Management of

Multiple Myeloma

Irza Wahid

Subdivision
Subdivision of
of Hematology
Hematology Medical
Medical Oncology
Departement of Internal Medicine
Medicine
Medical
Medical Faculty,
Faculty, Andalas University

Blok Muskuloskeletal

Bone Metastases

Clinical Importance and Prognosis of

Bone Metastases

Myeloma
Renal
Melanoma
Bladder
Thyroid
Lung
Breast
Prostate

PA-3

Disease prevalence,
U.S. (in thousands)

Bone mets.
incidence (%)

Median
survival (mo)

75 - 100
198
467
582
207
386
1,993
984

70 - 95
20 - 25
14 - 45
40
60
30 - 40
65 - 75
65 - 75

24
12
6
6-9
48
7
24
36

NCI, 197; International Myeloma Foundation, 2001.

Multiple Myeloma

Definition
B-cell malignancy characterised
by
abnormal proliferation of plasma cells to
produce a monoclonal immunoglobulin
( M protein )

Genesis of Blood Products

Lymphoid
Stem Cell

T-Cell

CFU-T

CFU-L
B-Cell
CFU-B

Pluripot
ent
Stem
Cell
Hemocytoblast

Sel Plasma

Ig

eosinophil
CFU-Eosin
basophil
CFU-Bas
neutrophil

monocyte

CFUGM

Myeloid
Stem Cell

CFU-M
Copyright 2006 by Elsevier, Inc.

macrophage
platelets

CFU-MEG

BFU-E

erythrocyte

MM Epidemiology
19,900 new cases per yr, 50,000 total
cases, 2% cancer deaths in U.S.
Higher incidence in African
Americans, Pacific Islanders
Median age 71 yrs
Exposure to radiation, petroleum
products, pesticides & Agent Orange

Greenlee
Greenlee RT.
RT. CA
CA Cancer
Cancer JJ Clin
Clin 2001;51:15.
2001;51:15. Bergsagel
Bergsagel DE.
DE. Blood
Blood 1999;94:1174
1999;94:1174

Statistics
Second most prevalent blood cancer
Approximately 1% of all cancers and 2%
of all cancer deaths.
45,000 currently have multiple myeloma
14,600 new cases of myeloma each year.
Responsible for more than 10,000 deaths
in the United States annually.

http://www.multiplemyeloma.org/about_myeloma/2.03.asp

How Plasma Cells Work

Develop from stem cells in bone marrow
Stem cells develop into B cells (B
lymphocytes)
Antigens enter body then B cells develop
into plasma cells
Produce antibodies

Normal Cell (5%)

Myeloma Cells (10%)

What Causes Myeloma Cells To

Grow?
Adhesion molecules
Stromal cells
Interactions:

Cytokins (chemical messengers)

Growth factors that promote angiogenesis
Inactivated immune system

CLINICAL MANIFESTASION
Clinical manifestations are related to malignant
behavior of plasma cells and abnormalities produce
by M protein
plasma cell proliferation:
- multiple osteolytic bone lesions
- hypercalcemia
- bone marrow suppression ( pancytopenia )
monoclonal M protein
- decreased level of normal immunoglobulins
- hyperviscosity

Symptoms
Anemia
Fatigue
Bone pain

Back
Back
Ribs
Ribs

Unexplained bone fractures

Repeated infections

Pneumonia
Pneumonia
Bladder
Bladder and
and kidney
kidney infection
Urinary
Urinary tract infection

Weight loss
Weakness and numbness in limbs

Symptoms
Abnormal proteins

Blood and urine

Polyclonal to Monoclonal proteins

High level of calcium in blood

Excessive thirst and urination
Sleepiness
Constipation
Nausea
Loss of appetite
Mental confusion

Signs & Symptoms in 1027 Newly

Diagnosed Myeloma Patients
80
80
70
70

79
73

% patients
patients
%

60
60

66

50
50
40
40
30
30

32

20
20

19

10
10

13

12

00
Bone
Bone
lesions
lesions

Bone
Bone
pain
pain

Hb<12
Hb<12
g/dL
g/dL

Kyle
Kyle RA.
RA. Mayo
Mayo Clin
Clin Proc
Proc 2003;78:21-33
2003;78:21-33

Fatigue
Fatigue

Cr
Cr >2
>2
mg/dL
mg/dL

Ca
Ca >11
>11
mg/dL
mg/dL

Wt
Wt loss
loss
(>9
(>9 kg)
kg)

Screening and Diagnosis

Blood and urine tests

X-rays
Magnetic Resonance Imaging (MRI)
Computerized Tomography (CT)
Bone marrow examination

Diagnostic Criteria for Multiple Myeloma

Major criteria
I. Plasmacytoma on tissue biopsy
II. Bone marrow plasma cell > 30%
III. Monoclonal M spike on electrophoresis IgG >
3,5g/dl,
IgA > 2g/dl, light chain > 1g/dl in 24h urine
sample
Minor criteria
a. Bone marrow plasma cells 10-30%
b. M spike
c. Lytic bone lesions
d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

Diagnostic Criteria for Multiple Myeloma

Diagnosis:

I + b, I + c, I + d
II + b, II + c, II + d
III + a, III + c, I II + d
a + b + c, a +b + d

Staging of Multiple Myeloma

Clinical staging
is based on level of haemoglobin, serum
calcium, immunoglobulins and presence or
not of lytic bone lesions
subclassification
A - creatinine < 2mg/dl
B - creatinine > 2mg/dl

Myeloma Prognostic Factors

Serum 2 microglobulin
Cytogenetics - del13 or 13q-,
t(4;14), 17p-, hypodiploid
C-reactive protein
LDH
Plasmablastic morphology
Peripheral blood plasma cells
Gene expression profile

Incidence of Chromosomal
Abnormalities in MM
Genomic Aberrations

Incidence of aberration

Del (13)

48%

Del (17p)

11%

t(4;14) (p16;q32)

14%

Hyperdiploidy

39%

t(11;14) (q13;q32)

21%

n = 1064 patients
patients
Chromosomal changes observed in 90% of patients

International Staging System (ISS)

for Symptomatic Myeloma
Stage

Criteria

Median
Survival (mo)

2m < 3.5 mg/L

albumin 3.5 g/dL

62

II*

Not stage I or III

44

III

2m 5.5 mg/L

29

*2m
*2m << 3.5
3.5 mg/L
mg/L and
and albumin
albumin << 3.5
3.5 g/dL
g/dL or
or
2m
2m 3.5
3.5 -- << 5.5
5.5 mg/L,
mg/L, any
any albumin
albumin
Greipp
Greipp et
et al.
al. JJ Clin
Clin Oncol
Oncol 2005;
2005; 23:
23: 3412-20
3412-20

Serum Protein Electrophoresis

Normal

Monoclonal Protein
in Myeloma

Kyle
Kyle RA
RA and
and Rajkumar
Rajkumar SV.
SV. Cecil
Cecil Textbook
Textbook of
of Medicine,
Medicine, 22nd
22nd Edition,
Edition, 2004
2004

Distribution of
Monoclonal Proteins
M protein found in serum or urine
or both at time of diagnosis: 97%
Serum M spike by protein
electrophoresis: 80%
Abnormal serum immunofixation:
93%
Abnormal urine immunofixation:
75%
Non-secretory myeloma: 3%

Malignant Plasma Cells in

Marrow

Normal Bone Biology

Bone
Bone is always
always in
in an
an active
active state
state of
of
remodeling
remodeling (build up/break down)

Resorption:
Resorption: stimulated
stimulated osteoclasts
osteoclasts
erode
erode bone,
bone, creating
creating aa cavity
cavity

Reversal:
Reversal: bone
bone surface
surface is
is prepared
prepared
for
osteoblasts
to
begin
forming
for osteoblasts to begin forming bone
bone

Formation:
Formation: osteoblasts
osteoblasts replace
replace
resorbed
resorbed bone
bone and
and fill
fill the
the cavity
cavity with
with
new
bone
new bone

Resting:
Resting: bone
bone surface
surface rests
rests until
until aa
new
new remodeling
remodeling cycle
cycle begins
begins

Adapted from Novert's Pharmaceuticals

Vicious cycle of Bone Metastases

Tumor Cells in
Bone

Bone-derived tumor
growth factors
Transforming growth factor
Insulin-like growth factors
Fibroblast growth factors
Platelet-derived growth factor
Bone morphogenic proteins

Osteoblastic factors
Endothelin-1
Fibroblast growth factor
Bone morphogenic proteins
Insulin-like growth factors

Osteolytic factors

RANKL
PTH-rp
Interleukins 1,6,8
TNFs
M-CSF

Osteoblasts

Osteoclasts
New bone
Mineralized bone matrix
Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

Osteolytic metastases
Tumor cells produce growth factors
that stimulate bone destruction
i.e. RANK ligand
Osteoclasts are activated and break
down bone
Osteoblasts cannot build bone back
fast enough
Decreased bone density and
strength; high risk for fracture
Patel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7.

Osteoblastic Metastasis
Osteoblasts are
stimulated by tumors to
lay down new bone
Bone becomes
abnormally dense and
stiff
Paradoxically bones are
also at risk of breaking

Bone Imaging in MM
Skeletal radiography is the primary
diagnostic test to detect destructive
bony lesions in multiple myeloma
MRI is useful in assessing whether
spinal compression fractures are due
to a focal mass or from osteopenia
due to increased osteolysis
PET scans can be used to detect soft
tissue or bone metastases
Angtuaco
Angtuaco EJ
EJ et
et al.
al. Radiology.
Radiology. 2004;231:11-23.
2004;231:11-23.

Treatment Options
Goals:
Attack the cancer
Strengthen the bone
Reduce symptoms

Includes:
Systemic therapy
Local therapy

Initial Approach to Treatment

Clearly not a transplant
candidate

Potential transplant
candidate

Can include melphalanbased combinations

Non-alkylator based
induction

Stem cell harvest

Therapy Options:
NonTransplant Candidate
Melphalan + Prednisone (MP)
Melphalan + Prednisone + Thalidomide
(MPT)
Dexamethasone (Dex)
Thalidomide + Dexamethasone (Thal/Dex)
Lenolidomide + Dexamethasone (Rev/Dex)
Bortezomib +/- Dexamethasone (Vel/Dex)

NCCN
NCCN Practice
Practice Guideline-v.2.2008
Guideline-v.2.2008

 Alternative chemotherapy
M2 ( Vincristine, Melphalan,
Cyclophosphamid, BCNU,
Prednisone)
VAD (Vincristin, Adriamycin,
Dexamethasone)
Response rate 50-60% patients
Long term survival 5-10% patients

Bortezomib (Velcade)
Reversible inhibitor of chymotrypsinlike activity of 26-S proteasome
Prevents proteolysis of ubiquitinated
proteins & can lead to apoptosis of
tumor cells
Dosing: 1.3 mg/m2 IV bolus d 1, 4, 8,
& 11 (21-d treatment cycle) for a
maximum of 8 cycles
FDA approved for MM that has
relapsed after 1 prior standard
therapies

Systemic Therapies
Pain control
Pain medication
Tylenol,
Tylenol, NSAIDs (ibuprofen), narcotics, steroids
steroids
Success
Success can
can be
be limited
limited by
by side
side effects
effects

Radiopharmaceuticals
Strontium-89
Strontium-89 and
and samarium-153:
samarium-153: radioactive
radioactive
particles
particles travel
travel directly to tumor
tumor in
in bone
bone
Can
Can reduce
reduce pain
pain refractory
refractory to
to other
other measures
measures
Infrequently
Infrequently used

Systemic Therapies: Bisphosphonates

Bind to and inhibit osteoclast action
Inhibit
Inhibit bone
bone breakdown
breakdown
Prevent
Prevent bone
bone damage
damage
Improve
Improve bone
bone density
density and
and strength
strength

Recommended for almost everyone with

cancer bone metastases

Thank You