PARA

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PARA PROTEINEMIAS
Sheikha
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Professor Anwar Sheikha MD, FRCP, FRCPath.,
FCAP, FRCPA, FRCPI, FACP Senior Consultant
Clinical Lab. Hematologist Clinical Professor
of Hematology University of Mississippi Medical
Center, Jackson, Mississippi Professor of
Hematology, University of Salahaddin, Erbil,
Kurdistan, IRAQ
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PARAPROTEINEMIAS
Sheikha
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Sheikha
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MULTIPLE MYELOMA
PARA PROTEINEMIAS
WALDENSTROMS MACROGLOBULINEMIA
PRIMARY AMYLOIDOSIS
HEAVY CHAIN DISEASES
M-GUS
Sheikha
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ANEMIA BLEEDING INFECTION
BONE PAIN VERTEBRAL COLLAPSE LYTIC BONE LESIONS
ORTHOPEDIC SURGEON
HEMATOLOGIST
NEPHRO- LOGISTS
NEURO- LOGIST
RENAL FAILURE
HYPERVISCOSITY
Sheikha
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1 of All Cancers
2 of All Cancer Deaths
MULTIPLE MYELOMA
Average Age 65
Black White 21
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MULTIPLE MYELOMA
BONE MARROW INFILTRATION
PARAPROTEIN PRODUCTION
OSTEOLYTIC BONE LESIONS
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? PLATELET
ANEMIA
? WBC
PANCYTOPENIA
BONE MARROW INFILTRATION
MULTIPLE MYELOMA
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Sheikha
INFECTION
BLEEDING
? PLATELET
? WBC
ANEMIA
PANCYTOPENIA
IMMUNE SUPPRESSION
BONE MARROW INFILTRATION
MULTIPLE MYELOMA
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INFECTION
? Chemotherapy myelosuppression
? Steroid immunosuppression
MULTIPLE MYELOMA
? WBC
PANCYTOPENIA
IMMUNE SUPPRESSION
BONE MARROW INFILTRATION
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MULTIPLE MYELOMA
ANEMIA
BONE PAIN
OSTEOLYTIC BONE LESIONS
BONE
VERTEBRAL COLLAPSE
? Ca
RENAL FAILURE
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MULTIPLE MYELOMA
ANEMIA
HEMO- DILUTION
PARAPROTEIN PRODUCTION
HYPER VISCOSITY
CNS SYMPTOMS
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MULTIPLE MYELOMA
INTERFERENCE WITH CLOTTING FACTORS
BLEEDING
ANEMIA
PARAPROTEIN PRODUCTION
COATING OF PLATELETS
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MULTIPLE MYELOMA
LIGHT CHAINS
PARAPROTEIN PRODUCTION
RENAL FAILURE
AMYLOID
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?RENAL FAILURE
INFECTION
PYELONEPHRITIS
LIGHT CHAINS
? Ca
RENAL FAILURE
AMYLOID
MULTIPLE MYELOMA
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?BLEEDING
PARAPROTEIN INTERFERENCE WITH CLOTTING FACTORS
BONE MARROW INFILTRATION
BLEEDING
MULTIPLE MYELOMA
PARAPROTEIN COATING OF PLATELETS
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?ANEMIA
MULTIPLE MYELOMA
BLEEDING
BONE MARROW INFILTRATION
HEMO- DILUTION
RENAL FAILURE
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BONE MARROW INFILTRATION
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PARAPROTEIN PRODUCTION
OSTEOLYTIC BONE LESIONS
INFECTION
BLEEDING
RENAL FAILURE
MULTIPLE MYELOMA
BONE PAIN, VERT. COLLAPSE
ANEMIA
HYPER- VISCOSITY
? Ca
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Rouleaux ?ESR
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The cytoplasm of Myeloma Cells contains abundant
Endoplasmic Reticulum (ER) , which may contain
retained, condensed or crystallised cytoplasmic
Ig producing a variety of morphologically
distinctive findings, including Multiple pale
bluish-white, grape-like accumulation ? Mott
or Morula Cells Cherry-red refractive round
bodies ? Russell Bodies Vermilion staining
glycogen-rich IgA ? Flame Cells Overstuffed
fibrils ? Gaucher-like cells thesaurocytes C
rystalline Rods THESE CHANGES ARE NOT
PATHOGNOMONIC FOR MM SINCE THEY MAY BE FOUND IN
REACTIVE PLASMA CELLS
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IgG gt50
Sheikha
MULTIPLE MYELOMA
IgA 25
Light Chain 20
Bi-clonal
IgD rare
Non- Secretory
? IgM
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NORAMAL
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Immunofixation performed on serum from a
patient with monoclonal immunoglobulin Gk (IgGk)
a patient without a monoclonal protein
IgG k
normal
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OAF (IL-1/ TNF)
OSTEOCLASTS
PLASMA CELLS
PDGF/ IL-6
IL- 6
BMSC Bone Marrow Stromal Cells
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??? ????????
????
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PC
Osteoclasts
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Interleukin-6-mediated myeloma cell growth
BMSC bone marrow stromal cell IL
interleukin NF nuclear factor TGF
transforming growth factor
MM rely on contact with BM Stromal Cells
BMSC Adhesive interaction between MM cells
BMSC induce cells to secrete IL-6 which then acts
a paracrine growth factor promoting survival of
MM cells inhibiting apoptosis
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IL-1 ß TGF- ß Other Cytokines
Osteoclast Activation Osteoblast Suppression
OSTEO- LYTIC BONE LESIONS
OAF
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STAGING OF MYELOMA
Sheikha
1 trillion PC (1012) 1 Kg
I lt 1 Kg PC
III gt 2 Kg PC
II 1 to 2 Kg PC
HIGH CELL MASS gt1.2 X 1012/m2
LOW CELL MASS lt0.6 x 1012/m2
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Durie-Salmon Myeloma Staging System
Stage I All of the following
Hemoglobin value gt10 g/dL
Serum calcium value normal (lt12 mg/dL)
On roentgenogram, normal bone structure (scale) or solitary bone plasmacytoma only
Low monoclonal component production rates
IgG value lt50 g/L
IgA value lt30 g/L
Urine light chain monoclonal component on electrophoresis lt4 g/24 h
Stage II Overall data minimally abnormal as shown for stage I and no Single value abnormal as defined For stage III
Stage III one or more of the following
Hemoglobin value lt8.5 g/L
Serum Ca value gt12 mg/dL
Advanced lytic bone lesions (scale 3)
High monoclonal component production rates
IgG value gt70 g/L
IgA value gt50 g/L
Urine light chain monoclonal component on electrophoresis gt12 g/24 h
Subclassification a Relatively normal renal
function (serum creatinine value lt2.0 mg/dL) b
Abnormal renal function (serum creatinine gt2.0
mg/dL)
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Durie-Salmon Myeloma Staging System
Stage I All of the following
Hemoglobin value gt10 g/dL
Serum calcium value normal (lt12 mg/dL)
On roentgenogram, normal bone structure (scale) or solitary bone plasmacytoma only
Low monoclonal component production rates
IgG value lt5 g/dL
IgA value lt3 g/dL
Urine light chain monoclonal component on electrophoresis lt4 g/24 h
Stage II Overall data minimally abnormal as shown for stage I and no Single value abnormal as defined For stage III
Stage III one or more of the following
Hemoglobin value lt8.5 g/L
Serum Ca value gt12 mg/dL
Advanced lytic bone lesions (scale 3)
High monoclonal component production rates
IgG value gt7 g/dL
IgA value gt5 g/dL
Urine light chain monoclonal component on electrophoresis gt12 g/24 h
lt 1 Kg PC
1 to 2 Kg PC
gt 2 Kg PC
Subclassification a Relatively normal renal
function (serum creatinine value lt2.0 mg/dL) b
Abnormal renal function (serum creatinine gt2.0
mg/dL)
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Criteria for Diagnosis of Multiple Myeloma
Major criteria
1. Plasmacytomas on tissue biopsy
2. Bone marrow plasmacytosis (gt30 plasma cells)
3. Monoclonal immunoglobulin spike on serum electrophoresis IgG gt35 g/L or IgA gt20 g/L k or l light-chain excretion gt1.0 g/d on 24-h urine protein electrophoresis
Minor criteria
a. Bone marrow plasmacytosis (10-30 plasma cells)
b. Monoclonal immunoglobulin spike present but of lesser magnitude than in 3
c. Lytic bone lesions
d. Normal IgM lt0.50 g/L, IgA lt1.00 g/L, or IgG lt6.00 g/L
Any of the following sets of criteria will confirm the diagnosis
Any two major criteria
Major criterion 1 plus minor criterion b, c, or d
Major criterion 3 plus minor criterion a or c
Minor criteria a, b, and c or a, b, and d
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Normal Ig Values
g/L mg/dL IgM 0.5 1.5 50 -
150 IgA 1.5 5.0 150 - 500 IgG 5.0
15.0 500-1500
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Presenting Features of Multiple Myeloma
Feature Incidence,
Age gt40 yr 98
Male 61
Bone pain 68
Anemia 62
Renal insufficiency 55
Hypercalcemia 30
Hepatomegaly 21
Splenomegaly 5
Proteinuria 88
Bence Jones proteinuria 49
Skeletal roentgenographic abnormalities 79
Spike on SEP 76
Hypogammaglobulinemia on SEP 9
Minor or no abnormalities on SEP 15
Spike on urinary protein electrophoresis 75
Monoclonal heavy chain on serum IEP 83
Monoclonal light chain on IEP 8
Nonsecretory 0.3
Amyloidosis 7
IEP Immuno- electro- phoresis SEP
Serum protein electro- phoresis
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Frequency of Different Types of Monoclonal Proteins Produced By Plasma Cell Tumors Frequency of Different Types of Monoclonal Proteins Produced By Plasma Cell Tumors
Monoclonal Protein Frequency,
IgG 52
IgA 21
IgD 2
IgE lt0.01
IgM (Waldenström's) 12
Light chain only 11
Heavy chain only lt1
2 or more 0.5
None detected 1
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A. M-GUS Monoclonal Gammopathy of Unclear Significance
1. Monoclonal component level
IgG lt35 g/L IgA lt20 g/L
Bence Jones protein lt1.0 g/24 h
2. Bone marrow plasma cells lt10
3. No bone lesions
4. No symptoms
B. Indolent myeloma (as in A except)
No bone lesions or only limited bone lesions (lt3 lytic lesions) no compression fractures
2. Monoclonal component levels
a. IgG lt70 g/L b. IgA lt50 g/L
3. No symptoms or associated disease features
a. Performance status gt70
b. Hemoglobin gt10 g/dL
c. Serum calcium normal
d. Serum creatinine lt2.0 mg/dL
e. No infections
Classification of Monoclonal Gammopathies
C. Smoldering myeloma (as in B except)
1. No bone lesions
2. Bone marrow plasma cells lt30
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IMMUNOPHENOTYPING OF MYELOMA CELLS
Myeloma cells typically express monotypic
Cytoplasmic Ig lack SmIg
CD 38
CD56/58 -
CD19
Most Myeloma Cells Lack Pan-B CD19
CD20 Markers
NORMAL PC
CD45 -
CD79a
CD56/58
MYELOMA CELL
CD19 -
CD 138
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Prognostic Parameters in Multiple Myeloma
?2- Microglobulin
LDH
Chromosome 13 abnormalities
?2- Microglobulin ug/mL Albumin g/L MEDIAN SUVIVAL Months
lt6 Plus ? gt 30 55
gt6 Plus ? gt 30 19
gt6 Plus ? lt 30 4
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MANAGEMENT OF MULTPLE MYELOMA
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VAD
M2 PROTOCOL
MP
Quicker Response Better control of symptoms Less
Myelotoxic more convenient before autologous
Transplant Good after MP relapse 4 day infusion
is cumbersome need central Line
STANDARD REGIMEN NO OTHER REGIMEN PRODUCED
BETTER OS OS gt 3YRS
Aggressive Alkylating Combination Better
reserved for relapse after autotransplant failure
other Special cases
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VAD
M2 PROTOCOL
MP
Vincristine 0.4 mg/m2/day i.v. infusion over 4
days Adriamycin 9 mg/m2/day i.v. infusion over 4
days Dexamethasone 20 mg/m2 p.o. on days 1-4,
9-12, 17-20 REPEAT COURSE EACH 28 DAYS
Melphalan 1 mg/kg 5 days Each 5 weeks Tailor
dose ANC nadir
Vincristine Carmustine Cyclophosphamide Melphal
an Prednisolone
Prednisolone 60 mg/day For 5 days Each 5 weeks
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Thalidomide
Begin at 200 mg p.o. daily Increase by 200 mg
every 2 weeks for a goal of 800 mg p.o. daily
Thalidomide is NOT Myelotoxic
Sheikha
Constipation
Neuropathy
Somnolence
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Thalidomide
Begin at 200 mg p.o. daily Increase by 200 mg
every 2 weeks for a goal of 800 mg p.o. daily
Angio- genesis
Thalidomide potential mechanisms of antimyeloma
activity (a) Direct effects (b)
antiadhesive action (a)(c) GF inhibition (d)
antiangiogenesis (a)(e) immunomodulation bFGF
basic fibroblast growth factor TNF tumor
necrosis factor ICAM intracellular adhesion
molecule IFN interferon IL interleukin
VEGF vascular endothelial growth factor
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Thalidomide
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Dexamethasone
Described as the single most effective agent in
Myeloma Effective efficacy comparable to VAD in
Primary Refractory Myeloma Not Myelosuppressive
and suits patients with severe marrow
compromise In Frail Elderly patients start
with a lower dose
Dexamethasone 20 mg/m2 p.o. on days 1-4, 9-12,
17-20 REPEAT COURSE EACH 28 to 42 DAYS
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MP
2006 ASH UPDATE
VAD
DEXA
THALID- OMIDE
MDT
MPT
RMP Revlimid Lena- lidomide
Thalidomide Lenalidomide Revlimid Bortezomib
Velcade Pegylated Ribosomal Doxorubicin
Thal DD Pegylated Ribosomal Doxorubicin Dexa
VMP Velcade Bortezomib
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French randomized trial of conventional versus
high-dose therapy
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BONE MARROW or PERIPHERAL STEM CELL TRANSPLANTATIO
N
HIGH DOSE CHEMOTHERAPY VAD Autologous Transpl
ant
ALLOGENEIC TRANSPLANT Ideal for Young Patients
with Histocompatible Donor Sibling
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Stem Cell Transplantation as Up-Front versus Rescue Treatment Stem Cell Transplantation as Up-Front versus Rescue Treatment Stem Cell Transplantation as Up-Front versus Rescue Treatment
Measure PBSCT Early PBSCT Late
Estimated median overall survival 64.6 mo 64.0 mo
Median event-free survival 39.0 mo 13.0 mo
Quality-adjusted time without symptoms or toxicity 27.8 mo 22.3 mo

PBSCT, peripheral blood stem cell transplantation
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ADJUVANT TREATMENTS IN MULTIPLE MYELOMA
INTERFERON
BIS- PHOSPHONATES PAMIDRONATE ZOLEDRONATE
HEMO- DIALYSIS
EPO
RADIATION
Inhibit Bone Resorption Reduces Bone
Suppresses Hypercalcemia Convenient 1
injection/month
Pneumovax
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Novel treatment approaches to Myeloma from the
bench to the bedside
DC dendritic cell IL interleukin IMIDS
immunomodulatory drugs MM multiple myeloma
VEGF vascular endothelial growth factor
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THANK YOU
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Angio- genesis

• Thalidomide
• potential mechanisms of antimyeloma activity.
• Direct effects (b) antiadhesive action
• (c) growth factor inhibition (d)
  antiangiogenesis
• (e) immunomodulation. bFGF, basic fibroblast
  growth factor
• ICAM, intracellular adhesion molecule IFN,
• interferon IL, interleukin TNF, tumor necrosis
  factor
• VEGF, vascular endothelial growth factor

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AMYLOIDOSIS
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PRIMARY AMYLOIDOSIS
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Primary Amyloidosis PC neoplasm that secretes an
abnormal Ig, Which deposits in various tissues
forms a ß-pleated sheet structure that binds
Congo Red dye with characteristic birefringence

15 of Myeloma have or develop 10 Amyloidosis
80 of Patients have Monoclonal Ig 20
have Myeloma
Diagnostic Biopsy Sites Abd. s.c. fat-pad Bone
Marrow Rectum
Rare Adult Disease
GUT Mal- Absorp- tion
NERVES Sensorimotor neuropathy Loss of
Sphincter control
CHF
HMG
N.S. CRF
Macroglossia
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Primary Amyloidosis
Deposition in organs ? ORGANOMEGALY
BLEEDING Increased vessel fragility Coagulation
factors binding
Amyloid is a fibrillary protein that causes organ
failure
ß2 Micro- globulin Dialysis
AA Secondary inflammation
AF Familial
AL Primary or Ig- light chain Amyloidosis (
Myeloma)
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SOP
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SOP
Solitary Osseous Plasmacytoma
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SOP 5 of PC neoplams No other Lytic lesions
should be detected Marrow away from the lesion
should not have plasmacytosis Site depends on
marrow activity In order of frequency sites
are Vertebrae ? Ribs ? Skull ? Pelvis ? Femur ?
Clavicle ? Scapula
Sheikha
Treatment RT
35 CURED
If Paraprotein ve it should disappear after
treatment
10 Local Recurrennce or Another SOP
gt10 years
55 MM
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EXTRA-OSSEOUS PLASMACYTOMA
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EOP
Extra Osseous Plasmacytoma
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Role of adhesion molecules in disease
pathogenesis
BMSC, bone marrow stromal cell ECM,
extracellular matrix ICAM, intracellular
adhesion molecule IL, interleukin LFA,
lymphocyte function-associated antigen MM,
multiple myeloma VCAM, vascular cell adhesion
molecule VLA, very late antigen
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EOP
Sheikha
EXTRA MEDULLARY
EXTRA OSSEOUS
5 of PC neoplasms No Lytic lesions or marrow
plasmacytoma Median Age 55 years M/F ratio
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80 UPPER RESPIRATORY TRACT Oropharynx Nasophary
nx Sinuses Larynx
PAROTID
L. N.
SKIN
TESTIS
GIT
CNS
BREAST
THYROID
BLADDER
Treatment RT
15 MM
25 Recurrence
15 20 may have PARAPROTEINEMIA
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WALDENSTOROMS MACROGLOBULINEMIA
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MONOCLONAL GAMMOPATHY OF UNDETERMINATE
SIGNIFICANCE
M-GUS
BENIGN MONOCLONAL GAMMOPATHY
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HCD
HEAVY CHAIN DISEASES
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a µ ?
HCD
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HCD
a Alpha HCD
? Gamma HCD
µ mu HCD
A variant of CLL
A variant of LPC Lymphoma
A variant of Extranodal Margianl
Zone MALT Lymphoma
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a Heavy Chain Disease
IPSID Immunoproliferative Small Intestinal Disaese
Mediterranean Lymphoma
H. pylori
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POLYNEUROPATHY (Sensorimotor Demyelination)
ORGANOMEGALY (Hepato- Splenomegaly)
OSTEOSCLEROTIC MYELOMA
POEMS SYNDROME
SKIN CHANGES (Hyperpigmentation Hypertrichosis)
ENDOCRINOPATHY (Diabetes Gynecomastia Testicular
Atrophy Impotence)
MONOCLONAL GAMMOPATHY
Marrow infiltrated by PC bone trabeculae
thickened Rare 1 to 2 of PC dyscrasias Median
Age 50 years
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HIWA HEMATOLOGY HOSPITAL
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THANKS
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Cellular origin of myeloma genetic and cellular
events in disease pathogenesis
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Interleukin-6-mediated myeloma cell growth.
BMSC, bone marrow stromal cell IL,
interleukin NF, nuclear factor TGF,
transforming growth factor
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Apoptosis signaling cascades in myeloma cells.
IL, interleukin JNK, c-jun N-terminal kinase
PYK, proline-rich tyrosine kinase RAFTK,
related adhesion focal tyrosine kinase SAPK,
stress-activated protein kinase
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Interleukin-6 growth and antiapoptotic cascades
in myeloma cells. MAP, mitogen-activated
protein RAFTK, related adhesion focal tyrosine
kinase SHP, Src homology protein tyrosine
phosphatase
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Role of adhesion molecules in disease
pathogenesis
BMSC, bone marrow stromal cell ECM,
extracellular matrix ICAM, intracellular
adhesion molecule IL, interleukin LFA,
lymphocyte function-associated antigen MM,
multiple myeloma VCAM, vascular cell adhesion
molecule VLA, very late antigen
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SOP
Solitary Osseous Plasmacytoma
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