Treatment of Myeloma Bone Disease

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1 Treatment of Myeloma Bone Disease James R. Berenson, MD Medical & Scientific Director Institute for Bone Cancer & Myeloma Research West Hollywood, CA

2 Clinical Consequences of Myeloma Bone Disease Pathological fractures Non-vertebral Vertebral compression Spinal cord compression/collapse Radiation therapy Surgery to bone Hypercalcemia Bone pain Use of analgesics Quality-of-life effects Survival

compression/collapse Radiation therapy Surgery to bone

3 Prevalence of Skeletal Complications in 21 months among MM Patients Total Pathologic fracture Radiation to bone Hypercalcemia of malignancy Surgery to bone Spinal cord compression Patients With SREs, % 9-month data. Placebo arm of pamidronate randomized trial. Berenson JR et al. N Engl J Med. 1996;334: Berenson JR, et al. J Clin Oncol. 1998;16:

30 40 50 60 Patients With SREs, % 9-month data. Placebo arm of pamidronate randomized trial.

4 Clinical Consequences of Myeloma Bone Disease Pathological fractures Non-vertebral Vertebral compression Spinal cord compression/collapse Radiation therapy Surgery to bone Hypercalcemia Bone pain Use of analgesics Quality-of-life effects Survival

5 Kyphoplasty: A Minimally Invasive Fracture Reduction Procedure KyphX Introducer Tool Kit: Allows precise, minimally invasive access to the vertebral body. Provides working channel. KyphX IBT inflation: Reduces the fracture. Compacts the bone. May elevate endplates. KyphX IBT Removal: Leaves a defined cavity and trabecular dam that can be filled with an approved bone void filler of the physician s choice.

$KyphX IBT inflation: Reduces the fracture. Compacts the bone. May elevate endplates.$

6 Kyphoplasty: Use in Myeloma Patients w/ Vertebral Compression Fractures 55 procedures in 18 patients Assess safety and efficacy using the Short Form Health Survey (SFHS) scoring system at pre, 1, 6, 12, 36, & 52 weeks Body pain, Physical function, Vitality, Social Function Results Levels: T6-L5 (majority (56%) from T11-L5) No major complications Improvement in SFHS assessments Dudeney et al. J Clin Oncol 2002

36, & 52 weeks Body pain, Physical function, Vitality, Social Function Results Levels: T6-L5 (majority

7 The CAFÉ Study A Multicenter, Prospective, Randomized, Controlled Study to Compare Balloon Kyphoplasty to Non-Surgical Fracture Management* in the Treatment of Cancer Patients with Painful Vertebral Body Compression Fractures *Allowed to have kyphoplasty 30 days later

Management* in the Treatment of Cancer Patients with Painful

8 Bisphosphonates in the Treatment of Myeloma Bone Disease: Randomized Studies Oral Etidronate* - Belch et al, J Clin Oncol 1991 Clodronate* - Lahtinen et al, Lancet 1992; McCloskey et al, Br J Haematol 1998 Pamidronate* Brincker et al, Br J Haematol 1998 Intravenous Pamidronate* Berenson et al, N Engl J Med 1996 Ibandronate* Menssen et al J Clin Oncol 2002 Zoledronic acid + Berenson et al, Cancer 2001; Rosen et al, The Cancer J 2001 * Placebo-controlled; + Pamidronate-controlled

Br J Haematol 1998 Intravenous Pamidronate* Berenson et al, N Engl J Med 1996 Ibandronate* Menssen et al J Clin Oncol

9 Effect of Monthly Intravenous Pamidronate (90 mg) in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma: A Phase III Trial Berenson JR, et al. N Engl J Med. 1996;334(8):

10 Zoledronic acid Zoledronic acid belongs to a new class of bisphosphonates 1,2 Heterocyclic, nitrogen-containing bisphosphonate composed of: A core bisphosphonate moiety An imidazole-ring side chain containing 2 critically positioned nitrogen atoms 2-3 logs more potent than pamidronate in preclinical studies 1,2 N N O HO P O OH P OH OH OH 1. Green J, et al. J Bone Miner Res Green J, et al. Pharmacol Toxicol

containing 2 critically positioned nitrogen atoms 2-3 logs more potent than pamidronate in preclinical

11 Zoledronic Acid in Myeloma and Breast Cancer Patients: Protocol 010 Trial Design 24-mo dosing regimen Pamidronate 90 mg every 3 to 4 wk/ 120-min infusion Zoledronic acid 4 mg and 8/4 mg every 3 to 4 wk/ 5-min amended to 15-min infusion Double-blind, double-dummy Study duration: 25 mo Patients received oral vitamin D 400 IU and calcium 500 mg

acid 4 mg and 8/4 mg every 3 to 4 wk/ 5-min amended to 15-min infusion Double-blind,

12 Breast Cancer and Multiple Myeloma Efficacy Summary Time to Multiple- Proportion first SRE Mean skeletal event analysis with SRE, % (median)* morbidity rate* hazard ratio* ZA** 4 mg Pam 90 mg P value *Hypercalcemia of malignancy is included as a skeletal-related event ** ZA- zoledronic acid Extension data

ZA** 4 mg 47 376 1.04 0.841 Pam 90 mg 51 356 1.39 P value.243.151.084.

13 Multiple Myeloma Time to First Serum Creatinine Increase* Patients without increase, % Time, days n Hazard ratio P value ZOMETA 4 mg 15 min Pamidronate 90 mg-2 hr 84 ZOMETA 4 mg Pamidronate *Post 15-minute infusion amendment. Versus pamidronate infused over 2 hours After start of study drug.

502 Pamidronate 90 mg-2 hr 84 ZOMETA 4 mg 91 76 71 57 32 30 18 Pamidronate 84 71 62 50 23 17 8

14 How to Approach the Patient w/ Rises in Creatinine While on a Bisphosphonate (BP) Look for possible causes besides the BP The Cancer (myeloma, etc) Other co-morbid diseases (diabetes, hypertension, etc) Medications (NSAIDS, COX-2 inhibitors, statins, etc) Consider a kidney biopsy If the BP still may be the cause, hold the dose until the creatinine returns to baseline, & since the rate of infusion relates to kidney toxicity, SLOW the infusion down To 60 min for Zometa To > 4 hours for Aredia If problems persists, consider switching to the other IV BP If does not improve the problem, discontinue intravenously administered BPs and consider Fosamax orally

until the creatinine returns to baseline, & since the rate of infusion relates to kidney toxicity, SLOW the infusion down To 60 min for Zometa To > 4 hours for

15 Osteonecrosis of the Jaw (ONJ) & Bisphosphonate (BP) Use Observed among CA patients receiving IV BPs (both pamidronate & zoledronic acid) Less frequent among pts receiving oral BPs Relationship to BPs unproven Treatment Good oral hygiene Peridex (chlorhexidine gluconate) rinse or Arestin (minocycline hydrochloride) periodontal pockets Intermittent antibiotics, antifungals or antivirals Keep surgery to a minimum No evidence that discontinuation of BP changes course of jaw problem Prophylaxis- Excellent oral hygiene

(chlorhexidine gluconate) rinse or Arestin (minocycline hydrochloride) periodontal pockets Intermittent antibiotics, antifungals

16 6 cases of ONJ Range of severity ONJ in Myeloma Patients- The IMBCR Experience 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

patients (Aredia + Zometa, Zometa only) discontinued bisphosphonate secondary to significant effect on mastication Status of myeloma 3 in long-term complete remission

17 IV Bisphosphonates for Patients With Myeloma Bone Disease Benefits vs Risks Benefits Risks Fractures Radiotherapy Bone pain ONJ? Renal (infrequent) Humeral fracture in a myeloma patient

$Renal (infrequent) Humeral fracture in a$

18 Monoclonal Gammopathy of Undetermined Significance (MGUS) Pts w/ monoclonal immunoglobulin 3% of individuals over 70 years None of the clinical manifestations of myeloma, however Bone effects Increased osteoclastic activity High rate of bone loss Enhanced risk of fracture especially vertebral compression fracture* *Melton et al. J Bone Min Res 2004

$Enhanced risk of fracture especially vertebral compression fracture* *Melton et al.$

19 Phase I/II Study of ZOMETA in MGUS Patients with MGUS and osteopenia/osteoporosis (n=80) (t-score < 1) ZOMETA 4 mg via 15-minute infusion at 0, 6 and 12 months Primary endpoint: Posterior-anterior spine BMD (0 & 13 mo) Secondary endpoints: Nondominant proximal femur BMD Skeletal radiographs in M-protein Progression

infusion at 0, 6 and 12 months Primary endpoint: Posterior-anterior spine BMD

20 Myeloma Bone Disease Conclusions (I) Major clinical manifestation of MM High risk of pathological fractures Many patients receive radiotherapy Keep radiotherapy to a minimum Side effects Compromises bone marrow function Increasing recognition of the role of kyphoplasty to treat vertebral compression fractures

radiotherapy to a minimum Side effects Compromises bone marrow function

21 Myeloma Bone Disease Conclusions (II) IV zoledronic acid and pamidronate Reduce skeletal complications Pathologic fractures Radiation therapy Monitoring of kidney function (assess monthly serum creatinine) necessary although other causes more likely to cause renal dysfunction Osteonecrosis of the jaw may be associated with bisphosphonate use Good oral hygiene important to emphasize Avoid invasive dental procedures Potential anti-tumor effects being explored

Bone Disease in Myeloma

Bone Disease in Myeloma Washington, DC August 8, 2009 Brian G.M. Durie, M.D. Bone Disease in Myeloma Lytic Lesions Spike Bone Marrow Plasma Cells Collapse of Vertebrae Biology of Myeloma Vascular Cytokines