Nordic
Myeloma
Study
Group
Bisphosphonates, can the dose be lowered
Peter Gimsing
Department of haematolgy, Rigshospitalet
University of Copenhagen
Denmark
Disclosures for Peter Gimsing, M.D.
Research Support/P.I.
Janssen-Cilag
Scientific Advisory Board
Novartis
1
· For the last 2-3 decades prophylactic
treatment with bisphosphonates (BPs) has
been 'standard of care' in multiple myelom
· Evidence is based on placebo controlled
trials and comparative studies of new BPs
and a 'gold' standard
· The development of nitrogen containing BPs
has increased the potency and shown
significant antimyeloma effect in the
laboratory and to some extend in clinical trials
2
Bisphosphonates and myeloma bone disease
Relative potency
·
Etidronate
(non-N-containing bisphosphonate)
1
·
Clodronate
(non-N-containing bisphosphonate)
10
·
Tiludronate
(non-N-containing bisphosphonate)
10
·
Pamidronate
(N-containing bisphosphonate)
100
·
Alendronate
(N-containing bisphosphonate)
1000
·
Ibandronate
(N-containing bisphosphonate)
10000
·
Zoledronic acid (N-containing bisphosphonate)
100000
ASCO Guidelines JCO 2002
Bisphosphonates and myeloma bone disease
Relative potency for clinical controlled studies
Relative dose/month
9000
8000
7000
6000
5000
Relative dose/month
4000
3000
2000
1000
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3
Cinical trials of bisphosphonates in multiple myeloma or
partly in multiple myeloma
OR Etidronate
I.v. Zoledronic Acid
0.4 mg/4w
OR Clodronate
2 mg/4w
1
1600 mg/d
11
4 mg/4w
3
2400 mg/d
2
67
4/8 mg/4w
4
Pamidronate
10
Placebo
i.v. 90 mg/4w
Pamidronate
5
OR 75 mg/bid
9
i.v. 30 mg/4w
8
Ibandronate
Ibandronate
i.v. 2 mg
i.v. 4 mg
1. Belch et al (1991)
2. Lahtinen et al (1992)
7.Rose et al (2001,2003)
3.McCloskey et al (1994,1998,2001)
8.Menssen et al (2002)
4.Berenson et al (1996,1998)
9. Terpos et al (2003)
5.Brinker et al (1998)
10. Gimsing et al (2010)
6.Berenson et al (2001)
11. Morgan et al (2010)
Cinical trials of bisphosphonates in multiple myeloma or
partly in multiple myeloma
OR Etidronate
I.v. Zoledronic Acid
0.4 mg/4w
OR Clodronate
2 mg/4w
1
1600 mg/d
11
4 mg/4w
3
2400 mg/d
2
67
4/8 mg/4w
4
Pamidronate
10
Placebo
i.v. 90 mg/4w
Pamidronate
5
OR 75 mg/bid
9
i.v. 30 mg/4w
8
Ibandronate
Ibandronate
i.v. 2 mg
i.v. 4 mg
1. Belch et al (1991)
2. Lahtinen et al (1992)
7.Rose et al (2001,2003)
3.McCloskey et al (1994,1998,2001)
8.Menssen et al (2002)
4.Berenson et al (1996,1998)
9. Terpos et al (2003)
5.Brinker et al (1998)
10. Gimsing et al (2010)
6.Berenson et al (2001)
11. Morgan et al (2010)
4
Cinical trials of bisphosphonates in multiple myeloma or
partly in multiple myeloma
OR Etidronate
I.v. Zoledronic Acid
0.4 mg/4w
OR Clodronate
2 mg/4w
1
1600 mg/d
11
4 mg/4w
3
2400 mg/d
2
67
4/8 mg/4w
4
Pamidronate
10
Placebo
i.v. 90 mg/4w
Pamidronate
5
OR 75 mg/bid
9
i.v. 30 mg/4w
8
Ibandronate
Ibandronate
i.v. 2 mg
i.v. 4 mg
1. Belch et al (1991)
2. Lahtinen et al (1992)
7.Rose et al (2001,2003)
3.McCloskey et al (1994,1998,2001)
8.Menssen et al (2002)
4.Berenson et al (1996,1998)
9. Terpos et al (2003)
5.Brinker et al (1998)
10. Gimsing et al (2010)
6.Berenson et al (2001)
11. Morgan et al (2010)
The optimal bisphosphonate dose
Efficacy:
Cost:
· bone disease
· Toxicity
·Bone markers
·Renal toxicity
·Bone density
·ONJ
·SRE
·Drug-cost
·Skeletal event free survival
·Related cost (i.v. vs. OR)
·QoL
·Compliance
·OS
·Logsistics
5
The optimal bisphosphonate dose
Efficacy:
Cost:
· bone disease
· Toxicity
·Bone markers
·Renal toxicity
·Bone density
·ONJ
·SRE
·Drug-cost
·Skeletal event free survival
·Related cost (i.v. vs. OR)
·QoL
·Compliance
·OS
·Logsistics
Bisphsphonates and myeloma bone disease
Theoretical relation between toxicity and efficay
Toxicity
DLT
Efficacy
Dose
EP
C
Z
Z
OR
1.6 C2.4 P90
4
8
6
Bisphsphonates and myeloma bone disease
Theoretical relation between toxicity and efficay
Toxicity
DLT
OS ?
QoL ?
SRE
OS ?
QoL ?
Dose
EP
C
Z
Z
OR
1.6 C2.4 P90
4
8
Berenson et al. Cancer 2001
MM 39%
Patients irradiated against
Any skeletal
U-NTX/creatinine
BC 61%
bone (primary end-point)
event
(change from baseline)
PAM 90
18% (p<0.05)
30% (p<0.05)
-57.5% (p<0.05)
(N=73)
ZOL 0.4
24%
46%
-37.1%
(N=68)
ZOL 2.0
19% (p<0.05)
35%
-58.6% (p<0.05)
(N=72)
ZOL 4.0
21% (p<0.05)
33%
-60.8% (p<0.05)
(N=67)
Conclusion:
Zoledronic acid 2 mg and 4 mg/month is as effective as pamidronate 90 mg/month,
while zoledronic acid 0.4 mg/month was less effective
7
Rosen et Cancer 2003
Cancer J 2001
MM 31%
Patients with any SRE
Time to 1. SRE
OS
ECOG PS
BC 69%
(primary end-point)
13 months
25 months
PAM 90
46%
51%
356 days
n.s.
n.s
(N=555)
(MM: 49%)
(MM: 54%) (MM: 286 days)
ZOL 4.0
44%
47%
376 days
n.s.
n.s
(N=561)
(MM: 47%)
(MM: 50%) (MM: 380 days)
ZOL 4.0/8.0 46%
49%
351 days
n.s.
n.s
(N=524)
(MM: 49%)
(MM: 50%)
Rosen et Cancer 2003
Cancer J 2001
Conclusion:
Zoledronic acid 4 mg/month is as
effective as pamidronate 90 mg/month
in patients with advanced multiple
myeloma.
No difference in overall survival or
performance status
8
EORTC QLQ C30 Time to
Skeletal event Overall
PFS
Physical function
first SRE free suvival
survival
(median)
score at 12 months (median)
(median)
(median)
(primary endpoint)
PAM 90
65
NR
21.4 months
42 months
21 months
(N=252)
PAM 30
68
NR
22.1 months
48 months
22 months
(N=252)
(p=0.56)
(p=0.63)
(p=0.98)
(p=0.54)
(p=0.51)
Conclusion:
No significant difference in QoL, SRE, OS or PFS between pamidronate 90 mg/month
and 30 mg/month
Quality of Life (EORTC QLQ C30)
9
·Time to first SRE
·Skeletal event free surival
·Overall survival
·Profressions free survival
Overall survival
PFS
Patients with any SRE
(primary end-point)
CLO 1600
44.5 months (p=0.04)
17.5 months (p=0.07)
35.3% (p=0.0004)
(N=979)
ZOL 4.0
50.0 months
19.5 months
27.0%
(N=981)
Conclusion:
Zoledronic 4 mg/month is more effective than clodronate 1600 mg/day
with survival benefit and reduced number of patients with skeletal
events.
10
Dose toxicity
· Nephropathy
· Osteonecrosis of the jaw
Berenson et al. Cancer 2001
MM 39%
Increase in S-creatinine
Grade 3 creatinine
ONJ
BC 61%
> 0.5 mg/L
elevation
PAM 90
7 (9.6 %)
2
Unknown
(N=73)
ZOL 0.4
? (?%)
1
Unknown
(N=68)
19 (13.6%)
ZOL 2.0
? (?%)
1
Unknown
(N=72)
ZOL 4.0
11 (16.4 %)
1
Unknown
(N=67)
Conclusion:
No significant difference on creatinine between Zoledronic acid 4 mg/month and
pamidronate 90 mg/month. OJN was not an issue at the time of the study.
11
Rosen et Cancer 2003
Cancer J 2001
MM 31%
Discontinuation of study
Creatinine increase
Grade 3-4
BC 69%
medicine due to AE
ZOL infusion rate
creatinine
13 months
25 months
5 min
15 min
increase (25 m)
PAM 90
1.4%
9.6 %
6.3%
9.3%
1.9%
(N=555)
ZOL 4.0
1.8%
9.0%
14.3%
10.7%
0.4%
(N=561)
ZOL 4.0/8.0
4.3%
10.6%
21.3%
19.4%
2.7%
(N=524)
Conclusion:
No significant difference on creatinine between Zoledronic acid 4 mg/month given as
15 min infusion and pamidronate 90 mg/month. Zoledronic acid 8 mg/month gave higer
incidence of creatinine increase. OJN was not an issue at the time of the study.
Discontinuation of study
Time to more than 15% ONJ
medicine due to increased
increase of creatinine
(%)
creatinine
(median)
PAM 90
15
10.7 months
8 (4.2%)
(N=252)
PAM 30
7
14.8 months
2 (1.0%)
(N=252)
(p=0.072)
(p=0.48)
(p=0.087)
Conclusion:
There was a trend of increased incidence of nephrotoxicity and
ONJ with pamidronate 90 mg/month compared to 30 mg/months
12
Tim
Ti
e to exi
x t due to nephrotoxi
otox c
i i
c t
i y - Ka
K ppl
a
a
ppl n
a Meie
i r Pl
P ot
l
Kaplan-Meier Cum . Survival Plot for Tim e to ONJ
1
1
,8
,8
laiv ,6
p=0.087
,6
rv
,6
rv
p=0.072
u
.S
Cum. Survival (A)
.Sm ,4
,4
PAM 90 mg
Cu
Cum. Survival (B)
,2
,2
PAM 30 mg
0
0
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
80
Mon
Mo t
n h
t s
h
Months
Conclusion:
Trend toward cumulative dose dependent risk of nephrotoxicity
and ONJ by pamidronate treatment.
Time-related AE should be presented to determined cumulative
dose related AE.
Acute renal failure
ONJ (crude incidence)
CLO 1600
60 (6%)(p=0.75)
3 (0.003%) (p<0.0001)
(N=979)
ZOL 4.0
57 (6%)
35 (0.036%)
(N=981)
Conclusion:
Zoledronic 4 mg/month increased the risk of ONJ significantly compared
to clodronate 1600 mg/day while there was no significant difference of
the incidence of acute renal failure.
13
Summary and conclusion
?
PAM 30 mg
PAM 90 mg = ZOL 4 mg
=
= ZOL2 mg
Placebo
CLO 1600 mg
Conclusions:
1.
Pamidronate 30 mg/month is the recommended pamidronate dose
2.
Zoledronic acid 4 mg/months is more effective than clodronate
1600 mg/day but with 10 fold increased risk of ONJ
3.
Future studies are needed to determine
·
If pamidronate 30 mg /month is as effective as zoledronic acid
4 mg/month with less side effects
·
If another dose schedule of zoledronic acid (e.g. 2 mg/month or
4 mg/3 month) is as effective as zoledronic acid 4 mg/month
with less side effects
14