Transcript Slide 1

PARA
PROTEINEMIAS
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
PARAPROTEINEMIAS
MULTIPLE MYELOMA
WALDENSTROM’S
MACROGLOBULINEMIA
PARA
PROTEINEMIAS
PRIMARY AMYLOIDOSIS
HEAVY CHAIN DISEASES
M-GUS
ANEMIA
BLEEDING
BONE PAIN
#
VERTEBRAL COLLAPSE
LYTIC BONE LESIONS
INFECTION
ORTHOPEDIC
SURGEON
NEUROLOGIST
HEMATOLOGIST
HYPERVISCOSITY
NEPHROLOGISTS
RENAL
FAILURE
1% of All Cancers
2% of All Cancer Deaths
MULTIPLE
MYELOMA
Average Age ~ 65
Black: White = 2:1
MULTIPLE
MYELOMA
OSTEOLYTIC
BONE LESIONS
BONE MARROW
INFILTRATION
PARAPROTEIN
PRODUCTION
↓ PLATELET
↓ WBC
PANCYTOPENIA
BONE MARROW
INFILTRATION
MULTIPLE
MYELOMA
ANEMIA
INFECTION
BLEEDING
↓ PLATELET
↓ WBC
IMMUNE
SUPPRESSION
PANCYTOPENIA
BONE MARROW
INFILTRATION
ANEMIA
MULTIPL
E
MYELOM
A
INFECTION


Chemotherapy myelosuppression
Steroid immunosuppression
MULTIPLE
MYELOMA
↓ WBC
IMMUNE
SUPPRESSION
PANCYTOPENIA
BONE MARROW
INFILTRATION
MULTIPLE
MYELOMA
ANEMIA
BONE
PAIN
BONE
#
OSTEOLYTIC
BONE LESIONS
VERTEBRAL
COLLAPSE
↑ Ca++
RENAL
FAILURE
MULTIPLE
MYELOMA
ANEMIA
HEMODILUTION
PARAPROTEIN
PRODUCTION
CNS
SYMPTOMS
HYPER
VISCOSITY
MULTIPLE
MYELOMA
INTERFERENCE
WITH CLOTTING
FACTORS
BLEEDING
ANEMIA
PARAPROTEIN
PRODUCTION
COATING OF
PLATELETS
MULTIPLE
MYELOMA
LIGHT
CHAINS
PARAPROTEIN
PRODUCTION
RENAL
FAILURE
AMYLOID
INFECTION
?RENAL
FAILURE
PYELONEPHRITIS
LIGHT
CHAINS
↑ Ca++
RENAL
FAILURE
MULTIPLE
MYELOMA
AMYLOID
PARAPROTEIN
INTERFERENCE
WITH CLOTTING
FACTORS
BONE MARROW
INFILTRATION
?BLEEDING
BLEEDING
MULTIPLE
MYELOMA
PARAPROTEIN
COATING OF
PLATELETS
MULTIPLE
MYELOMA
?ANEMIA
BLEEDING
BONE MARROW
INFILTRATION
HEMODILUTION
RENAL
FAILURE
BONE MARROW
INFILTRATION
OSTEOLYTIC
BONE LESIONS
PARAPROTEIN
PRODUCTION
INFECTION
BLEEDING
↑ Ca++
ANEMIA
MULTIPLE
MYELOMA
RENAL
FAILURE
HYPERVISCOSITY
BONE PAIN,
# & VERT.
COLLAPSE
Rouleaux
↑ESR
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
&
Crystalline Rods
THESE CHANGES ARE NOT PATHOGNOMONIC FOR MM
SINCE THEY MAY BE FOUND IN REACTIVE PLASMA CELLS
IgG
>50%
MULTIPLE
MYELOMA
IgA
25%
Light
Chain
20%
Bi-clonal
IgD
rare
NonSecretory
?
IgM
NORAMAL
Immunofixation
performed on serum
from a patient with
monoclonal
immunoglobulin Gk
(IgGk)
IgG k
&
a patient without a
monoclonal protein
normal
OAF
(IL-1/ TNF)
OSTEOCLASTS
PLASMA CELLS
IL- 6
BMSC
PDGF/ IL-6
“Bone Marrow Stromal Cells”
‫ﺣﺮﺱ‬
‫ﺍﻝﺠﻤﻫﻭﺭﻱ‬
‫ﺻﺪﺍﻡ‬
PC
Osteoclasts
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
IL-1 β
OAF
TGF- β
Other
Cytokines
Osteoclast
Activation
Osteoblast
Suppression
OSTEOLYTIC
BONE
LESIONS
STAGING OF MYELOMA
1 trillion PC (1012) = 1 Kg
I
II
III
<
1
Kg
PC
1
to
2
Kg
PC
>
2
Kg
PC
LOW
CELL
MASS
<0.6 x 1012/m2
HIGH
CELL
MASS
>1.2 X 1012/m2
Durie-Salmon Myeloma Staging System
Stage I
All of the following:
Hemoglobin value >10 g/dL
Serum calcium value normal
(<12 mg/dL)
On roentgenogram,
normal bone structure
(scale) or solitary bone
plasmacytoma only
Low monoclonal component
production rates
IgG value <50 g/L
IgA value <30 g/L
Urine light chain monoclonal
component on
electrophoresis <4 g/24 h
Stage II
Overall
data
minimally
abnormal
as shown
for
stage I
and no
Single
value
abnormal
as defined
For
stage III
Subclassification:
Stage III
one or more of the following:
Hemoglobin value <8.5 g/L
Serum Ca value >12 mg/dL
Advanced lytic bone lesions
(scale 3)
High monoclonal component
production rates
IgG value >70 g/L
IgA value >50 g/L
Urine light chain monoclonal
component on electrophoresis
>12 g/24 h
a: Relatively normal renal function (serum creatinine value <2.0 mg/dL)
b: Abnormal renal function (serum creatinine >2.0 mg/dL)
Durie-Salmon Myeloma Staging System
Stage I
All of the following:
Hemoglobin value >10 g/dL
Serum calcium value normal
(<12 mg/dL)
<
1
Kg component
Low monoclonal
production rates
PC
IgG value <5 g/dL
On roentgenogram,
normal bone structure
(scale) or solitary bone
plasmacytoma only
IgA value <3 g/dL
Urine light chain monoclonal
component on
electrophoresis <4 g/24 h
Stage II
Overall
data
minimally
abnormal
as shown
for
stage I
and no
Single
value
abnormal
as defined
For
stage III
1
to
2
Kg
PC
Stage III
one or more of the following:
Hemoglobin value <8.5 g/L
Serum Ca value >12 mg/dL
>
2 component
High monoclonal
production rates
Kg
IgG value >7 g/dL
PC
IgA value >5 g/dL
Advanced lytic bone lesions
(scale 3)
Urine light chain monoclonal
component on electrophoresis
>12 g/24 h
Subclassification:
a: Relatively normal renal function (serum creatinine value <2.0 mg/dL)
b: Abnormal renal function (serum creatinine >2.0 mg/dL)
Criteria for Diagnosis of Multiple Myeloma
Major criteria
1. Plasmacytomas on tissue biopsy
2. Bone marrow plasmacytosis (>30% plasma cells)
3. Monoclonal immunoglobulin spike on serum electrophoresis: IgG >35 g/L or IgA >20
g/L; k or l light-chain excretion >1.0 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 <0.50 g/L, IgA <1.00 g/L, or IgG <6.00 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
Normal Ig Values
IgM
g/L
0.5 – 1.5
mg/dL
50 - 150
IgA
1.5 – 5.0
150 - 500
IgG
5.0 – 15.0
500-1500
Presenting
Features
of Multiple
Myeloma
Feature
Incidence, %
Age >40 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:
Immunoelectrophoresis;
SEP:
Serum
protein
electrophoresis
Frequency of Different Types of Monoclonal Proteins
Produced By Plasma Cell Tumors
Monoclonal Protein
Frequency, %
IgG
IgA
52
21
IgD
IgE
2
<0.01
IgM (Waldenström's)
Light chain only
12
11
Heavy chain only
2 or more
<1
0.5
None detected
1
A. M-GUS
Monoclonal Gammopathy of Unclear Significance
1. Monoclonal component level:
IgG <35 g/L
IgA <20 g/L
Bence Jones protein <1.0 g/24 h
2. Bone marrow plasma cells <10%
3. No bone lesions
4. No symptoms
Classification
of
Monoclonal
Gammopathies
B. Indolent myeloma (as in A except:)
1. No bone lesions or only limited bone lesions
(<3 lytic lesions); no compression fractures
2. Monoclonal component levels
a. IgG <70 g/L
b. IgA <50 g/L
a. Performance status >70%
C. Smoldering
myeloma
(as in B except:)
b. Hemoglobin >10 g/dL
1. No bone lesions
c. Serum calcium normal
2. Bone marrow
plasma cells <30%
3. No symptoms or associated disease features
d. Serum creatinine <2.0 mg/dL
e. No infections
IMMUNOPHENOTYPING OF MYELOMA CELLS
Myeloma cells typically express monotypic Cytoplasmic Ig & lack SmIg
Most
Myeloma
Cells
Lack
Pan-B
CD19
&
CD20
Markers
CD56/58 -
CD19+
CD
38
NORMAL PC
CD45 CD79a
CD19 -
CD
138
CD56/58 +
MYELOMA CELL
Prognostic Parameters in Multiple Myeloma
Β2Microglobulin
LDH
Chromosome
13
abnormalities
<6 Plus 
Albumin
g/L
> 30
>6 Plus 
> 30
19
>6 Plus 
< 30
4
Β2- Microglobulin
ug/mL
MEDIAN SUVIVAL
Months
55
MANAGEMENT
OF
MULTPLE
MYELOMA
MP
VAD
M2
PROTOCOL
Quicker Response
Better control of symptoms
STANDARD
REGIMEN
NO OTHER
REGIMEN
PRODUCED
BETTER OS
OS > 3YRS
Less Myelotoxic &
more convenient before
autologous Transplant
Good after MP relapse
4 day infusion is
cumbersome & need
central Line
Aggressive
Alkylating
Combination
Better reserved
for relapse after
autotransplant
failure & other
Special cases
MP
VAD
M2
PROTOCOL
Vincristine
Melphalan
1 mg/kg
÷ 5 days
Each 5 weeks
Tailor dose ~
ANC nadir
Prednisolone
60 mg/day
For 5 days
Each 5 weeks
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
Vincristine
Carmustine
Cyclophosphamide
Melphalan
Prednisolone
Thalidomide
Begin at
200 mg
p.o. daily
Increase by
200 mg
every
2 weeks
for a goal
of
800 mg
p.o.
daily
Constipation
Neuropathy
Thalidomide
is
NOT
Myelotoxic
Somnolence
Thalidomide
Begin at 200 mg p.o. daily
Increase by 200 mg every
2 weeks for a goal of
800 mg p.o. daily
Angiogenesis
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
Thalidomide
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
2006 ASH UPDATE
MP
VAD
DEXA
Thalidomide
Lenalidomide “Revlimid”
Bortezomib “Velcade”
Pegylated Ribosomal Doxorubicin
THALIDOMIDE
Thal
DD
Pegylated
Ribosomal
Doxorubicin
+
Dexa
MDT
*
MPT
RMP
VMP
Velcade
“Bortezomib”
Revlimid
“Lenalidomide”
French randomized trial of
conventional versus high-dose therapy
BONE
MARROW
or
PERIPHERAL
STEM CELL
TRANSPLANTATION
HIGH DOSE
CHEMOTHERAPY
“VAD”
Autologous
Transplant
ALLOGENEIC
TRANSPLANT
Ideal for Young
Patients with
Histocompatible
Donor Sibling
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
ADJUVANT TREATMENTS IN MULTIPLE MYELOMA
BISPHOSPHONATES
INTERFERON
PAMIDRONATE
ZOLEDRONATE
HEMODIALYSIS
EPO
RADIATION
Inhibit Bone Resorption
Reduces Bone #
Suppresses Hypercalcemia
Convenient 1 injection/month
Pneumovax
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
THANK
YOU
Angiogenesis
Thalidomide:
potential mechanisms of antimyeloma activity.
(a)Direct effects; (b) antiadhesive action;
(b)(c) growth factor inhibition; (d) antiangiogenesis;
(c)(e) immunomodulation. bFGF, basic fibroblast growth factor;
(d)ICAM, intracellular adhesion molecule; IFN,
(e)interferon; IL, interleukin; TNF, tumor necrosis factor;
(f)VEGF, vascular endothelial growth factor
AMYLOIDOSIS
PRIMARY
AMYLOIDOSIS
Primary Amyloidosis
PC neoplasm that secretes an abnormal Ig,
Which deposits in various tissues & forms a
β-pleated sheet structure that binds Congo Red
dye with characteristic birefringence
Rare
Adult
Disease
CHF
HMG
15% of
Myeloma
have or
develop
10
Amyloidosis
80% of
Patients have
Monoclonal Ig
20% have
Myeloma
GUT
N.S.
CRF
Diagnostic
Biopsy Sites
Abd. s.c. fat-pad
Bone Marrow
Rectum
NERVES
Sensorimotor
neuropathy
Loss of Sphincter
control
MalAbsorption
Macroglossia
Sheikha
Primary Amyloidosis
Deposition in organs 
ORGANOMEGALY
BLEEDING
Increased vessel fragility
Coagulation factors binding
Amyloid is a fibrillary protein that causes organ failure
AL
Primary or
Ig- light chain
Amyloidosis
(~ Myeloma)
AA
Secondary
~
inflammation
AF
Familial
β2
Microglobulin
~ Dialysis
Sheikha
SOP
SOP
Solitary
Osseous
Plasmacytoma
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
Treatment
RT
35%
CURED
If Paraprotein +ve
it should disappear
after treatment
55%
MM
>10
years
10%
Local Recurrennce
or
Another SOP
Sheikha
EXTRA-OSSEOUS
PLASMACYTOMA
EOP
Extra
Osseous
Plasmacytoma
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
EOP
EXTRA
MEDULLARY
EXTRA
OSSEOUS
5% of PC neoplasms
No Lytic lesions or marrow plasmacytoma
Median Age: 55 years
M/F ratio:
2:1
80%
UPPER
RESPIRATORY
TRACT
Oropharynx
Nasopharynx
Sinuses
Larynx
15%
MM
L. N.
SKIN
PAROTID
TESTIS
GIT
Treatment RT
BLADDER
25%
Recurrence
CNS
BREAST
THYROID
15 – 20% may have PARAPROTEINEMIA
WALDENSTOROM’S
MACROGLOBULINEMIA
MONOCLONAL GAMMOPATHY
OF UNDETERMINATE SIGNIFICANCE
M-GUS
BENIGN MONOCLONAL GAMMOPATHY
HCD
HEAVY
CHAIN
DISEASES
μ
α
HCD
γ
HCD
γ
Gamma
HCD
A
variant
of
LPC
Lymphoma
α
Alpha
HCD
A
variant
of
Extranodal
Margianl Zone
MALT
Lymphoma
μ
mu
HCD
A
variant
of
CLL
α
Heavy Chain Disease
IPSID
Immunoproliferative Small Intestinal Disaese
Mediterranean Lymphoma
~ H. pylori
POLYNEUROPATHY
OSTEOSCLEROTIC
MYELOMA
(Sensorimotor
Demyelination)
ORGANOMEGALY
(HepatoSplenomegaly)
POEMS
SYNDROME
SKIN
ENDOCRINOPATHY
CHANGES
(Hyperpigmentation;
Hypertrichosis)
MONOCLONAL
GAMMOPATHY
(Diabetes;
Gynecomastia;
Testicular Atrophy;
Impotence)
Marrow infiltrated by PC & bone trabeculae thickened
Rare: 1 to 2% of PC dyscrasias Median Age: 50 years
HIWA HEMATOLOGY HOSPITAL
THANKS
Cellular origin of myeloma:
genetic and cellular events in disease pathogenesis
Interleukin-6-mediated myeloma cell growth.
BMSC, bone marrow stromal cell; IL, interleukin;
NF, nuclear factor; TGF, transforming growth factor
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
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
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
SOP
Solitary
Osseous
Plasmacytoma
None
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