Bone Disease in Myeloma
St. Petersburg, Russia
September 16, 2009
Bi
Brian G.M. D
i
ur e, M.D.
Bone Disease in Myeloma
Lytic Lesions
Spik
p e
Bone Marrow Plasma Cells
Collapse of Vertebrae
Biology of Myeloma
Vascular
Microenvironment
Cytokines
Lymphocytes/ Macrophages/
Hormones
Hematopoietic
p
Cells/ DNA/
// RNA
Chemicals
Myeloma Cells
Microbes
Neuro
Bone
Nor-adrenaline
osteoclasts/ osteoblasts/
matrix
Other organs Liver/ lymphatic/ brain...
Bone Disease and Response to
Treatm
eat en
e t
Bone damage is one aspect
aspect of
of myeloma
myeloma
Whether or not the myeloma cells are
sensitive to
to treatment
treatment is something
different
DNA changes
changes (SNPs: polymorphisms)
linked to severe bone disease are NOT
linked to
to high
high risk
risk by
by GEP
GEP (G17)*
(G17)
*Durie et al, Leukemia 2009
Bone Lesions in Myeloma
80% of patients have:
Lytic lesions and/or
Diffuse osteoporosis
Bone lesions cause:
cause:
Pain
Fractures
Pressure on nerves/spine
Ii
Increase in bl
blood calcium
Diagnosis of Bone Lesions
X-
X ray:
ray full
full skeletal
skeletal survey
CT scan or MRI with
gadolinium*
Bone density
Whole body FDG/PET with CT
and SUV assessment
Bone turnover studies, e.g.
NTX
* Caution required with gadolinium
Bone Disease Classification
Based upon Focal Lesions on X-ray
and/or
MRI
Staging With FDG-PET and CT
Multiple Myeloma FDG PET:
FL
PET & MRI
Severe Diffuse (D) and Focal (F) Disease
FL on PET & MRI:
Severe Diffuse (D) and Focal (F)
F
F
D
F
D
D
F
D
D
D
FDG PET scan
MRI STIR
of thoracic
weighted of
spine
thoracic spine
Serial PET Shows Early Response
X-ray
JAN
APRIL
JUNE
January
M-protein
MRI
November
T1
STIR
January
April
MRI-CR "lags" Behind Clinical Response
Incidence of nCR/CR and Incidence of MRI-CR
PET Shows Earlier Evidence of Response
Patients with 1+ Baseline FL detectable by PET and by
yy MRI
100%
80%
PET & actual
60%
MRI
40%
12-Month
20%
Events / N Estimate
MRI-CR
12 / 59
17%
nCR/CR
33 / 59
61%
P<0.001
0%
0
6
12
18
24
Months After Starting VAD
* Walker, et al. 2005 ASH
Treatment for Bone Disease
Treat the
the myeloma
Chemotherapy
Radiation
Treat the bone
Bisphosphonates
Calcium/Vitamin D
St
Suppor itive care
Kyphoplasty
Radiotherapy
May be useful in specific situations
Pain control
Spinal cord compression
Prevent or treat pathologic fractures
However, dl
destroys normal marrow
Vertebroplasty
Source: Fourney et al. J Neurosurg (Spine 1) 2003;98:2130.
Balloon Kyphoplasty
Insert Balloon
Inflate Balloon
Fill Compacted
Then Remove
Space with Cement
Bisphosphonates
Primary Therapy for myeloma
myeloma
bone disease to reduce skeletal
related events (SREs)
Recommended as ongoing
therapy for all myeloma patients
with bone disease
Starting Bisphosphonates
Lesions on
on x-ray are
are main indication
Positive findings on MRI and/or CT PET
also show
show bone
bone lesions
lesions
MRI: > 7 lesions and/or progression/ pain
PET: high SUV plus
plus bone
bone destruction
destruction on CT
Reduced bone mineral density and/or
id
increased
i
ur nary NTX
NTX
Both support possibility of bone disease
Bisphosphonate Guidelines
Mayo/ IMF/ASCO Perspectives*
Starting BP
Duration of therapy
Choice of BP
Rl
Renal issues
Dental evaluation
*SEE: Mayo Clinic Proceedings, 82(4);516-522. April 2007
Duration of Bisphosphonates
Not indefinite
Maximum 2 years
Can consider
consider stopping
stopping early ifif > VGPR
AND
Nt
No ac itive bone di
disease
Stop or reduce frequency at 2 years if
no active bone disease
Restart if new disease
Choice of Bisphosphonate
Consensus that "efficacy equivalent"
equivalent for
available drugs:
Aredia (Pamidronate)
()
Zometa (Zoledronic Acid)
Concern that there is higher risk of toxicities
with Zometa
Jaw osteonecrosis and renal toxicity both potential
issues.
... BUT toxicities preventable with
with proper
proper awareness
awareness
Current Bisphosphonates
Aredia
90 mg over 2-4 hrs. monthly
Zometa
4 mg over 15-45 minutes monthly
Questions:
If
Inf i
us on titimes
Long term duration/ schedule
Osteonecrosis of Jaw on Panorex
Time to Onset of Osteonecrosis in Myeloma
Zometa vs Aredia
25%
36-
36 Month
25%
Events / N Estimate
Zometa
10 / 211
10%
P = .002
20%
Aredia
10 / 413
4%
15%
Data censored at 36 months
10%
5%
0% 0
12
24
36
Months from start of Aredia or Zometa
Management Recommendations for ONJ
Before starting bisphosphonates (BP)
Dental evaluation/ treatment
treatment
While On BP
Regul
egu ar
a den
de tal
ta car
ca e/ check
ec -ups
Avoid dental extraction/ procedures
Review type/ schedule of BP with MD
? Redk
duce Frequency or take "d
"drug hol d
i ay"
Established ONJ
Antibiotics
Minor dental procedures
Rinses/ supportive
pp
measures
Stop BP Rx to allow healing
Possible hyperbaric 02
Impact of Preventive Strategies
Dimopolous et al 2008 (Am J Oncology)
Group A
2 year hazard of ONJ (with Zometa)
16%
Group B (after implementation)
2 year hazard
5%
New Approaches to Target Osteoclast
and/or Osteoblast
Denusomab (Amgen)
MIP 1 modulation
DKK 1 protein inhibition
VELCADE
Cholesterol lowering statins,
g, e.g.
g
Lipitor
Quadramet (Samarium)
Mechanism of Action for Denosumab
Overall Strategies
Diagnose & monitor bone
bone
disease
Use bisphosphonate therapy
with good monitoring
Recommend exercise, pain
reduction and avoidance of
risky situations
situations