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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