Bone Disease Update
Evangelos Terpos, MD, PhD Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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Disclosures
Name of
Company
Research
support
Advisory Board Honoraria
Amgen X X X
Janssen X X X
Celgene X X X
Novartis X
Takeda X X
BMS X X COMy C
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Bone Disease in Multiple Myeloma
A burdensome and frequent complication in MM
• Present in up to 80% of patients at diagnosis
Characterized by osteolytic bone lesions secondary to increased bone resorption and impaired bone formation
Sequelae
• Pathological fractures
• Osteoporosis
• Hypercalcemia
• Bone pain
• Spinal cord compression Kyle. Mayo Clin Proc. 1975;50:29-40
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Bone Involvement in Myeloma Leads to Skeletal Related Events
51%
37% 34%
5% 3%
0%
10%
20%
30%
40%
50%
60%
Pa
tie
nts
(%
)
Total SREs
Pathologic fracture
Radiation therapy
Surgical intervention
Spinal cord compression
n = 179
SRE, skeletal-related event. a. 21-month data (including osteolytic lesions) except for surgical intervention and spinal compression, for which only 9-month data are available from placebo arm of randomized study. Berenson JR, et al. J Clin Oncol. 1998;16:593-602.
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SREs Are a Serious Problem for Patients With Multiple Myeloma (our experience)
n = 284
Terpos et al. Blood 2013 (ASH Annual Meeting Abstracts);122:3090
0 5 10 15 20 25 30
pathological fractures
surgery to bone
radiotherapy
SCC
5.5%
26%
5%
5.2%
SREs at diagnosis
10 %
22%
0 10 20 30
bortezomib-basedregimens
IMiD-based regimens
SREs at 1st relapse (%)
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Vertebral fractures: more common in T8-L5
2 1 4 5 6
1 2 3 4 7 8
13
18
12
19
32
45
39
28
22 20
18
0
5
10
15
20
25
30
35
40
45
50
C1 C2 C3 C4 C5 C6 C7 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5
Spinal Vertebral fractures (n=309) Fr
actu
re N
o
Over 80% of the vertebral fractures occur in D6-L4 region of the spine, and 50% of them can be found in the T11-L1 region
Terpos et al. Blood 2013 (ASH Annual Meeting Abstracts);122:3090
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Vertebral fractures lead to deformities-kyphosis
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Pathophysiology of
Myeloma-Related Bone Disease
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RANK ligand: an essential mediator of osteoclasts
Growth factors Hormones Cytokines
RANK
RANKL
Mature osteoclast
CFU-M
Prefusion osteoclast
Multinucleated osteoclast
Bone
CFU-M = colony forming unit macrophage. Boyle WJ, et al. Nature. 2003;423:337-42.
Osteoblast lineage
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Osteoprotegerin: the decoy receptor of RANKL
Growth factors Hormones Cytokines
RANK
RANKL
Inactive osteoclast
CFU-M
Prefusion osteoclast
Multinucleated osteoclast
Boyle WJ, et al. Nature. 2003;423:337-42.
Osteoblast lineage
OPG
Osteoclast formation, function, and survival inhibited by OPG
Bone
OPG = osteoprotegerin.
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RANKL/OPG balance drives osteoclast activity
Alterations of the RANKL ligand/OPG ratio are critical in the pathogenesis of bone diseases that result from increased bone resorption
Prevents OC activation
Promotes OC activation
Osteoclast activity
Hofbauer LC, et al. JAMA. 2004;292:490-5. Lacey DL, et al. Cell. 1998;93:165-76. Boyle WJ, et al. Nature. 2003;423:337-42.
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Myeloma cells IL-6, IGF-1 BAFF, APRIL
a4b1 integrin
BMSCs
VCAM-1
VCAM-1
OPG (-)
Osteoclast precursor
IL-11, IL-1b, bFGF TNFa, M-CSF
MIP-1a, MIP-1b, SDF-1a, IL-3, HGF, OPN
IL-6
CD138
OPG
(-)
RANKL
RANKL RANKL
RANKL
Bone matrix
Activated osteoclasts
Bone resorption
TRACP-5b
Collagen type-1 degradation products: NTX, ICTP, CTX
Dkk-1, sFRP-2
Osteoblasts ↓ bALP, ↓ osteocalcin
sclerostin, activin-A
RANK
Terpos E, et al. Ann Oncol. 2005;16(8):1223-1231. Moreaux J, et al. Blood. 2011;117(4):1280-1290.
Myeloma Microenvironment and Bone Disease
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Treatment of Myeloma-Related Bone Disease
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Therapies for Myeloma-related Bone Disease
Osteoblasts
RUNX-2
B-catenin
WNT rec
eptor
Sotatercept
Activin ABisphosphonates
RANK
IL-6
MIP-1a
osteoclastIntegrin
fms
MAPK TRAF6
p50/p52
AP-1
ERK
JNKp38
BAFF
MLN3897
bone marrowstromal cell
VEGF
mesenchymal cell
osteoblasts
ICAM1
VLA-4
CD40MUC1
CD40LVCAM1
Bone
multiple myelomaplasma cell
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Targeting Osteoclasts With Bisphosphonates
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Which Bisphosphonate? ZOL Was as Efficacious as PAM in MM
16
Risk ratio (zoledronic acid 4 mg versus pam)
In favor of zoledronic acid In favor of Pam
P value
.030Total
Breastcancer
Multiple myeloma
.593
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 20
.025
Breast Cancer and Multiple MyelomaMultiple Event Analysis
*Hypercalcemia of malignancy is included as an SRE.
Risk
reduction
16%
7%
20%
Zoledronic acid is more effective than pamidronate resulting in
an additional 16% reduction in the the risk of developing an SRE
0.841
0.932
0.799
Rosen et al. Cancer 2003;98:1735-1744.
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ZOL Significantly OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350)
50
60
70
80
90
100
40
30
Surv
ival
Dis
trib
uti
on
Fu
nct
ion
Est
imat
e
OS,
% p
atie
nts
20
10
0
0 1 2 3 4 5 6
668 682
544 534
447 437
292 271
165 143
64 53
3 0
Time Since Initial Randomisation, years
Clodronate (n = 682)
Zoledronic acid (n = 668)
P = .0107
HR = 0.82 (95% CI = 0.70, 0.96)
+ Censored
ZOL CLO
∆ ~10 mo
Morgan G, et al . Blood 2012;119:5374-83.
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Bisphosphonates Choice: Cochrane Meta-analysis
Mhaskar R, et al. Cochrane Database Syst Rev. 2012;5:CD003188.
• ZOL and PAM exhibit comparable efficacy in reducing SREs in
patients with MM and are recommended for preventing SREs in MM
patients (grade A).
• IV ZOL is recommended over oral CLO because it is significantly
more efficacious in preventing SREs (grade A).
• ZOL is the only BP shown to increase survival in the whole
studied population of a prospective randomized trial.
No evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) for any outcome.
However, zoledronate appears to be superior to placebo and etidronate in improving OS.
Terpos E, et al. J Clin Oncol. 2013;31:2347-2357.
IMWG Recommendations for BPs Choice
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When Do We Start Treatment With BPs? ZOL SREs vs CLO Regardless of Bone Lesions at Baseline
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; MRC, Medical Research Council; SRE, skeletal-related event; ZOL, zoledronic acid.
Highlights the importance of treating all patients regardless of skeletal morbidity at presentation
0 6 12 18 24 30 36 42
Bone Lesions at Baseline No Lesions at Baseline
0.5
0.4
0.3
0.2
0.1
0
Time From Randomization, months
Cu
mu
lati
ve In
cid
ence
Fu
nct
ion
, SR
Esa /
Pat
ien
t
0 6 12 18 24 30 36 42
0.5
0.4
0.3
0.2
0.1
0
Time From Randomization, months
Cu
mu
lati
ve In
cid
ence
Fu
nct
ion
, SR
Esa /
Pat
ien
t
CLO
ZOL
CLO
ZOL
P = .0038
43%
34%
17%
9%
P = .0068
Morgan G, et al. Lancet Oncol. 2011;12(8):743-52.
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IMWG Recommendations: BPs Initiation
BPs should be initiated in patients with MM, with (grade A) or without (grade B) detectable osteolytic bone lesions on conventional radiography, who are receiving antimyeloma therapy as well as patients with osteoporosis (grade A) or osteopenia (grade C) resulting from myeloma.
The beneficial effect of ZOL in patients without detectable bone disease by MRI or PET/CT is unknown.
BPs are recommended asymptomatic MM if osteoporosis is identified by dual-energy x-ray absorptiometry scan in doses used in patients with osteoporosis (grade C).
Terpos E, et al. J Clin Oncol. 2013;31:2347-2357.
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IMWG Recommendations: BPs Treatment Duration
ZOL improves OS and reduces SREs over CLO in patients who received treatment for more than two years; thus it should be given until disease progression in patients not in CR or a vgPR and further continued at relapse (grade B).
There is not similar evidence for PAM. PAM may be continued in patients with active disease at the physician’s discretion (grade D), and PAM therapy should be resumed after disease relapse (grade D).
For patients in CR/vgPR, the optimal treatment duration of BPs is not clear; the panel agrees that BPs should be given for at least 12 months and up to 24 months and then at the physician’s discretion (grade D; panel consensus).
Terpos E, et al. J Clin Oncol. 2013;31:2347-57.
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BPs Severe Adverse Events: MRC IX study
Non-Intensive Pathway (n = 851) Intensive Pathway (n = 1,111)
MP (n = 424) C-TDa (n = 427) CVAD (n = 556) C-TD (n = 555)
ZOL (n = 213)
CLO (n = 211)
ZOL (n = 215)
CLO (n = 212)
ZOL (n = 278)
CLO (n = 278)
ZOL (n = 277)
CLO (n = 278)
ONJb 10 (5) 0 (0)a 4 (2) 1 (< 1) 13 (5) 2 (1)a 8 (3) 0 (0)a
Thromboembolic 10 (5) 10 (5) 43 (20) 25 (12)a 59 (21) 41 (15) 45 (16) 41 (15)
Acute renal failure 15 (7) 13 (6) 13 (6) 14 (7) 14 (5) 17 (6) 15 (5) 16 (6)
Infection TESAE 4 (2) 4 (2) 12 (6) 14 (7) 28 (10) 37 (13) 24 (9) 25 (9)
All SAEs 97 (46) 81 (38) 115 (53) 117 (55) 167 (60) 155 (56) 160 (58) 125 (45)a
TESAEs 27 (13) 18 (9) 63 (29) 67 (32) 74 (27) 69 (25) 84 (30) 72 (26)
Morgan G, et al . Blood 2012;119:5374-83.
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Patients with Renal Failure
Patients with mild to moderate renal impairment (CrCl: 30-60 mL/min) should receive reduced doses of zoledronic acid and clodronate. No change to zoledronic acid infusion time is recommended.
Pamidronate should be administered via 4 hours infusion in patients with mild to moderate renal impairment.
Pamidronate and zoledronic acid are not recommended for patients with CrCl <30 mL/min.
Bisphosphonate therapy should be discontinued in patients experiencing renal problems until CrCl returns to within 10% of baseline values.
Terpos E, et al. J Clin Oncol. 2013;31:2347-57.
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Denosumab is the first fully human MAb against RANKL in clinical use
Simonet WS, et al. Cell 1997;89:309–19.
Fc-OPG OPG-Fc RANK-Fc Denosumab
Present 1997
Fully human antibody against RANK-ligand
Fusion proteins: • Induced
antibodies • Short half-life
= Fc
= RANK COM
y Con
gres
s 201
7
Denosumab Mechanism of Action
Denosumab inhibits osteoclast formation, function and survival
Mature
Osteoclast
CFU-M
Pre-Fusion
Osteoclast
Multinucleated
Osteoclast Growth Factors
Hormones
Cytokines
RANK
RANKL
OPG
Bone
denosumab
Boyle et al. Nature 2003;423:337-42.
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CENTER FOR MULTIPLE MYELOMA, MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MA, USA1; UNIVERSITY OF ATHENS SCHOOL OF MEDICINE, ALEXANDRA GENERAL HOSPITAL, ATHENS, GREECE2; MEDICAL UNIVERSITY OF INNSBRUCK, INNSBRUCK, AUSTRIA3; NATIONAL HOSPITAL
ORGANIZATION HIGASHI NAGOYA NATIONAL HOSPITAL, NAGOYA, JAPAN4; HOSPITAL UNIVERSITARIO DE SALAMANCA, SALAMANCA, SPAIN5; CEDARS-SINAI MEDICAL CENTER, LOS ANGELES, CA, USA6; MEDICAL UNIVERSITY OF LUBLIN, POLAND7; UNIVERSITY HOSPITAL BRNO, BRNO, CZECH REPUBLIC8; CENTRE
HOSPITALIER, LE MANS, FRANCE9; AMGEN INC., THOUSAND OAKS, CA, USA10; INDIANA UNIVERSITY SIMON CANCER CENTER, INDIANAPOLIS, INDIANA, USA11
1NOOPUR RAJE, 2EVANGELOS TERPOS, 3WOLFGANG WILLLENBACHER, 4KAZUYUKI SHIMIZU, 5RAMÓN GARCÍA-SANZ, 6BRIAN DURIE, 7WOJCIECH LEGIEĆ, 8MARTA KREJČÍ, 9KAMEL LARIBI, 10LI ZHU,
10PAUL CHENG, 10DOUGLAS WARNER, 11G. DAVID ROODMAN
An International, Randomized, Double Blind Trial Comparing Denosumab With
Zoledronic Acid for the Treatment of Bone Disease in Patients With Newly Diagnosed
Multiple Myeloma
OP-46
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Study Design
Denosumab 120 mg SC +
Placebo IV over 15 minutes Q4W
(n = 850)
Placebo SC +
Zoledronic acid 4 mg IV over
15 minutes Q4W (n = 850)
Benefit:Risk
positive?
Offered open-label
denosumab up to
2 years
2-year
follow-up for
survival
Yes
No
Randomization
(N=1700)
Stratified by:
• Planned autologous
PBSC transplant (yes/no)
• Disease stage
(ISS 1, 2, or 3)
• Antimyeloma agent:
Novel therapy-based vs
non-novel therapy-based
• Previous SRE (yes/no)
• Region (Japan yes/no)
676
Events
Raje N, et al. IMW 2017 (plenary session); abstract OP-46
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Results: First On-Study SRE
Primary Endpoint Met: Noninferiority for First On-Study SRE
Raje N, et al. IMW 2017 (plenary session); abstract OP-46
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Results: OS
HR (95% CI) = 0.90 (0.70, 1.16); P=0.41 Denosumab: 121 deaths (14.1%) Zoledronic acid: 129 deaths (15%)
Raje N, et al. IMW 2017 (plenary session); abstract OP-46
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Results: PFS
HR (95% CI) = 0.82 (0.68, 0.99); descriptive P=0.036
Denosumab median (95% CI) = 46.09 months (34.3, NE)
Zoledronic acid median (95%CI) = 35.38 months (30.19, NE)
Raje N, et al. IMW 2017 (plenary session); abstract OP-46
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Results: Adverse Events of Interest
particularly in those with baseline CrCl ≤ 60mL/min 26.4% 12.9%
Raje N, et al. IMW 2017 (plenary session); abstract OP-46
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*Antibiotic prophylaxis recommended for all patients undergoing cement augmentation. **As per National Cancer Guidelines. NOTE: start bisphosphonates as soon as possible. Avoid metal work where possible to reduce risk of infection and potential screw pull-out in weakened bone. ***Thermoplastic/TLSO brace if available to prevent progressive deformity +/- further vertebral body collapse. †High-risk patient, e.g. patient with bilateral facet joint destruction. Kyriakou C, et al. Leukemia (submitted)
New Kyphoplasty IMWG Recommendations
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New Kyphoplasty IMWG Recommendations
Kyriakou C, et al. Leukemia (submitted)
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Conclusions
Osteolytic bone disease is the main complication of myeloma
BPS: treatment of choice;: zoledronic acid, pamidronate
ZOL OS versus clodronate in MM patients with bone disease at baseline. It is recommended for use in active myeloma (not in CR/vgPR after 2 years); caution is needed for ONJ and renal impairment
For patients with renal impairment (RI) bortezomib can reverse RI and then can be combined with BPs; denosumab dosing is not dependent on kidney function
Denosumab will be the next standard of care: its beneficial effects on bone metabolism along with possible prolongation of PFS and better renal safety profile makes it an appealing new treatment for bone disease management in MM
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Thank you
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