The Role of Bisphosphonates in
Ml
Myeloma Bone Di
Disease
James R. Berenson, MD
Medical & Scientific Director
Institute for Myeloma & Bone Cancer Research
Los Angeles, CA
Effect of Monthly Intravenous Pamidronate (90
mg) in Reducing Skeletal Events in Patients with
Advanced Multiple Myeloma: A Phase III Trial
Berenson JR, et al. N Engl J Med. 1996;334(8):488-493.
Zoledronic Acid Compared to Pamidronate in
Multiple Myeloma and
and Breast Cancer Patients:
Protocol 010 Trial Design
· 24-mo dosing regimen
Pi
Pam d
idronate 90
90 mg every 3 to 4 k
w /
k/
120-min infusion
Zoledronic acid 4 mg and 8/4
8/4 mg every 3 to 4 wk/
wk/
5-min amended to 15-min infusion
Double-blind, double-dummy
Study duration: 25 mo
· Patients received oral
oral vitamin
vitamin D 400 IU and
calcium 500 mg
Rosen LS, et al. Cancer. 2003;98:1735-1744.
Breast Cancer and Multiple Myeloma
Efficacy Summary
Time to
Multiple-
Proportion
first SRE
Mean skeletal event analysis
with SRE
SRE, % (median)* morbidity rate*
rate
hazard ratio*
ratio
Zol acid 4 mg
47
376
1.04
0.841
Pam 90
90 mg
mg
51
356
13
1. 9
39
--
P value
.243
.151
.084
.030
*Hypercalcemia of malignancy is included as a skeletal-related event.
Extension data
Bisphosphonates: Anti-Tumor Effects in Myeloma
· Pre-cli i
n cal
Direct
Id
In i
direct
Immune stimulatory effects
Reduce myeloma
myeloma tumor burden in
in murine
murine models
models
· Clinical data
Indirect
· Occurrence of SREs predict poor survival
· IV bisphosphonates (BPs) reduce the occurrence of SREs
Preserving QOL which should extend survival
Improved survival and responses
· Anecdotal clinical reports w/ IV BPs alone
alone
· Subsets in trials (w/ other anti-myeloma therapy)
Reduced Multivariate Model for Survival in
ZOL-
ZOL Treated MM Patients--Continuous Variables
P
value
2.76
Prior SRE
.003
(6.4)
3.36
Paraprotein: IgA vs IgG
.0001
(6.2)
1.93
NTX (per 100
)
.010
2.24
Hgb < 10
.006
0.5
1.0
2.0
3.0
4.0
Risk ratio
Reduced risk of death
Increased risk
risk of
o
of death
d
death
Data from Protocol 10 analyzed by Richard Cook, Ph.D. in collaboration w/ Drs. Berenson and Terpos
Predictive Value of Bone-Specific
Alkaline Phosphatase
Phosphatase (BALP)
· BALP
Bone formation marker
marker
Higher levels correlate w/ bone pain, bone lesions, and fractures in
untreated patients with multiple myeloma1
· P t
a i
ti
t
en s ith
w
l
e evated BALP levels are at
significantly higher risk for negative clinical outcomes2
· Thus, a retrospective analysis
analysis of
of MM
MM pts
pts enrolled on
on
Protocol 010 was performed among myeloma patients
stratified by BALP levels at baseline
High BALP ( 146 IU/L)
Low BALP (< 146 IU/L)
Survival analysis assessed using Cox regression model3
1. Fonseca R, et al. Br J Haematol. 2000;109:24-29.
2. Coleman RE, et al. J Clin Oncol. 2005;23:4925-4935.
3. Berenson J, et al. ASCO 2006.
Among Patients With MM and High BALP,
Zoledronic Acid
Acid Improved
Improved Survival Compared w/ Pamidronate
Survival rate at 25 months
P = .026
P = .041
Zoledronic acid 4 mg
100
Pami
Pam dr
i
onate 90
90 mg
mg
90
82
76
80
73
67
71
66
70
63
60
53
al,%
50
40
30
20
Surviv
10
n 186 167
109 103
42 47
67 56
0
Overall
BALP Subset*
High BALP
Low BALP
N = 353
n = 212
n = 89
n = 123
*Multiple myeloma patients with information on baseline BALP levels and at least 1 postbaseline
safety evaluation. BALP = Bone-specific alkaline phosphatase; ZOL = Zoledronic acid.
Berenson J, et al. Presented at ASH 2006. Abstract 3589.
Bisphosphonates: Adverse Events
· Oral: GI intolerance (in up to 1/3rd of pts)
especially esophagitis & esophageal ulcers
· Intravenous (pamidronate or zoledronic acid)
Flu-like symptoms (fever, myalgias, arthralgias)
· Occurs usually 12-48 hrs following
following the infusion
infusion
· Lasts 6-24 hrs
· Occurs in a minority of pts (10-20%)
· Not observed w/ continued dosing
· Similar frequency w/ different drugs
· Steroids may help reduce risk & intensity
Ol
Ocular eff
ff t
ec s
Anemia
Renal dysfunction
dysfunction
Osteonecrosis of the jaw (ONJ)
Zoledronic Acid over 15 minutes Compared to
Pamidronate over 2 hours: Similar Time to First
Serum Creatinine Increase in Breast Cancer & MM
100
80
thouti e,% 60
tsw
40
creas
n
Hazard ratio
P value
ien
in
at
20
Zol 4 mg
272
1.057
.839
P
Pam 90 mg
268
0
0
120
240
360
480
600
720
Time,
Time, days
Zol 4 mg
272
226
197
152
81
68
30
Pam 90 mg
268
213
182
138
73
59
27
After t
s art f
o
t
s d
u y drug.
Rosen LS, et al. Cancer. 2003;98:1735-1744.
Use of Zoledronic Acid: Renal Issues
· Monitor renal function prior to each dose
· Maintain hydration status
status
· If serum creatinine increases, resume
therapy only after
after it
it returns to within
10% of baseline
Consider increasing the infusion time
· Dose of zoledronic acid can be adjusted
based on initial creatinine clearance rate
However, renal risk largely determined by Cmax
not AUC
Thus, rate of
of infusion
infusion largely
largely determines
determines renal
risk and not the dose
Use of BPs for Patients w/ Renal Dysfunction
· Use among patients with worse function (Cr >3)
minimally assessed
Pamid
id
t
rona e (Berenson t
e
l
a . J Cli
Clin Ph
l
armaco 1997)
Zoledronic acid (Novartis, data on file)
· Hi
However, f
if t
p is on di
dialysis (i
(irreversibl
ibly), may use
IV BPs at same dose, infusion time & interval as pt
w/ normal renal function
· Poor renal function at diagnosis
Initially, treat MM without BPs unless hypercalcemia or
or
severe bone disease is also present
When renal function improves, IV BPs may be initiated
· If hypercalcemia occurs, use zoledronic acid even
w/ renal dysfunction
Osteonecrosis of the Jaw (ONJ):
Clinical Presentation and Working
Working Diagnosis
Clinical Features of Suspected ONJ*
· Exposed bone in maxillofacial area that occurs in
association with dental surgery
gy or occurs
spontaneously, with no evidence of healing
Working Diagnosis of ONJ
· No evidence of healing after
6 weeks of appropriate evaluation and dental care
· Ni
No ev d
idence f
o metastatic di
disease in the jaw or
osteoradionecrosis
Weitzman R, et al. Critical Reviews in Oncology and Hematology. 2007;62(2):148-152.
Frequency of ONJ in Malignant Bone Disease:
Prior to
to Implementation
Implementation of
of Prevention
Prevention Strategies
Pts
Study
treated
Pts w Suspect or
STUDY
type
wB
w P,
BP n
Proven ONJ, n
Frequency,
Frequency %
Hoff et al MDACC
Chart review
4,019
34
0.8%
ASCO 2006
Durie et al
Web-based
survey
1,203
152
12.6%
survey
,
Pozzi et al Italian
Multicenter study
Chart review
888
16
1.8%
Badros et al
Chart review/
al
bt
observa i
ti
l
340
11
3.2%
onal
340
11
Tosi et al Analysis of
Retrospective
Bologna 2002 trial
review of trial
259
6
2.7%
database
Zervas et al
Observational
254
28
11%
Dimopoulos et al
Chart review
202
15
7.4%
Cf
Cafro et l
a
Chart
i
rev ew
118
11
14
11 9
. %
9%
Berenson et al.
Chart review
100
10
10.0%
Time to ONJ from Initiation of
Zoledronic Acid Treatment1
Zoledronic Acid Treatment
50%
40%
30%
20%
Range 15-125 mo; median-
median 52 mo
24-Month
10%
Events / N
Estimate
ALL
10 / 100
5%
0% 0
24
48
72
96
120
Months After Starting Zoledronic Acid
1death is a competing risk;
Retrospective Chart Review at Berenson Oncology;
Statistical analysis by John Crowley, Ph.D., Cancer Research & Biostatistics
Course and Treatment of ONJ (n=10)1
· Current stage of ONJ2
Stage 1- 9 pts
Stage 2- 1 pt
· Overall survival from date of ONJ (mo)
Range [4 49+]; Median 31+
· Status of zoledronic acid administration:
8 continued
1 restarted after 19 mo hiatus3
1 stopped2
· Course of ONJ
3 Resolved
Resolved, 3 Improved
Improved, 3 Stable
Stable, 1 Progressive
Minimal impact on quality of life
· Conservative management w/o surgical interventions
· Infrequent treatment w/ oral antibiotics, antivirals, and/or antifungals
1Retrospective Chart Review at Berenson Oncology
2Staging system from Mehrotra, Long Island Jewish Medical Center
3Patients moved from our clinic
Minimizing the Risk of ONJ
· Excellent oral hygiene is the best
prophylaxis
· Limit EtOH
EtOH & tobacco
tobacco use
· Pts who are starting IV BPs should
hd
have a dental assessment fi
first
Dental procedures (extensive) should be
done prior to starting IV BPs if possible
· Avoid dental procedures once start
IV BPs
Managing ONJ
· Make a diagnosis
diagnosis
i.e.- get someone to evaluate who knows the entity
· Assess its severity
it takes on a wide spectrum!
· Maintain excellent dental hygiene &
l
regu ar exams
· Keep surgical intervention to a minimum
· There is no standard treatment
Antibacterial & antifungal rinses (chlorhexidine
gluconate & nystatin)
Syst
i
em c oral antibacterial, antiviral & antf
tfungal
treatments have been used
· Hyperbaric
yp
oxygen
yg
has not proven
p
useful
· No evidence that discontinuing IV BPs is
necessary or changes the course of ONJ
SMR is Lower for Patients w/ ONJ
Skeletal Morbidity Rate1
w/o ONJ (n=90)
()
w/ ONJ (n=10)
()
0.184
0.07
P<0.05
1defined as number of SREs per year
py
from start of Zometa
Retrospective Chart Review at Berenson Oncology
Prognostic Factors for Overall Survival from MM Dx
Survival from MM
Diagnosis
Variable
n/N (%)
HR (95% Cl)
P-value
Univariate ONJ (time-dependent)
0.00 (0.00,.)
N/D
SRE (time-dependent)
30
3. 6(
06 13
(1. 1
31, 7 1
. 4)
14)
0 010
.
ISS Stage 2 or 3
29/100 (29%)
2.04 (0.88, 4.72)
0.098
Creatinine > 2 mg/dL
g
at Dx 10/100 (10%)
() 3.35 (0.92, 12.13)
()
0.066
Calcium > 10 mg dL at Dx
17/100 (17%)
2.60 (0.98, 6.88)
0.055
HR- Hazard Ratio, 95% Cl- 95% Confidence Interval,
P-value from Wald
Wald Chi-Square Test
T
in Cox Regression
Regression
Retrospective Chart Review at Berenson Oncology;
Statistical analysis by John Crowley, Ph.D., Cancer Research & Biostatistics
Overall Survival
Survival from Landmark of 60 Months
Overall Survival
From Myeloma Diagnosis + 60 months
100%
Median
Deaths / N in Months
ONJ within 60 Months
0 / 6
NR
80%
No ONJ within 60 Months10 / 34 71 (56,71)
60%
40%
20%
0% 0
24
48
72
96
120
144
Months After MM Diagnosis + 60 Months
Retrospective Chart Review at Berenson Oncology;
Statistical analysis by John Crowley, Ph.D., Cancer Research & Biostatistics
ASCO 2007 Practice Guidelines
fB
for i
Bisphosph
t
ona e Use in Myeloma
· Lytic disease on plain radiographs or
osteopenic spinal crush fracture
· PAM 90 mg (via 2-hr infusion) q 3 - 4 wk
· ZOL 4 mg (via 15-
15 min infusion)
infusion) q 3 - 4w
4 k
wk
· Reasonable to initiate IV BPs in
osteopenic pts
pts (i.e. low
low BMD on
on DXA)
DXA)
PAM = Pamidronate disodium; ZOL = Zoledronic acid; BP = Bisphosphonate.
Kyle RA, et al. J Clin Oncol. 2007
ASCO Practice Guidelines and Mayo Clinic
Consensus Statement for the Use of BPs in Myeloma:
Dt
Dura i
tion f
o Th
Therapy
· Mayo Clinic1
for only 2 yrs
yy
among pts in plateau phase
only for pts that require active treatment but change the
frequency to every 3 months
· ASCO2
for only 2 yrs and then "seriously consider discontinuing BPs
in pts w/ responsive or stable disease"
re-initiate w/ the development of an SRE
· Basis for recommendation
Duration of randomized trials completed w/ zoledronic acid and
pamidronate were only
py 2 y
Randomized trial involving pamidronate post-transplant3
showing no significant reduction in proportion of pts w/ SREs in
the two pamidronate-treated groups compared to no Rx group
Ll
Long e ilimi
t
na i
tion half
lf-life of BP
BP in bone (>
(> 300 d)
Risk of ONJ
1Lacy et al. Mayo
May Clin Proc 2006
2Kyle
Ky et al. J Clin Oncol 2007
3Attal et al. Blood 2007
Discontinuing IV BPs after 2 Years of Treatment
Likely Puts
Puts MM
MM Patients
Patients at
at Skeletal
Skeletal Risk
· IV BPs reduce risk of SREs for MM pts regardless whether
pts show stable/responsive
pp
or pro
p gressive
g
disease
· Post-transplant trial
Actually showed differences in SREs: 24% (No Rx) vs 21%
(PAM)
() vs 18% (PAM + THAL)- not a primary endpoint of the trial
Survival benefit observed in the combination arm and no single
agent THAL arm
Zoledronic acid was not evaluated!
· Discontinuation ff
of oral BPs after several years of chronic
use for osteoporosis leads to ongoing bone loss & fracture
risk compared to pts that continue the drugs
Rate of bone loss much more rapid in pati
tients with MM
MM
· Thus, one would expect to see clinical deleterious effects of
discontinuing IV BPs more rapidly than in osteoporotic pts
Berenson et al. N Engl Med 1996; Ravn et al. Ann Intern Med 1999;
Brumsden et al. J Bone Miner Res 2002; Bone et al. N Engl J Med 2004;
Attal et al. Blood 2007
IV BPs for MM Patients: Effects of Changes
in Schedule on
on ONJ
ONJ and Skeletal
Skeletal Risk
· No evidence that
that discontinuing
discontinuing IV BPs
changes the risk of ONJ
In fact, risk of ONJ may be not related to # of
doses but simply
simply time from
from first dose-
· i.e. whether pt receives 5 or 50 doses, pt may be at the
same risk after 50 mo
· Less frequent dosing (q
(q 3 mo) dosing
schedules have not been evaluated for
Safety or efficacy
· Ol
Only 3
q -4k
4 week d
i
os ng has been h
s own to be eff
ffecti
tive in
reducing skeletal complications
· Bone resorption marker data shows enhanced bone loss
occurs 4 weeks after dose of IV BP
Changing the risk of ONJ
ASCO Practice Guidelines and Mayo Clinic
Consensus Statement for the Use of BPs in Myeloma:
Pamidronate vs Zoledronic Acid
MCli i 1
· Mayo Clinic
Pamidronate over zoledronic acid based on
· No difference in reducing skeletal complications
· Higher risk of ONJ w/ zoledronic acid compared to
pamidronate
· ASCO2
Patients may prefer
prefer pamidronate to zoledronic
acid based on the risk of ONJ until more data
become available
1Lacy et al. Mayo
May Clin Proc 2006
2Kyle
Ky et al. J Clin Oncol 2007
Limitations of the Data on ONJ Risk in
MM Patients Treated with IV BP
· Mostly retrospective
· Web-based surveys
· Diagnosis not confirmed
· Time to event analyses
analyses biased by time ZOM vs
vs
PAM has been available
· Recognition
g
of ONJ in BP-treated pts
p
made in
post-ZOM era (little use of PAM)
Heightened sense of awareness of dental issues
recently
· Risk not evaluated for these drugs during same time
New drugs used in MM p
gpts
Marked increased median survival of MM pts
· i.e. longer window of time for ONJ to occur in a MM pt
IV Bisphosphonates for MM Pts: Perspective
· ONJ
Incidence- 1%/yr
Vast majority
jy of cases associated w/ minimal or no
consequences for the pt
No evidence that risk is affected by
· Different drugs (Aredia vs Zometa)
· Change in schedule
· Discontinuation of IV BP treatment
· Skeletal complications (
p(SREs)
w/o BP therapy, more than half of pts by 21 mo
· Only approximately 1/3rd of median lifespan of MM pt today
· IV BPs reduce absolute proportion
pp
of pts
p
w/ SREs by 15%!
> 2 SREs/pt/yr
· IV BPs reduce this to 1 SRE/pt/yr!
Consiste
stent ongoing be
benefit shown for duration
o of
o
placebo-controlled studies (up to 2 yrs)
IV Bisphosphonates for Patients
With Metastatic Bone
Bone Disease--
Benefits vs Risks
Benefits
Risks
Fractures
ONJ ?
Radiotherapy
Renal
Bone pain
(infrequent)
Hl
Humeral fracture in
a myeloma patient