Bone Disease in Myeloma
Wa
W shington, DC
DC
August 8, 2009
Brian G.M. Durie, 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 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 skeletal survey
CT scan or MRI
Whole body CT/PET
Bone density
Bone turnover studies, e.g.
NTX
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, radiation damages
normal marrow
Vertebroplasty
Source: Fourney et al. J Neurosurg (Spine 1) 2003;98:2130.
Balloon Kyphoplasty: A Minimally
Invasive Fracture Reduction Procedure
KyphX Introducer Tool
KyphX IBT inflation:
KyphX IBT Removal:
Kit:
· Rd
Reduces th
the f
t
rac ure.
· Leaves a defined
defined cavity
· Allows precise,
· Compacts the bone.
and trabecular dam that
minimally invasive access
· May elevate endplates
can be filled with an
to the vertebral body.
approved bone void filler
· Pro ides
v
working
king
of the physician
physician'sc
s hoice
choice
channel
Balloon Kypho
yp
plast
p
y Case Study
Patient:
61 YO Female
Diagnosis:
g
Multiple My
pyeloma
Fracture Reduced:
T11, L2, 1 ½ yrs old
Courtesy of Kent Grewe, M.D., Portland, OR
Lieberman and Reinhardt Study
Myeloma Patient Outcomes: Pain Improvement
Vis
Vi ual
al An
Anal
a o
l g Scal
S
e
cal
7
6.18
)01 6
to 5
(0inaP 4d
2.84
te 3
a
f-R 2
elSn 1a
Me
0 = no pain
0
pre-
e op
op
post-
t op
op
p<0.0001
Source: Lieberman and Reinhardt. Clinical Orthopaedics and Related Research. 2003;415(S):176-186.
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
Bisphosphonate Use Guidelines
Starting BP
Duration of therapy
Choice of BP
Rl
Renal issues
Dental evaluation
See both
both May
Ma o
y and
and IMWG Guidelines
Guidelines
Mayo Clinic Proceedings, 82(4);516-522. April 2007
Starting Bisphosphonates
Lesions on
on x-ray? Yes or
or No?
No?
Positive findings on MRI and/or CT PET?
MRI: > 7 lesions
lesions and/or progression/ pain
PET: high SUV; CT abnormal
Rd
Reduced bone mineral densitity?
Urinary NTX increased?
Duration of Bisphosphonates
Not indefinite
Minimum 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
Stopping versus Reduced
Dose/ Schedule
Consider both renal/ ONJ issues
No data on Q2 or 3 months
Clinical trials needed
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
New Approaches to Enhance Osteoblast
Activity and Heal
Heal Bones
Bones
Denosumab (Amgen)
(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
Take bisphosphonate therapy
with good monitoring
Exercise
Get pain relief
Avoid risky
risky situations