Bone Disease in Myeloma
Boston, Massachusetts
Saturday, July 26, 2008
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...
Micro Environment and Bone Biology
St
Syst
i
em c
· 1GF1
· Osteoblasts...
Local
· Cells
· Matrix
· Blood Vessels...
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
Bisphosphonates
Primary Therapy
Therapy for myeloma
myeloma bone
bone
disease to reduce skeletal related
events (SREs)
Recommended as ongoing therapy
for all myeloma patients with bone
disease
Bisphosphonate Use Guidelines 2007
Mayo/ IMF Perspectives*
Starting BP
Duration of therapy
Choice of BP
Rl
Renal issues
Dental evaluation
*SEE: Mayo Clinic Proceedings, 82(4);516-522. April 2007
Starting Bisphosphonates
Lesions on
on x-ray
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 actitivitity?
Increased bone turnover?
Not "smoldering"
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* at 2 years if no active bone
disease
Restart if new disease
*Every 3 months also an option.
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
that "efficacy equivalent"
equivalent
(S.R.E.s) for available BPs:
Pamidronate; Clodronate; Zoledronic
Zoledronic
acid....
Concern that
that there
there is higher risk of
toxicities with Zometa
Jaw osteonecrosis
osteonecrosis major concern
concern,
but renal toxicity also greater.
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
How Frequent is Osteonecrosis?
Rare prior to 2001
2003 Marx epo
r
rted
ted 36 patients [JOMF SURG 61:115 2003]
2004 Ruggiero, et al reported 63 patients
diag
da n
g osed
osed 200
001-2003 [JOMF SURG 62:527 2004]
[]
Durie, et al reported 75 patients from IMF
survey [NEJM July 7th, 2005] : 4% for Aredia; 10%
for Zometa
2005 Groups from US, Italy, Greece and elsewhere
document bisphosphonate
pp
associated
osteonecrosis (BAO).
M.D. Anderson 4.5% [J. Bon Min Res 20(1) 555; 1218 2005]
Greece 99
9. %
9% [JCO 23:8580 2005]
How frequent is osteonecrosis?
(Continued)
()
2007 Now total of 26 case reports and 13
case series (120 cases) evaluating
bisphosphonate associated osteonecrosis
[Krieger, et al. The Annuals of Pharmacotherapy 41: 276-284 2007]
ONJ more
more common
common with
with Zometa
ONJ >6-7% at 2 years
Additional risk factors under investigation,
including:
Diabetes mellitus
[Khamaisi, et al. J. Clin Endocrinol Metab 92: 1172-1175 2007]
Oxidative stress;
stress; bone remodeling factors
factors...
2008- New report from Germany: ONJ 3.5 times
higher with Zometa [Boonyapakorn et al Oral Onc.
Feb 2008]
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
Denusomab (Amgen)
MIP 1 modulation
DKK 1 protein inhibition
VELCADE
Cholesterol lowering statins,
g, e.g.
g
Lipitor
Quadramet (Samarium)
Overall Strategies
Diagnose & monitor bone
bone
disease
Take bisphosphonate therapy
with good monitoring
Exercise
Get pain relief
Avoid risky
risky situations