Transcript Document

Management of
Multiple Myeloma
Irza Wahid
Subdivision of Hematology – Medical Oncology
Departement of Internal Medicine
Medical Faculty, Andalas University
Blok Muskuloskeletal
Bone Metastases
Clinical Importance and Prognosis of
Bone Metastases
Myeloma
Renal
Melanoma
Bladder
Thyroid
Lung
Breast
Prostate
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
PA-3
NCI, 197; International Myeloma Foundation, 2001.
Multiple Myeloma
• Definition
B-cell malignancy
characterised
by
abnormal proliferation of plasma cells able
to produce a monoclonal immunoglobulin
( M protein )
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 RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 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
Multiple Myeloma
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
– Ribs
• Unexplained bone fractures
• Repeated infections
– Pneumonia
– Bladder and kidney infection
– 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
70
79
73
% patients
60
66
50
40
30
32
20
19
10
13
12
0
Bone
Bone
Hb<12
lesions
pain
g/dL
Kyle RA. Mayo Clin Proc 2003;78:21-33
Fatigue
Cr >2
mg/dL
Ca >11
mg/dL
Wt loss
(>9 kg)
Screening and Diagnosis
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•
•
•
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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
• correlates with myeloma burden and
prognosis
I. Low tumor mass
II. Intermediate tumor mass
III. High tumor mass
• 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
• Chromosomal changes observed in 90% of patients
International Staging System (ISS)
for Symptomatic Myeloma
Stage
Criteria
Median
Survival (mo)
I
β2m < 3.5 mg/L
albumin ≥ 3.5 g/dL
62
II*
Not stage I or III
44
III
β2m ≥ 5.5 mg/L
29
*β2m < 3.5 mg/L and albumin < 3.5 g/dL or
β2m 3.5 - < 5.5 mg/L, any albumin
Greipp et al. J Clin Oncol 2005; 23: 3412-20
Serum Protein Electrophoresis
Normal
Monoclonal Protein
in Myeloma
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 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 is always in an active state of
remodeling (build up/break down)
•
Resorption: stimulated osteoclasts
erode bone, creating a cavity
•
Reversal: bone surface is prepared
for osteoblasts to begin forming bone
•
Formation: osteoblasts replace
resorbed bone and fill the cavity with
new bone
•
Resting: bone surface rests until a
new remodeling cycle 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 EJ et al. Radiology. 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 Practice 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, NSAIDs (ibuprofen), narcotics, steroids
• Success can be limited by side effects
– Radiopharmaceuticals
• Strontium-89 and samarium-153: radioactive
particles travel directly to tumor in bone
• Can reduce pain refractory to other measures
• Infrequently used
Systemic Therapies: Bisphosphonates
• Bind to and inhibit osteoclast action
– Inhibit bone breakdown
– Prevent bone damage
– Improve bone density and strength
• Recommended for almost everyone with
cancer bone metastases
Thank You