Zoledronic Acid in the Management of
Multiple Myeloma:
Results From the MRC Myeloma IX Study
J A Child
Clinical Trials Research Unit
University of Leeds
W Gregory, A Szubert, S Bell, N Navarro-Coy, M Drayson, R Owen,
G Cook, F M Ross, S Feyler, A J Ashcroft, G Jackson, F Davies, G
Morgan
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Disclosures
· The trial was funded by the Medical Research Council of
the UK
· Support for the linked scientific investigational studies was
received from Bayer-Schering, Celgene, Chugai, Novartis,
Pharmion, and Ortho Biotech in the form of unrestricted
educational grants
· Professor J. A. Child was the principal grant holder of these
on behalf of the Myeloma IX Chief Investigators and the
University of Leeds, the sponsor of the trial
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Bone Destruction and Myeloma
Growth--a Stimulatory Loop
Osteolytic lesion
BP
Bone matrix
Osteoclast
Osteoblast
RANKL
TGF-
TNF-
FGF-1&2
IL-1
IGF-1&2
IL-6
Myeloma cells
PDGF
Stromal cells
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Bisphosphonates Have Demonstrated
Significant Palliative Benefits in MM1
Reduction
Reduction
Survival
First Author (year)
BP
Dosage
Na
of Pain
of SREsb
Benefit
Placebo-controlled trialsb
Lahtinen (1992) and
CLO
2.4 g/day PO for 2 yr
350
Yes
Yes
NE
Laakso (1994)
McCloskey (1998; 2001)
CLO
1.6 g/day PO
530
Yes
Yes
Subsetc
Brincker (1998)
PAM
300 mg/day PO
300
Yes
No
No
Berenson (1996; 1998)
PAM
90 mg IV q 4 wks for 21 cycles
392
Yes
Yes
Subsetc
Menssen (2002)
IBN
2 mg IV monthly
198
No
No
No
Aviles (2007)2
ZOL
4 mg IV q 28 days
94
Yes
Yes
Yes
PAM-controlled trials
Berenson (2001)
ZOL
2 or 4 mg IV monthly
108
Yes
Yes
NE
Rosen (2001; 2003)
ZOL
2 or 8 mg IV monthly
513
Yes
Yes
Subsetc
a Number of patients with MM.
b SREs include new lytic lesions, vertebral and nonvertebral fractures, and need for radiation or surgery to the bone.
c Subsets were patients without vertebral facture (McCloskey), patients with relapsed/refractory MM (Berenson), patients with elevated baseline bone-specific alkaline phosphatase levels (Rosen).
Abbreviations: BP, bisphosphonate; CLO, clodronate; IBN, ibandronate; IV, intravenous; MM, multiple myeloma; NE, not evaluated; PAM, pamidronate; PO, by mouth; SREs, skeletal-related events;
ZOL, zoledronic acid.
1. Adapted from Terpos E, et al. Ann Oncol. 2009;20(8):1303-1317; 2. Aviles A, et al. Med Oncol. 2007;24(2):227-230.
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MRC Myeloma IX--
Trial Design
N = 1,960
Intensive
Non-intensive
RANDOMISATION
RANDOMISATION
Clodronate
Zoledronic acid
Clodronate
Zoledronic acid
Clodronate
Zoledronic acid
Clodronate
Zoledronic acid
CVAD
CVAD
C-TD
C-TD
MP
MP
C-TDa
C-TDa
MEL-200
Maximal
ASCT
Response
RANDOMISATION
RANDOMISATION
Thal
+Thal
Thal
+Thal
Treatment continued until disease progression
Primary endpoints: PFS, OS, Response
Secondary endpoints: SREs (time to first SRE, SRE incidence), Safety, and QoL
Zoledronic acid (4 mg IV q 3-4 wk); Clodronate (1,600 mg/d PO)
Abbreviations: ASCT, autologous stem-cell transplantation; CVAD, cyclophosphamide (500 mg PO days 1, 8, and 15), vincristine (0.4 mg/d IV days 1-4), doxorubicin (9 mg/m2/d days 1-4),
dexamethasone (40 mg/d PO days 1-4, 12-15 q 3 wk); C-TD, cyclophosphamide (500 mg PO days 1, 8, and 15), thalidomide (100-200 mg/d), dexamethasone (40 mg/d PO days 1-4, 12-15 q 3
wk); C-TDa, attenuated C-TD (except thalidomide 50-200 mg/d, dexamethasone 20 mg/d days 1-4, 15-18 q 4 wk); MEL, melphalan; MP, melphalan (7 mg/m2), prednisolone (40 mg) PO for 4
days; Thal, thalidomide (50-100 mg/d); PFS, progression-free survival; OS, overall survival, SRE, skeletal-related event; QoL, quality of life.
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MRC Myeloma IX--
Analysis Schematic for ZOL vs CLO
R
Zoledronic acid (4 mga IV q 3-4 wk) +
A
intensive or non-intensive chemotherapy
N
(n = 981)
D
N = 1,960
O
Patients with newly
M
Bisphosphonate treatment continued at least
diagnosed MM
I
until disease progression
(stage I, II, III)
S
A
T
Clodronate (1,600 mg/d PO) +
I
intensive or non-intensive chemotherapy
O
(n = 979)
N
Endpoints (ZOL vs CLO)
Primary: PFS, OS, and Response
Secondary: SREs (time to first SRE, SRE incidence), and Safety
a Dose-adjusted for patients with impaired renal function, per the prescribing information.
Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; OS, overall survival, PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.
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MRC Myeloma IX--
Study Endpoints
· Primary endpoints
Overall survival (OS)
Progression-free survival (PFS), defined as time from randomisation
to disease progression or death
Response
· Secondary endpoints
Skeletal-related events (SREs): proportion of patients with an SRE
Safety
· Statistical methods
PFS and OS were assessed by Kaplan-Meier and Cox proportional
hazards models
Statistical significance was assigned for P < .05 with no correction
for multiplicity of comparisons
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Morgan GJ, et al. Lancet. 2010;376:1989-1999.
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MRC Myeloma IX--
Trial Status
· 1,960 evaluable patients
· 121 centres
ZOL
CLO
(n = 981)
(n = 979)
Median follow-up, years
3.7
3.8
(cutoff date 5 Oct 2009)
Still receiving BP, n (%)
111 (11.3)
132 (13.5)
Administration of BP not confirmed, n (%)
54 (5.5)
36 (3.7)
Stopped before progression, n (%)
235 (24)
185 (18.9)
Progressed or died, n (%)
581 (59.2)
626 (63.9)
Median time on treatment, days
Intensive
396
409
Non-intensive
320
306
Abbreviations: BP, bisphosphonate; CLO, clodronate; ZOL, zoledronic acid.
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Morgan GJ, et al. Lancet. 2010;376:1989-1999.
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MRC Myeloma IX--
Trial Status
>70% remained on study
until progression or death
· 1,960 evaluable patients
or had ongoing treatment
· 121 centres
ZOL
CLO
(n = 981)
(n = 979)
Median follow-up, years
3.7
3.8
(cutoff date 5 Oct 2009)
Still receiving BP, n (%)
111 (11)
132 (14)
Administration of BP not confirmed, n (%)
54 (5.5)
36 (3.7)
Stopped before progression, n (%)
235 (24)
185 (18.9)
Progressed or died, n (%)
581 (59)
626 (64)
Median time on treatment, days
Intensive
396
409
Non-intensive
320
306
Abbreviations: BP, bisphosphonate; CLO, clodronate; ZOL, zoledronic acid.
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MRC Myeloma IX Trial--SRE Profile With CLO
and Improvement With ZOL
P < .0001
%
SRE,
P = .070
With
P < .00002
P < .001
P = .37
P = .040
Patients
P = .29
Abbreviations: CLO, clodronate; RT, radiotherapy; SRE, skeletal-related event; ZOL, zoledronic acid.
SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery
to bone lesions or the appearance of new osteolytic bone lesions.
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Does the Presence of Bone Lesions
at Baseline Make a Difference for
SRE Benefits?
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MRC Myeloma IX--ZOL SREs vs CLO
Regardless of Bone Lesions at Baseline
Bone Lesions at Baseline
No Lesions at Baseline
0.5
0.5
CLO
43%
0.4
P = .007
Function,
0.4
Function,
ient 0.3
ient
ZOL
0.3
34%
CLO 17%
Es/pat 0.2
Incidence
Es/pat 0.2
Incidence
e
SR
e
SR
P = .004
0.1
0.1
ZOL 9%
0
0
Cumulativ
Cumulativ
0
6
12
18
24
30
36
42
0
6
12
18
24
30
36
42
Time From Randomisation, months
Time From Randomisation, months
Patients, n
Patients, n
ZOL
668
415
325
250
189
136
100
69
ZOL
302
241
185
135
92
63
38
28
CLO
682
402
297
212
164
117
75
50
CLO
276
212
159
118
91
56
37
24
Highlights the importance of treating all patients
regardless of skeletal morbidity at presentation
SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic
bone lesions.
Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid.
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Are There Any Differences in SRE Effects
Between Antimyeloma Regimens?
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MRC Myeloma IX--Baseline Characteristics Were
Similar Across Non-Intensive Regimens
Non-Intensive Pathway (ITT; n = 849)
MP (n = 423)
C-TDa (n = 426)
ZOL
CLO
ZOL
CLO
(n = 212)
(n = 211)
(n = 214)
(n = 212)
Age, years
Median (range)
73 (59 - 89)
74 (57 - 88)
74 (61 - 87)
73 (58 - 85)
Sex, n (%)
Female
95 (44.8)
97 (46.0)
96 (44.9)
88 (41.5)
Male
117 (55.2)
114 (54.0)
118 (55.1)
124 (58.5)
ISS stage, n (%)
I
37 (17.5)
27 (12.8)
26 (12.1)
20 (9.4)
II
63 (29.7)
93 (44.1)
76 (35.5)
80 (37.7)
III
92 (43.4)
73 (34.6)
81 (37.9)
87 (41.0)
Data unavailable
20 (9.4)
18 (8.5)
31 (14.5)
25 (11.8)
Bone diseasea, n (%)
Yes
145 (68.4)
153 (72.5)
146 (68.2)
142 (67.0)
No
65 (30.7)
55 (26.1)
65 (30.4)
68 (32.1)
Data unavailable
2 (0.9)
3 (1.4)
3 (1.4)
2 (0.9)
a Bone disease was defined as vertebral fractures, other fractures, or osteolytic lesions.
Abbreviations: CLO, clodronate; C-TDa, cyclophosphamide (500 mg PO days 1, 8, and 15), thalidomide (50-200 mg/d), dexamethasone (20 mg/d days 1-4, 15-18 q 4 wk);
MP, melphalan (7 mg/m2, prednisolone (40 mg) PO for 4 days; ISS, International Staging System; ITT, intent to treat; ZOL, zoledronic acid.
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MRC Myeloma IX--Baseline Characteristics Were
Similar Across Intensive Regimens
Intensive Pathway (ITT; n = 1,111)
CVAD (n = 556)
C-TD (n = 555)
ZOL
CLO
ZOL
CLO
(n = 278)
(n = 278)
(n = 277)
(n = 278)
Age, years
Median (range)
59 (31 - 74)
58 (39 - 72)
58 (33 - 71)
59 (33 - 78)
Sex, n (%)
Female
100 (36.0)
108 (38.8)
101 (36.5)
110 (39.6)
Male
178 (64.0)
170 (61.2)
176 (63.5)
168 (60.4)
ISS stage, n (%)
I
59 (21.2)
65 (23.4)
70 (25.3)
81 (29.1)
II
93 (33.5)
98 (25.3)
105 (37.9)
84 (30.2)
III
98 (35.3)
85 (30.6)
76 (27.4)
84 (30.2)
Data unavailable
28 (10.1)
30 (10.8)
26 (9.4)
29 (10.4)
Bone diseasea, n (%)
Yes
202 (72.7)
212 (76.3)
202 (72.9)
199 (71.6)
No
75 (27.0)
63 (22.7)
74 (26.7)
75 (27.0)
Data unavailable
1 (1.4)
3 (1.1)
1 (0.4)
4 (1.4)
a Bone disease was defined as vertebral fractures, other fractures, or osteolytic lesions.
Abbreviations: CLO, clodronate; C-TD, cyclophosphamide (500 mg PO days 1, 8, and 15), thalidomide (100-200 mg/d), dexamethasone (40 mg/d PO days 1-4, 12-15 q 3 wk);
CVAD, cyclophosphamide (500 mg PO days 1, 8, and 15), vincristine (0.4 mg/d IV days 1-4), doxorubicin (9 mg/m2/d days 1-4), dexamethasone (40 mg/d PO days 1-4, 12-15 q 3 wk);
ISS, International Staging System; ITT, intent to treat; ZOL, zoledronic acid.
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MRC Myeloma IX--ZOL SREs vs CLOa in Both
Treatment Arms of the Intensive Pathway
0.5
CLO + CVAD
CLO + C-TD
on,
ZOL + CVAD
ZOL + C-TD
0.4
Functi
0.3
denceci
0.2
veIn
SREs/patient
ati
0.1
Cumul
0
0
6
12
18
24
30
36
42
Time From Randomisation, months
Patients, n
ZOL + C-TD
277
191
165
136
107
80
58
41
ZOL + CVAD
278
195
165
139
105
79
53
39
CLO + C-TD
278
186
159
131
106
69
47
29
CLO + CVAD
278
192
151
115
97
68
43
29
a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic
bone lesions.
Abbreviations: CLO, clodronate; C-TD, cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; SRE, skeletal-related event;
ZOL, zoledronic acid.
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MRC Myeloma IX--ZOL SREs vs CLOa in Both
Treatment Arms of the Non-Intensive Pathway
0.5
CLO + MP
CLO + C-TDa
on,
ZOL + MP
ZOL + C-TDa
0.4
Functi
0.3
denceci
0.2
veIn
SREs/patient
ati
0.1
Cumul
0
0
6
12
18
24
30
36
42
Time From Randomisation, months
Patients, n
ZOL + C-TDa
214
143
89
62
41
26
18
12
ZOL + MP
212
134
87
53
31
16
9
5
CLO + C-TDa
212
132
84
52
28
21
12
9
CLO + MP
211
119
71
39
25
15
10
7
a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic
bone lesions.
Abbreviations: CLO, clodronate; C-TDa, attenuated cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone;
MP, melphalan, prednisolone; SRE, skeletal-related event; ZOL, zoledronic acid.
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MRC Myeloma IX--
Relative Risk of SREs by Treatmenta
Risk
reduction
P value
Overall (N = 1,960)
0.74
ZOL vs CLO
26%
.0004
Non-intensive (n = 849)
0.74
C-TDa vs MP
26%
.021
0.72
ZOL vs CLO
28%
.017
Intensive (n = 1,111)
1.03
C-TD vs CVAD
0%
.80
0.76
ZOL vs CLO
24%
.017
00.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Hazard Ratio
Favours ZOL, C-TDa, C-TD
Favours CLO, MP, CVAD
a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic
bone lesions.
Abbreviations: CLO, clodronate; C-TD, cyclophosphamide, thalidomide, dexamethasone; C-TDa, attenuated CTD; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone;
MP, melphalan, prednisolone; SRE, skeletal-related event; ZOL, zoledronic acid.
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MRC Myeloma IX--ZOL Reduced SREs vs CLOa
During Maintenance Therapy
0.5
on,
0.4
functi
0.3
denceci
CLO
0.2
vein
SREs/patient
ati
0.1
ZOL
Cumul
0
0
6
12
18
24
30
36
42
Time from randomisation, months
Patients, n
ZOL
428
324
251
190
143
102
75
54
CLO
390
281
210
150
114
67
53
31
Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid.
a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions
or the appearance of new osteolytic bone lesions.
Morgan G, et al. Presented at ASH 2010. Abstract 311.
What About Antimyeloma Effects?
20
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Zoledronic Acid Exerts Both Direct and Indirect
Antimyeloma Effects Beyond SRE Prevention
Bone matrix
Osteoclast
Dendritic
Inhibits osteolysis,
Release of growth
and T cells
induces apoptosis,
factors from
and inhibits
bone matrix2
osteoclastogenesis
angiogenesis
Activation of
and recruitment1,2
Myeloma cells
anticancer
immunosurveillance6
Modulation of
adhesion molecules5
Anticancer synergy with
Stromal cells
chemotherapy agents3
Induction of apoptosis4
1. Rosen LS, et al. Cancer J. 2001;7(5):377-387; 2. Mundy GR. Nat Rev Cancer. 2002;2(8):584-593; 3. Winter MC, et al. Cancer Treat Rev. 2008;34(5):453-475;
4. Shipman CM, et al.
21
Br J Haematol. 1997;98(3):665-672; 5. Corso A, et al. Cancer. 2005;104(1):118-125; 6. Uchida R, et al. Biochem Biophys Res Commun. 2007;354(2):613-618.
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MRC Myeloma IX: ZOL Significantly OS
vs CLO
100
80
*P = .04
ts
en
60
pati %al,
ZOL
40
viv
Sur
CLO
20
5.5 mo
0
12
34
5
67
Number at risk:
Time, years
ZOL
981
806
675
418
222
79
3
CLO
979
776
642
399
208
69
0
Abbreviations: CLO, clodronate; OS, overall survival; ZOL, zoledronic acid.
* Kaplan-Meier analysis adjusted for treatment pathway (intensive vs not).
Reprinted from Morgan G, et al. Lancet. 2010;376(9757):19891999.
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MRC Myeloma IX--ZOL OS and PFS vs CLO
OS Benefit Was Independent of SRE Effect
Risk
reduction
P value
0.842
OS (overall)
16%
.0118
5.5 months
0.850
(adjusted for SRE)a
15%
.0178
0.883
PFS (overall)
12%
.0179
2.0 months
00.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Hazard Ratio (ZOL vs CLO)
In favour of ZOL
In favour of CLO
a Time to first SRE was included as a time-dependent covariate in an exploratory Cox model examining OS.
Abbreviations: CLO, clodronate; OS, overall survival; PFS, progression-free survival; SRE, skeletal-related event; ZOL, zoledronic acid.
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MRC Myeloma IX--ZOL Affects OS and PFS vs CLO
in Both Intensive and Non-Intensive Pathways*
Risk
Intensive Pathway
reduction
P value
0.84
16%
OS
.085
0.90
10%
.173
PFS
Non-Intensive Pathway
0.83
OS
17%
.049
0.87
PFS
13%
.065
00.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Hazard Ratio (ZOL vs CLO)
In favour of ZOL
In favour of CLO
* Cox model adjusted for chemotherapy and minimisation factors (including study centre).
Abbreviations: CLO, clodronate; OS, overall survival; PFS, progression-free survival; ZOL, zoledronic acid.
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MRC Myeloma IX--Intensive Pathway
Adverse Events
Intensive Pathway (n = 1,111)
CVAD (n = 556)
C-TD (n = 555)
ZOL
CLO
ZOL
CLO
(n = 278)
(n = 278)
Pa
(n = 277)
(n = 278)
Pa
Acute renal failure
14 (5.0)
17 (6.1)
.71
15 (5.4)
16 (5.8)
1.0
ONJb
13 (4.7)
2 (0.7)
.0067
8 (2.9)
0
.0037
Thromboembolic
59 (21.2)
41 (14.7)
.060
45 (16.2)
41 (14.7)
.64
Catheter-related
25 (9.0)
11 (4.0)
.024
3 (1.1)
2 (0.7)
.69
Infection TESAE
28 (10.1)
37 (13.3)
.29
24 (8.7)
25 (9.0)
1.0
All SAEs
167 (60.1) 155 (55.8)
.34
160 (57.8) 125 (45.0)
.0029
TESAEs
74 (26.6)
69 (24.8)
.70
84 (30.3)
72 (25.9)
.26
a Statistical significance determined by Fisher's exact test.
b ONJ cases were confirmed by an independent adjudication committee.
Abbreviations: CLO, clodronate; C-TD, cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; ONJ, osteonecrosis of the jaw;
SAE, serious adverse event; TESAE, treatment-emergent SAE; ZOL, zoledronic acid.
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MRC Myeloma IX--Non-Intensive Pathway
Adverse Events
Non-Intensive Pathway (n = 851)
MP (n = 424)
C-TDa (n = 427)
ZOL
CLO
ZOL
CLO
(n = 213)
(n = 211)
Pa
(n = 215)
(n = 212)
Pa
Acute renal failure
15 (7.0)
13 (6.2)
.85
13 (6.0)
14 (6.6)
.84
ONJb
10 (4.7)
0
.0018
4 (1.9)
1 (0.5)
.37
Thromboembolic
10 (4.7)
10 (4.7)
1.0
43 (20.0)
25 (11.8)
.024
Infection TESAE
4 (1.9)
4 (1.9)
1.0
12 (5.6)
14 (6.6)
.69
All SAEs
97 (45.5)
81 (38.4)
.14
115 (53.5) 117 (55.2)
.77
TESAEs
27 (12.7)
18 (8.5)
.21
63 (29.3)
67 (31.6)
.67
a Statistical significance determined by Fisher's exact test.
b ONJ cases were confirmed by an independent adjudication committee.
Abbreviations: CLO, clodronate; C-TDa, attenuated cyclophosphamide, thalidomide, dexamethasone; MP, melphalan, prednisolone; N/A, not applicable; ONJ, osteonecrosis of the jaw;
SAE, serious adverse event; TESAE, treatment-emergent SAE; ZOL, zoledronic acid.
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Osteonecrosis of the Jaw (ONJ)--
Risk and Prevention
ONJ is an uncommon
Preventive measures
Preventive measures
adverse event
before BP treatment1,2
during BP treatment
Dental examination and
ONJ is an uncommon adverse
appropriate preventive dentistry
Seek dental maintenance
event reported in cancer
reduces relative incidence of
care at least every
patients receiving complex
ONJ by
6 months
treatment regimens including
up to 70%3,4
bisphosphonates (BPs)
Remove abscessed non-
restorable teeth, teeth with
severe periodontal disease, and
Avoid invasive dental
teeth with poor long-term
procedures if possible
ONJ is relatively a more frequent
prognosis
event in multiple myeloma
Functionally rehabilitate
salvageable dentitions
Maintain good dental
Educate patients on oral
hygiene
hygiene and signs and
symptoms of ONJ
1. Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62(2):148-152; 2. Mehrotra B, et al. Hematology Am Soc Hematol Educ Program. 2006;356-360, 515; 3. Ripamonti CI, et al. Ann Oncol.
2009;20(1):137-145; 4. Dimopoulos MA, et al.
27
Ann Oncol. 2009;20(1):117-120.
IMW Paris 2011
MRC Myeloma IX--Conclusions
· ZOL significantly the relative risk of SREs vs CLO
(P = .0004)
ZOL relative risk of SREs vs CLO regardless of treatment pathway
ZOL relative risk of all types of SREs vs CLO regardless of
bone disease status at presentation
· ZOL significantly survival outcomes vs CLO
ZOL OS vs CLO (P = .012)
ZOL PFS vs CLO (P = .018)
ZOL in OS vs CLO was independent of SRE (P = .018)
28
14
IMW Paris 2011
MRC Myeloma IX--Conclusions
· ZOL and CLO were generally well tolerated, with AEs
consistent with established safety profiles
ONJ incidence was low, but for ZOL vs CLO (3.6% vs 0.3%)
Low incidence of renal failure; similar for ZOL vs CLO
· Patients who received thalidomide had the best outcomes
( CR/VGPR, OS, SREs)
ZOL benefits were seen across all treatment groups
(ie, CVAD, C-TD, MP, C-TDa)
In the non-intensive pathway, C-TDa + ZOL was strikingly superior
· These data suggest inhibiting progression of myeloma
improves bone status
In addition, improving bone integrity may beneficially affect the course
of disease (vicious circle becomes virtuous cycle)
29
IMW Paris 2011
MRC Myeloma IX--Remaining Questions
· What is the optimal timing of BP therapy?
Data already support early treatment of newly
diagnosed MM
· Evidence of maintenance benefit
What is the optimal duration and dose?
· Do benefits correlate with any risk factors?
· Is there synergy of ZOL's antimyeloma effects with
other novel agents?
30
15
Acknowledgements
Chief Investigators
University of
HMDS, Leeds
MRC Leukaemia Trial Steering
Birmingham
JA Child
RG Owen
Committee
GJ Morgan
MT Drayson
AC Rawstron
MRC Leukaemia Data Monitoring
GH Jackson
K Walker
R de Tute
and Ethics Committee
A Adkins
M Dewar
NCRI Haematological Oncology
CTRU, Leeds
N Newnham
S Denman
Clinical Studies Group
K Cocks
Wessex Regional
NIHR, through the National Cancer
W Gregory
ICR, London
Genetics Laboratory,
Research Network
A Szubert
Salisbury
FE Davies
UK Myeloma Forum Clinical Trials
S Bell
F Ross
M Jenner
Committee
N Navarro Coy
L Chieccio
B Walker
F Heatley
D Johnson
Myeloma UK
P Best
LTHT, Leeds
D Gonzalez
Funding
J Carder
G Cook
N Dickens
Medical Research Council
M Matouk
S Feyler
K Boyd
Pharmion
D Emsell
D Bowen
P Leone
Novartis
A Davies
L Brito
Chugai Pharma
D Phillips
A Avridromou
Bayer Schering Pharma
A Gillman
OrthoBiotech
L Flanagan
Celgene
C Tyas and others
Kay Kendall Leukaemia Fund
IMW Paris 2011
Acknowledgements
Patients and staff from 121 participating institutions in the UK
Nottingham City Hospital
Western General Hospital, Edinburgh
Royal Devon and Exeter Hospital
Leeds General Infirmary
Birmingham Heartlands Hospital
Royal Hal amshire Hospital, Sheffield
Hull Royal Infirmary
Royal Liverpool University Hospital
Mid Yorkshire NHS Trust
Ninewells Hospital, Dundee
University Hospital of Wales, Cardiff
Torbay Hospital, Torquay
Addenbrooke's Hospital, Cambridge
Aberdeen Royal Infirmary
Worcester Royal Infirmary
St James's University Hospital, Leeds
Russells Hal Hospital, Dudley
Derbyshire Royal Infirmary
Christie Hospital, Manchester
Royal Cornwal Hospital, Truro
Southampton General Hospital
Blackpool Victoria Hospital
James Cook University Hospital
Colchester General Hospital
Glan Clwyd Hospital
Medway Maritime Hospital, Gil ingham
Norfolk and Norwich University Hospital
James Paget Hospital, Great Yarmouth
Royal United Hospital, Bath
St Helier Hospital, Carshalton
The Great Western Hospital, Swindon
Gloucestershire Royal Hospital
Singleton Hospital, Swansea
New Cross Hospital, Wolverhampton
Ysbyty Gwynedd, Bangor
Monklands General Hospital, Airdrie
Eastbourne District General Hospital
Sandwel General Hospital
Wycombe General Hospital
Hil ingdon Hospital, Uxbridge
Lincoln County Hospital
Chesterfield & N Derbyshire Royal
Kings Mill Hospital, Sutton-in-Ashfield
Queen Elizabeth Hospital, Kings Lynn
Kent and Canterbury Hospital
University Hospital Aintree, Liverpool
St Bartholomew's Hospital, London
Cheltenham General Hospital
Western Infirmary, Glasgow
Southern General Hospital, Glasgow
Hereford County Hospital
Glasgow Royal Infirmary
Darent Val ey Hospital
Salisbury District Hospital
Stepping Hil Hospital, Stockport
Trafford General Hospital, Manchester
Bristol Haematology & Oncology Centre
Good Hope Hospital, Sutton Coldfield
St Richard's Hospital, Chichester
Oldchurch Hospital, Romford
Darlington Memorial Hospital
Pembury Hospital
Taunton and Somerset Hospital
Diana Princess of Wales Hospital, Grimsby
Warwick Hospital
Walsgrave Hospital
Bradford Royal Infirmary
Southend General Hospital
The Royal Bournemouth Hospital
Manchester Royal Infirmary
Whiston Hospital, Prescot
Derriford Hospital
Stoke Mandevil e Hospital, Aylesbury
Queen Elizabeth Hospital, Gateshead
Worthing Hospital
Scarborough General Hospital
Countess of Chester Hospital
Royal Victoria Infirmary, Newcastle
Hope Hospital, Manchester
Victoria Infirmary, Glasgow
Rotherham General Hospital
Poole Hospital
Princess Royal University Hospital
Milton Keynes General Hospital
Barnsley District Hospital
North Devon District Hospital
Kingston Hospital
Royal Alexandra Hospital, Paisley
Borders General Hospital
Queen Elizabeth Hospital, Birmingham
City Hospital, Birmingham
King George Hospital, Ilford
Conquest Hospital, St Leonard's on Sea
Pilgrim Hospital, Boston
Dorset County Hospital
Southmead Hospital, Bristol
Royal Surrey County Hospital
University Hospital of North Tees
George Eliot Hospital
Southport and Formby District General Hospital
North Tyneside General Hospital
Epsom General Hospital
Grantham and District Hospital
Harrogate District Hospital
Basildon Hospital
Doncaster Royal Infirmary
Royal Marsden Hospital, Sutton
Nevill Hal Hospital, Abergavenny
Queen Mary's Hospital, Sidcup
Prince Charles Hospital, Merthyr Tydfil
Prince Philip Hospital
Royal Bolton Hospital
Central Middlesex Hospital
Northwick Park Hospital, Harrow
Arrowe Park Hospital
Ipswich Hospital
South Tyneside District Hospital
Mid Staffordshire General Hospital
Mayday Hospital
Forth Val ey
West Suffolk Hospitals NHS Trust
32
16
Backups
33
IMW Paris 2011
MRC Myeloma IX--
Trial Status
>70% remained on study
until progression or death
· 1,960 evaluable patients
or had ongoing treatment
· 121 centres
ZOL
CLO
(n = 981)
(n = 979)
Median follow-up, years
3.7
3.8
(cutoff date 5 Oct 2009)
Still receiving BP, n (%)
111 (11)
132 (14)
Administration of BP not confirmed, n (%)
54 (5.5)
36 (3.7)
Stopped before progression, n (%)
235 (24)
185 (18.9)
Progressed or died, n (%)
581 (59)
626 (64)
Median time on treatment, days
Intensive
396
409
Non-intensive
320
306
Abbreviations: BP, bisphosphonate; CLO, clodronate; ZOL, zoledronic acid.
34
17
IMW Paris 2011
Bisphosphonate Use in Multiple Myeloma--
Systematic Review of Survival Outcomes
P valuea
Etidronate
1.42
.04
(2 trials, N = 244)
0.94
Clodronate
.44
(3 trials, N = 885)
0.92
Pamidronate
.48
(4 trials, N = 800)
1.09
Ibandronate
.77
(1 trial, N = 198)
0.99
Total (95% CI)
.99
00.2 0.4
0.6 0.8
1
1.2 1.4 1.6 1.8
2
Peto Odds Ratio (95% CI)
Favours bisphosphonate
Favours placebo
a Trials of bisphosphonates compared with placebo.
Note: Zoledronic acid was not included in this review.
Abbreviation: CI, confidence interval.
Adapted from Djulbegovic B, et al.
35
Cochrane Database Syst Rev. 2002;(4):CD003188.
IMW Paris 2011
Preventive Measures Reduce the Risk of ONJ
by 75% in Patients With Multiple Myeloma
· Retrospective analysis of patients with MM who received ZOL (N = 128)
PRE group (n = 38) received ZOL before implementation of preventive measures
POST group (n = 90) started ZOL after implementation of preventive measures
75% relative
reduction
P = .002
Abbreviations: MM, multiple myeloma; ONJ, osteonecrosis of the jaw; PRE, pre-implementation of preventive measures; POST, post-implementation of preventive measures;
ZOL, zoledronic acid.
36
Dimopoulos MA, et al. Ann Oncol. 2009;20(1):117-120.
18
IMW Paris 2011
MRC Myeloma IX--ZOL SREs vs CLOa in Both
Treatment Arms of the Intensive Pathway
0.5
CLO + CVAD
CLO + C-TD
on,
ZOL + CVAD
ZOL + C-TD
0.4
Functi
0.3
denceci
0.2
veIn
SREs/patient
ati
0.1
Cumul
0
0
6
12
18
24
30
36
42
Time From Randomisation, months
Patients, n
ZOL + C-TD
277
191
165
136
107
80
58
41
ZOL + CVAD
278
195
165
139
105
79
53
39
CLO + C-TD
278
186
159
131
106
69
47
29
CLO + CVAD
278
192
151
115
97
68
43
29
a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic
bone lesions.
Abbreviations: CLO, clodronate; C-TD, cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; SRE, skeletal-related event;
ZOL, zoledronic acid.
37
IMW Paris 2011
MRC Myeloma IX--ZOL SREs vs CLOa in Both
Treatment Arms of the Non-Intensive Pathway
0.5
CLO + MP
CLO + C-TDa
on,
ZOL + MP
ZOL + C-TDa
0.4
Functi
0.3
denceci
0.2
veIn
SREs/patient
ati
0.1
Cumul
0
0
6
12
18
24
30
36
42
Time From Randomisation, months
Patients, n
ZOL + C-TDa
214
143
89
62
41
26
18
12
ZOL + MP
212
134
87
53
31
16
9
5
CLO + C-TDa
212
132
84
52
28
21
12
9
CLO + MP
211
119
71
39
25
15
10
7
a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic
bone lesions.
Abbreviations: CLO, clodronate; C-TDa, attenuated cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone;
MP, melphalan, prednisolone; SRE, skeletal-related event; ZOL, zoledronic acid.
38
19
IMW Paris 2011
MRC Myeloma IX--Higher CR/VGPRa Rate With
C-TD vs CVAD in the Intensive Pathway
P < .0001
P = NS
%
PR,
VG
ving
chie
Similar ZOL vs CLO in
A
both C-TD and CVAD
Patients
n = 555
n = 556
n = 555
n = 556
a After induction therapy.
Abbreviations: CLO, clodronate; CR, complete response; C-TD, cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone;
NS, not significant; VGPR, very good partial response (defined as 90% but < 100% reduction in serum M-protein, with positive immunofixation); ZOL, zoledronic acid.
39
IMW Paris 2011
MRC Myeloma IX--Higher CR/VGPR Rates
for C-TDa and ZOL in the Non-Intensive Pathway
P < .0001
P = .11
P = .045
n = 426
n = 423
n = 214
n = 212
n = 212
n = 211
Abbreviations: CLO, clodronate; C-TDa, attenuated cyclophosphamide, thalidomide, dexamethasone; MP, melphalan, prednisolone; VGPR, very good partial response (defined as 90%
but < 100% reduction in serum M-protein, with positive immunofixation); ZOL, zoledronic acid.
40
20
IMW Paris 2011
MRC Myeloma IX--Higher CR/VGPR Rates
for C-TDa and ZOL in the Non-Intensive Pathway
P < .0001
The Wi P = .1
nner1
P = .045
C-TDa
ZOL
n = 426
n = 423
n = 214
n = 212
n = 212
n = 211
Abbreviations: CLO, clodronate; C-TDa, attenuated cyclophosphamide, thalidomide, dexamethasone; MP, melphalan, prednisolone; VGPR, very good partial response (defined as 90%
but < 100% reduction in serum M-protein, with positive immunofixation); ZOL, zoledronic acid.
41
IMW Paris 2011
European Myeloma Network Guidelines
Treat all patients with
· Osteolytic bone disease on plain radiographs
· Osteopenia or osteoporosis based on bone mineral density
· Patients on chemotherapy
Bisphosphonate therapy for 2 years
· After 1 year continue at physician's discretion
· Restart after disease relapse
· ZOL, PAM, or oral CLO (where indicated)
Do not treat patients with MGUS or
asymptomatic MM
Monitor patients for
· Compromised renal function (creatinine clearance)
· Osteonecrosis of the jawa
a Monitoring for ONJ includes: comprehensive dental examination prior to starting BP; avoid unnecessary invasive dental procedures; temporary suspension of BP for invasive dental
procedures; discontinue BP until completely healed.
Abbreviations: BP, bisphosphonate; CLO, clodronate; MM multiple myeloma; MGUS, monoclonal gammopathy of undetermined significance; ONJ, osteonecrosis of the jaw; PAM,
pamidronate; ZOL, zoledronic acid.
Terpos E, et al. Ann Oncol. 2009;20(8):1303-1317.
42
21
IMW Paris 2011
Zoledronic Acid Improves Disease Outcomes
in Advanced Disease
ZOL in combination with
ZOL activates T cells in
standard antimyeloma therapy
patients with MM
is active and generally
well tolerated
· ZOL-activated T-LAK cells
· ZOL (4 mg q 4 wk) +
increased the level of
thalidomide (100 mg/d) +
circulating T cells in the
dexamethasone produced a
peripheral blood and bone
68% overall response rate in
marrow in all patients after
patients with newly diagnosed
4 treatments (N = 6)1
MM (N = 26)3
· ZOL-activated T cells from
· ZOL (4 mg q 4 wk) +
the peripheral blood of MM
thalidomide was well tolerated
patients showed cytotoxic
in patients who had received
activity against
autologous stem cell
myeloma/lymphoma cell lines2
transplants4
Abbreviations: MM, multiple myeloma; T-LAK, lymphocyte-activated T killer; ZOL, zoledronic acid.
1. Abe Y, et al. Exp Hematol. 2009;37(8):956-958; 2. Saitoh A, et al. Med Oncol. 2008;25(2):137-147; 3. Klueppelberg U, et al. J Clin Oncol. 2004;22(14 suppl):606 . Abstract 6702;
43
4. Spencer A, et al. J Clin Oncol. 2004;22(14 suppl):594. Abstract 6655.
IMW Paris 2011
Adverse Events Associated With Intravenous
Bisphosphonates
· Observed in ~20% of patients after initial infusion1
Flu-like
· Characteristics: fever, muscle and joint aches, fatigue
symptomsa
· Manageable with over-the-counter analgesics
· Assess baseline serum calcium levels
Hypocalcemia
· Ensure adequate calcium and vitamin D supplements
· If elevated, thorough evaluation required
Increased
· Treatment should be withheld for renal impairment, defined as2
An increase of 0.5 mg/dL in patients with normal baseline Cr
serum
An increase of 1.0 mg/dL in patients with abnormal baseline Cr
creatinine (Cr)
· Treatment can be resumed when Cr levels return to within 10%
of baseline
levels
· Alternative dosing is recommended based on renal function
a Commonly observed with the administration of all intravenous bisphosphonates.
1. Berenson JR.
44
Oncologist. 2005;10(1):52-62; 2. ZOMETA® Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.
22
IMW Paris 2011
Renal Safety in Patients With Multiple Myeloma
Renal impairment occurs in up to 30% of patients at presentation
and in up to 50% of patients at some disease stage1
Other factors affecting renal function in patients with myeloma include
dehydration, hypercalcemia, hyperuricemia, infection,
and use of nephrotoxic drugs1
Failure to follow ZOL safety instructions can adversely affect
renal function in patients with renal impairment. Serum creatinine
must be monitored before each dose of ZOL2
· Dose should not exceed 4 mg
· Infusion time should not be less than 15 minutes
Abbreviation: ZOL, zoledronic acid.
45
1. Smith A, et al. Br J Haematology. 2005; 132:410-451; 2. ZOMETA® Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.
IMW Paris 2011
MRC Myeloma IX Trial--Caveats
Multi-comparator trial design
Newer agents are now available
Not all patients had bone lesions at study entry
· All patients had symptomatic MM
· Bone lesions develop in virtually all patients during the disease course
Potential effect of SREs on survival
· OS benefit with ZOL was maintained after adjustment for potential effects of SREs on
survival
All patients received bisphosphonate (ie, no control group)
· CLO and ZOL were used because both are approved in the UK for preventing SREs in
patients with myeloma bone disease
· SRE patterns are consistent with previously reported placebo-controlled studies in the
MM setting
Abbreviations: CLO, clodronate; MM, multiple myeloma; OS, overall survival; SRE, skeletal-related event; UK, United Kingdom; ZOL, zoledronic acid.
46
23
IMW Paris 2011
ZOL Can Be Administered With Bortezomib--
Promising Results in Initial Trials
Wang6
Teoh1
Teoh2
Di Renzo3
Terpos4
Oakervee5
VTD/ZOL
PAD/ZOL
VTD/ZOL
BRD/ZOL
PAD
VTD
Abbreviations: BRD, V+Len+Dex; CR, complete response; Dex, dexamethasone; Dox, doxorubicin; Len, lenalidomide; nCR, near-complete response; NR, no response; PAD, V+Dex+Dox; PR,
partial response; SD, stable disease; Thal, thalidomide; V, Velcade (bortezomib); VTD, V+Thal+Dox; ZOL, zoledronic acid.
1. Teoh G, et al. J Clin Oncol. 2006;24:683s. Abstract 17537; 2. Terpos E, et al. Blood . 2007;110. Abstract 3596; 3. Di Renzo N, et al. Blood. 2008;112. Abstract 5203;
47
4. Terpos E, et al. Blood. 2009;114. Abstract 1815; 5. Oakervee HE, et al. Br J Haematol. 2005;129(6):755-762; 6. Wang M, et al. Hematology. 2007;12(3):235-239.
IMW Paris 2011
MRC Myeloma IX Trial--ZOL Each Type of SRE
vs CLO Regardless of Baseline Bone Status
Lesions
No Lesions
P = .0031
P = .0069
%
P = .22
SRE,
With
P = .00002
P = .23
P = .035
Patients
SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic
bone lesions.
Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid.
48
24