lytic bone lesions
b. Dilution anemia
c. Renal failure
d. hypercalcemia
 5. Which of the following viruses have been considered as etiological pathogens in MM
a. Epstein Barr virus
b. Hepatitis C
c. Human herpes virus 8
d. Both hepatitis C and HHV8
 6. The most characteristic finding in MM:
a. Rouleaux formation of RBCs
b. Normocytic normochromic anemia
c. Hypercalcemia
d. Elevated ESR

32.  7. Which type of heavy chain diseases parallel CLL:
a. γ
b. α
c. δ
d. µ
 8. Reynaud's phenomenon is most common in
a. Multiple Myeloma
b. Waldenström's Macroglobulinemia
c. MGUS
d. Both MM and WM
 9. Dutcher bodies
a. Are PAS negative
b. Clearly seen to be within the cytoplasm
c. Their origin is different from Russell bodies
d. Invaginate into or overlie the nucleus
1. d
2. d
3. a
4. a
5. d
6. a
7. d
8. b
9. d

33.  M A. Gertz, R Fonseca S. V Rajkumar. Waldenström's Macroglobulinemia. The
Oncologist 2000; (): . http://theoncologist.alphamedpress.org/content/5/1/63.full
(accessed Feb 2016)
 V R BHATT, S MURUKUTLA, M NAQI, S PANT, . IgM Myeloma or
Waldenstrom's Macroglobulinemia Is the Big Question. Maedica 2014; 2014
Mar; 9(1): 72–75: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268296/.
 Autoimmune Hemolytic Anemia. G Garratty (ed).Immunobiology of Transfusion
Medicine. USA, LA California: American Red Cross Blood Services; 1994. pp.
511.
 B J.Bain. The histopathology of the macroglobulinemia of
Waldenstrom.. American Journal of Hematology 2009; 84(9):
http://onlinelibrary.wiley.com/doi/10.1002/ajh.21399/pdf.
 D M Harmening. Clinical Hematology and Fundamental of Hemostasis, 5th
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