The document provides a comprehensive overview of multiple myeloma, detailing the abnormal proliferation of plasma cells, the types of immunoglobulins produced, related symptoms, and the disease's progression. It discusses diagnostic criteria, genetic factors, treatment options, and associated risk factors. Additionally, it highlights various forms of the disease, including heavy chain disease and Waldenström's macroglobulinemia, along with their clinical presentations and prognosis.

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
ed. USA: F.A. Davis; 2009