1. Core Benefit/Risk (CR)
4/24/2017 8:48 PM
Clinical Benefit of Bisphosphonates for Cancer Patients with Metastatic Bone Disease
James R. Berenson, MD
Medical & Scientific Director
Institute for Myeloma & Bone Cancer Research
Los Angeles, California

2. Metastatic Bone Disease: Scope of the Problem
Core Benefit/Risk (CR)
4/24/2017 8:48 PM
Metastatic Bone Disease: Scope of the Problem
Extremely common - > 500,000 patients in USA
Myeloma - > 90%
Breast - two thirds of patients
Prostate - two thirds of patients
Lung - one third of patients
Median survival measured in years, not weeks or months
Major clinical consequences for patients, families, and society

3. Clinical Consequences of Metastatic Bone Disease†
Core Benefit/Risk (CR)
4/24/2017 8:48 PM
Clinical Consequences of Metastatic Bone Disease†
% of patients/yr
Pathologic fractures
Spinal cord compression/collapse 3 - 5
Radiation therapy
Surgery to bone
Hypercalcemia
Bone pain 50
Use of analgesics 40
Quality-of-life effects
Survival
SREs
SREs = Skeletal-related events.
† From PLAC arms of randomized clinical trials with Aredia® or Zometa®.

4. Core Benefit/Risk (CR)
4/24/2017 8:48 PM
IV Bisphosphonates—Major Impact in Reducing Skeletal Complications for Cancer Patients With Metastatic Bone Disease
% with SRE
# SREs per yr
Placebo BP
%† %
Prostate (Saad et al.) 49
Z-38
22*
1.5
0.7
47*
Breast (Hortobagyi et al.)
(Kohno et al.) 64 50
A-51
Z-30
20*
40*
3.7
1.42
2.4
35*
50*
Myeloma (Berenson et al.) 51
A-38
26*
2.0
1.0
Others (Rosen et al.) 46
Z-39 15
2.7
1.7
37*
SRE = Skeletal-related event; Pbo = Placebo; BP = Bisphosphonate; Z = Zometa®; A = Aredia®; * P < 0.05; † Relative decrease

5. Breast Cancer and Multiple Myeloma Efficacy Summary†
Core Benefit/Risk (CR)
4/24/2017 8:48 PM
Breast Cancer and Multiple Myeloma Efficacy Summary†
Proportion with SRE, %
Time to first SRE (median)‡
Mean skeletal morbidity rate‡
Multiple event analysis Hazard ratio‡
Zometa® 4 mg 47
376
1.04
0.841
Aredia® 90 mg 51
356
1.39 —
P value
.243
.151
.084
.030
† Rosen LS, et al. Cancer. 2003;98:1735–1744.
‡ Hypercalcemia of malignancy (included as a skeletal-related event).

6. Benefits of IV Bisphosphonates in Metastatic Bone Disease
Core Benefit/Risk (CR)
4/24/2017 8:48 PM
Benefits of IV Bisphosphonates in Metastatic Bone Disease
Reduce skeletal complications
Aredia®
Breast cancer and myeloma with lytic lesions
Ineffective in prostate cancer
Not tested in other tumor types
Zometa®
Breast cancer, myeloma, and prostate cancer
Tested and effective in other tumor types
Decrease pain and analgesic use
Prevent deterioration of quality of life

7. ONJ in Myeloma Patients—The IMBCR Experience
Core Benefit/Risk (CR)
4/24/2017 8:48 PM
ONJ in Myeloma Patients—The IMBCR Experience
6 cases of ONJ
Range of severity
3 patients required intermittent antibiotics (Aredia + Zometa, Zometa only in 2) - remain on bisphosphonate treatment
1 patient recently diagnosed with minor temporary discomfort (Aredia only) - remains on treatment
Largely resolved with clarithromycin PO
2 patients (Aredia + Zometa, Zometa only) discontinued bisphosphonate secondary to significant effect on mastication
Status of myeloma
3 in long-term complete remission (auto-PSCT, VAD, thalidomide)
1 in near complete remission (on steroids)
2 with long-term indolent myeloma requiring no other therapy
1 patient with 40% reduction in M-protein for > 4 yr

8. Core Benefit/Risk (CR)
4/24/2017 8:48 PM
Perspective—IV Bisphosphonates in Cancer Patients with Bone Involvement
Skeletal complications have profound effects on the lives of patients with metastatic bone disease
IV bisphosphonate (Zometa® and Aredia®)
Reduce bony complications
Number of events/yr one third to one half
Percent of patients with events by 15% to 40%
Decrease bone pain, reduce pain meds, and prevent deterioration in QOL

9. Core Benefit/Risk (CR)
4/24/2017 8:48 PM
Perspective—IV Bisphosphonates in Cancer Patients with Bone Involvement
Patients receiving IV bisphosphonates (Zometa and Aredia)
Infrequently develop any form of ONJ (0.1% to 2%/yr)
Severity varies; most patients improve while continuing bisphosphonate therapy
ONJ risk minor - rarely clinically significant compared with major problems that frequently occur without Aredia or Zometa treatment (eg, fractures, spinal cord compression, radiation therapy, or surgery)

10. Core Benefit/Risk (CR)
4/24/2017 8:48 PM
IV Bisphosphonates for Patients With Metastatic Bone Disease—Benefits vs Risks
Benefits Risks
Fractures
Radiotherapy
Bone pain
ONJ ?
Renal (infrequent)
Humeral fracture in a myeloma patient