2. 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
5. MULTIPLE MYELOMA
WALDENSTROM’S
MACROGLOBULINEMIA PARA
PROTEINEMIAS
PRIMARY AMYLOIDOSIS
HEAVY CHAIN DISEASES
M-GUS a
h
h eik
S
6. ANEMIA BONE PAIN
#
VERTEBRAL COLLAPSE
BLEEDING LYTIC BONE LESIONS
INFECTION
ORTHOPEDIC
SURGEON
NEURO- NEPHRO-
LOGIST HEMATOLOGIST LOGISTS
RENAL
HYPERVISCOSITY
FAILURE
kha
S hei
7. 1% of All Cancers 2% of All Cancer Deaths
MULTIPLE
MYELOMA
Average Age ~ 65 Black: White = 2:1
8. MULTIPLE
MYELOMA
BONE MARROW
INFILTRATION
OSTEOLYTIC PARAPROTEIN
BONE LESIONS PRODUCTION
ha
h eik
S
9. ↓ PLATELET
↓ WBC PANCYTOPENIA ANEMIA
BONE MARROW
INFILTRATION
MULTIPLE
MYELOMA
ha
h eik
S
10. ha
h eik
S
INFECTION
BLEEDING
↓ PLATELET
↓ WBC PANCYTOPENIA ANEMIA
IMMUNE BONE MARROW MULTIPL
SUPPRESSION INFILTRATION E
MYELOM
A
11. Chemotherapy myelosuppression
INFECTION
Steroid immunosuppression
MULTIPLE
MYELOMA
↓ WBC PANCYTOPENIA
IMMUNE BONE MARROW
SUPPRESSION INFILTRATION
ha
h eik
S
12. MULTIPLE
MYELOMA
ANEMIA
BONE
PAIN
BONE OSTEOLYTIC
#
BONE LESIONS
VERTEBRAL
COLLAPSE
↑ Ca++ RENAL
a FAILURE
heikh
S
13. MULTIPLE
MYELOMA
ANEMIA
HEMO-
DILUTION
PARAPROTEIN
PRODUCTION
HYPER
VISCOSITY
CNS
SYMPTOMS
ha
h eik
S
14. MULTIPLE
MYELOMA
INTERFERENCE
WITH CLOTTING
BLEEDING
FACTORS
ANEMIA
PARAPROTEIN COATING OF
PRODUCTION PLATELETS
ha
h eik
S
15. MULTIPLE
MYELOMA
LIGHT
CHAINS
PARAPROTEIN
PRODUCTION
RENAL
FAILURE
AMYLOID a
h
h eik
S
16. ?RENAL
INFECTION PYELONEPHRITIS FAILURE
LIGHT
CHAINS
↑ Ca++
RENAL
FAILURE
MULTIPLE
AMYLOID a
h
MYELOMA h eik
S
17. PARAPROTEIN ?BLEEDING
INTERFERENCE
WITH CLOTTING
FACTORS
BONE MARROW
INFILTRATION BLEEDING
MULTIPLE
MYELOMA
PARAPROTEIN
COATING OF ha
PLATELETS h eik
S
18. MULTIPLE
MYELOMA
?ANEMIA
BLEEDING
BONE MARROW
INFILTRATION
HEMO-
DILUTION
RENAL
kha FAILURE
S hei
19. a
BONE MARROW heikh
S
INFILTRATION
OSTEOLYTIC PARAPROTEIN
BONE LESIONS PRODUCTION
INFECTION
RENAL
BLEEDING
FAILURE
MULTIPLE BONE PAIN,
MYELOMA HYPER- # & VERT.
↑ Ca++ ANEMIA
VISCOSITY COLLAPSE
20. 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
21. ha
IgG S h eik
>50%
MULTIPLE Light
IgA
MYELOMA Chain
25% 20%
Bi-clonal
IgD
rare
Non-
Secretory
?
IgM
22. Immunofixation
performed on serum IgG k
from a patient with
monoclonal
immunoglobulin Gk
(IgGk)
&
a patient without a
monoclonal protein
normal
23. OAF
(IL-1/ TNF)
OSTEOCLASTS
PLASMA CELLS
IL- 6 PDGF/ IL-6
BMSC ha
h eik
S
“Bone Marrow Stromal Cells”
24. 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 IL6
which then acts a paracrine growth factor promoting survival of MM cells &
inhibiting apoptosis
25. IL-1 β
Osteoclast OSTEO-
Activation
OAF TGF- β LYTIC
BONE
Osteoblast LESIONS
Other
Suppression
Cytokines
26. STAGING OF MYELOMA ikh
a
S he
1 trillion PC (1012) = 1 Kg
I II III
< 1 >
1 to 2
Kg 2 Kg
PC Kg PC
PC HIGH
LOW
CELL CELL
MASS MASS
<0.6 x 1012/m2 >1.2 X 1012/m2
27. Durie-Salmon Myeloma Staging System
Stage I Stage II
All of the following: Stage III
Overall
one or more of the following:
Hemoglobin value >10 g/dL data
minimally Hemoglobin value <8.5 g/L
Serum calcium value normal
(<12 mg/dL) abnormal Serum Ca value >12 mg/dL
as shown Advanced lytic bone lesions
On roentgenogram,
for (scale 3)
normal bone structure
(scale) or solitary bone stage I
High monoclonal component
plasmacytoma only and no
production rates
Single
Low monoclonal component IgG value >70 g/L
value
production rates
abnormal IgA value >50 g/L
IgG value <50 g/L as defined Urine light chain monoclonal
IgA value <30 g/L For component on electrophoresis
Urine light chain monoclonal stage III >12 g/24 h
component on
electrophoresis <4 g/24 h
Sh
Subclassification: eik
h
a: Relatively normal renal function (serum creatinine value <2.0 mg/dL) a
b: Abnormal renal function (serum creatinine >2.0 mg/dL)
28. Durie-Salmon Myeloma Staging System
Stage I Stage II
All of the following: Stage III
Overall
one or more of the following:
Hemoglobin value >10 g/dL data
minimally Hemoglobin value <8.5 g/L
Serum calcium value normal
(<12 mg/dL) abnormal Serum Ca value >12 mg/dL
1
<
On roentgenogram,
as shown
>
Advanced lytic bone lesions
normal bone structure to
for (scale 3)
1
(scale) or solitary bone stage I 2
plasmacytoma only 2
and no
High monoclonal component
Kg Single Kg
production rates
Low monoclonal component
Kg IgG value >7 g/dL
PC
production rates
value
PC
IgG value <5 g/dL PC
abnormal
as defined
IgA value >5 g/dL
Urine light chain monoclonal
IgA value <3 g/dL For component on electrophoresis
Urine light chain monoclonal stage III >12 g/24 h
component on
electrophoresis <4 g/24 h
Sh
Subclassification: ei
a: Relatively normal renal function (serum creatinine value <2.0 mg/dL) kh
a
b: Abnormal renal function (serum creatinine >2.0 mg/dL)
29. 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; κ or λ 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 ha
h eik
S
31. Presenting
Features Feature Incidence, %
of Multiple
Age >40 yr 98
Myeloma
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 IEP:
Spike on SEP 76 Immuno-
Hypogammaglobulinemia on SEP 9 electro-
phoresis;
Minor or no abnormalities on SEP 15
Spike on urinary protein electrophoresis 75
SEP:
Monoclonal heavy chain on serum IEP 83 Serum
Monoclonal light chain on IEP 8 protein
Nonsecretory 0.3 electro-
Amyloidosis 7 phoresis
32. Frequency of Different Types of Monoclonal Proteins
Produced By Plasma Cell Tumors
Monoclonal Protein Frequency, %
IgG 52
IgA 21
IgD 2
IgE <0.01
IgM (Waldenström's) 12
Light chain only 11
Heavy chain only <1
2 or more 0.5
None detected 1
33. 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 Classification
2. Bone marrow plasma cells <10% of
3. No bone lesions Monoclonal
4. No symptoms 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
C. Smoldering
3. No symptoms or associated disease features
myeloma
a. Performance status >70% (as in B except:)
b. Hemoglobin >10 g/dL 1. No bone lesions
c. Serum calcium normal 2. Bone marrow
d. Serum creatinine <2.0 mg/dL plasma cells <30%
e. No infections
34. IMMUNOPHENOTYPING OF MYELOMA CELLS
Myeloma cells typically express monotypic Cytoplasmic Ig & lack SmIg
CD19+ CD56/58 -
CD
Most NORMAL PC
Myeloma
38
Cells CD45 -
Lack
PanB CD79a
CD56/58 +
CD19 CD19 -
& MYELOMA CELL
CD20
Markers
CD
138 h eik
ha
S
35. Prognostic Parameters in Multiple Myeloma
Chromosome
Β2-
Microglobulin
LDH 13
abnormalities
Β2- Microglobulin Albumin MEDIAN SUVIVAL
ug/mL g/L Months
<6 Plus > 30 55
>6 Plus > 30 19
>6 Plus < 30 4
ha
h eik
S
37. VAD M2
MP PROTOCOL
Quicker Response
Better control of symptoms
Less Myelotoxic &
Aggressive
more convenient before
STANDARD Alkylating
autologous Transplant
REGIMEN Combination
Good after MP relapse
NO OTHER Better reserved
REGIMEN for relapse after
4 day infusion is
PRODUCED autotransplant
cumbersome & need
BETTER OS failure & other
central Line
Special cases
OS > 3YRS
Sh
eik
ha
38. VAD M2
MP PROTOCOL
Vincristine
0.4 mg/m2/day
Melphalan i.v. infusion over 4 days
1 mg/kg Vincristine
÷ 5 days Adriamycin
9 mg/m2/day Carmustine
Each 5 weeks
i.v. infusion over 4 days
Tailor dose ~ Cyclophosphamide
ANC nadir Dexamethasone
20 mg/m2 Melphalan
Prednisolone p.o. on days
60 mg/day 1-4, 9-12, & 17-20 Prednisolone
For 5 days
REPEAT COURSE Sh
Each 5 weeks eik
EACH 28 DAYS ha
39. Thalidomide
Begin at
200 mg
p.o. daily
Thalidomide
Increase by
is
200 mg
every NOT
2 weeks Myelotoxic
for a goal
of
800 mg
p.o.
daily
Sh
eik
Constipation Neuropathy Somnolence ha
40. 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
45. BONE
MARROW
or
PERIPHERAL
STEM CELL
TRANSPLANTATION
HIGH DOSE
CHEMOTHERAPY ALLOGENEIC
“VAD”
TRANSPLANT
Autologous Ideal for Young
Patients with
Transplant Histocompatible
Donor Sibling ha
eik
Sh
46. 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
47. ADJUVANT TREATMENTS IN MULTIPLE MYELOMA
BIS
PHOSPHONATES
INTERFERON
PAMIDRONATE
ZOLEDRONATE
HEMO
EPO DIALYSIS
RADIATION
Inhibit Bone Resorption
Reduces Bone #
Suppresses Hypercalcemia
Pneumovax
Convenient 1 injection/month ha
h eik
S
48. 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
52. 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
80% of 15% of
Diagnostic
Rare Patients have Myeloma
Biopsy Sites
Monoclonal Ig have or
Adult develop
Abd. s.c. fat-pad
Disease 20% have 10
Bone Marrow
Myeloma Amyloidosis
Rectum
GUT NERVES
HMG Sensorimotor
CHF N.S. Mal- neuropathy
Absorp- Loss of Sphincter
CRF tion control
Macroglossia
Sheikha
53. Primary Amyloidosis
Deposition in organs BLEEDING
Increased vessel fragility
ORGANOMEGALY Coagulation factors binding
Amyloid is a fibrillary protein that causes organ failure
AL AA β2
Primary or Secondary AF Micro-
Ig- light chain globulin
Amyloidosis ~ Familial
inflammation ~ Dialysis
(~ Myeloma)
Sheikha
56. SOP a
heikh
S
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
10%
55% >10 Local Recurrennce
MM years or
Another SOP
59. 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
60. EOP ha
h eik
S
EXTRA EXTRA
OSSEOUS MEDULLARY
5% of PC neoplasms
No Lytic lesions or marrow plasmacytoma
80% Median Age: 55 years
UPPER
RESPIRATORY
M/F ratio: 2:1
TRACT
L. N. PAROTID
SKIN
Oropharynx TESTIS
Nasopharynx
Sinuses
Larynx GIT
BLADDER CNS BREAST THYROID
15% 25%
MM Treatment RT Recurrence
15 – 20% may have PARAPROTEINEMIA
66. HCD
γ α μ
Gamma Alpha mu
HCD HCD HCD
A
variant A
A
of variant
variant of
LPC of
Extranodal CLL
Lymphoma
Margianl Zone
MALT ha
Lymphoma h eik
S
67. α
Heavy Chain Disease
IPSID
Immunoproliferative Small Intestinal Disaese
Mediterranean Lymphoma
~ H. pylori
kha
S hei
68. OSTEOSCLEROTIC
POLYNEUROPATHY MYELOMA ORGANOMEGALY
(Sensorimotor (Hepato-
Demyelination) Splenomegaly)
POEMS
SYNDROME
ENDOCRINOPATHY
SKIN CHANGES (Diabetes;
(Hyperpigmentation; Gynecomastia;
Hypertrichosis)
MONOCLONAL Testicular Atrophy;
GAMMOPATHY Impotence)
Marrow infiltrated by PC & bone trabeculae thickened
Rare: 1 to 2% of PC dyscrasias Median Age: 50 years
69.
70.
71. Cellular origin of myeloma:
genetic and cellular events in disease pathogenesis
72. Interleukin-6-mediated myeloma cell growth.
BMSC, bone marrow stromal cell; IL, interleukin;
NF, nuclear factor; TGF, transforming growth factor
73. 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
74. 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
75. 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