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

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

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 10 - 25 Spinal cord compression/collapse 3 - 5 Radiation therapy 15 - 20 Surgery to bone 5 - 10 Hypercalcemia 2 - 10 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®.

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

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).

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

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

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

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)

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