1. Advances in the Management of Bone Health in Multiple Myeloma James Berenson, MD President and Chief Executive Officer Medical and Scientific Director Institute for Myeloma and Bone Cancer Research West Hollywood, California This program is supported by an educational donation from

2. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Overview  Scope of the problem –Cancer induced –Cancer treatment induced –Precancerous conditions associated with enhanced bone loss  Pathophysiology of bone disease in cancer  Prevention and treatment of bone loss, bone pain, and skeletal complications  Complications of treatments to prevent bone loss  New treatment options in development

4. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Cancer-Induced Bone Disease: Scope of the Problem  > 500,000 patients in US –Myeloma: > 90% of patients –Breast: two thirds of patients –Prostate: two thirds of patients –Lung: one third of patients  Often only site of metastatic disease  Prolonged survival; often measured in years, not weeks or months  Major clinical consequences for patients, families, and society

5. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology 3 Types of Bone Lesions  Lesions may be osteolytic, osteoblastic, or mixed in solid tumors –In breast cancer –Most metastases are osteolytic –Approximately 15% to 20% of patients have predominately osteoblastic lesions –In certain other tumors (eg, kidney and thyroid), lesions may be primarily osteolytic –In prostate cancer, most metastases are osteoblastic –Any patient with metastatic solid tumor can have all 3 types of metastases  Only in MM are lesions osteolytic Roodman GD. N Engl J Med. 2004;350:1655-1664. Yin JJ, et al. Cell Res. 2005;15:57-62.

6. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Bone Tumor Cells in Bone Osteoclast Tumor-derived osteoclast activating factors  Parathyroid hormone– related protein  Interleukins  Tumor necrosis factor  Macrophage colony- stimulating factor Bone-derived tumor growth factors  Transforming growth factor   Insulin-like growth factors  Fibroblast growth factors  Platelet-derived growth factor  Bone morphogenic proteins (+) Pathogenesis of Osteolytic Bone Lesions Enhanced bone loss Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

7. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Clinical Consequences of Cancer-Induced Bone Lesions  Pathological fractures –Nonvertebral –Vertebral compression  Spinal cord compression/collapse  Radiation therapy  Surgery to bone  Hypercalcemia  Bone pain  Use of analgesics  Quality-of-life effects  Survival Skeletal-related events

8. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Prevalence of Skeletal-Related Events in Clinical Trials Patients Affected in Placebo Arms TrialsPamidronate TrialsZoledronic Acid DiseaseBreastMyelomaProstateLung/Other Observation time, mos24212421 Total SREs, %64514946 Radiation to bone, %43343334 Pathologic fractures, %52372522 Hypercalcemia of malignancy, % 13914 Surgery to bone, %11545 Spinal cord compression, % 3384

9. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Negative Impact of Bone Complications on Patients Skeletal Complications Negative impact on survival [5] Men with prostate cancer without skeletal fracture survived 39 months longer than those with a fracture Increased medical costs [1] Treatment of bone complications more than doubles the total treatment costs for patients with bone metastases Impaired mobility [6] Hip fracture is associated with 50% disability rate, and in 25%, nursing home care is required Diminished quality of life [2-4] History of a skeletal complication is associated with lower QoL in breast and prostate cancer 1. Groot MT, et al. Eur Urol. 2003;43:226-232. 2. Weinfurt KP, et al. Ann Oncol. 2002;13(suppl 5):180. 3. Weinfurt KP, et al. Med Care. 2004;42:164-175. 4. Saad F, et al. Eur Urol. 2004;46:731-740. 5. Oefelein MG, et al. J Urol. 2002;168:1005-1007. 6. Riggs BL, et al. Bone. 1995;17:505S-511S.

10. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology OS Among Patients With MM Treated With Zoledronic Acid  Retrospective chart review –300 patient charts reviewed consecutively from 15 US sites –All patients had to have a diagnosis of MM and received at least 2 dose of zoledronic acid at the study site –Data were collected from the time of MM diagnosis  Median survival: 131 months Berenson JR, et al. Clin Lymphoma Myeloma. 2009;28:Abstract 204.

11. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Predictors of OS From Time of MM Diagnosis Variablen/N (%)HR (95% CI)P Value* Female sex129/300 (43)0.90 (0.51-1.60).725 White race230/300 (77)0.69 (0.36-1.32).258 ISS stage II or III135/300 (45)1.69 (0.97-2.94).064 ISS stage III50/300 (17)1.89 (0.91-3.91).088 Calcium > 10 mg/dL at diagnosis68/294 (23)1.59 (0.84-3.03).156 Creatinine ≥ 2 mg/dL at diagnosis 28/295 (9)3.35 (1.54-7.32).002 Diabetes51/300 (17)1.17 (0.57-2.41).677 History of smoking122/299 (41)0.80 (0.46-1.42).450 History of alcohol use83/299 (28)0.66 (0.33-1.33).244 SRE (time dependent)2.92 (1.64-5.22)<.001 *P value from Wald chi-square test in Cox regression. Berenson JR, et al. Clin Lymphoma Myeloma. 2009;28:Abstract 204.

12. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Reduced Multivariate Model for Survival in ZOL-Treated MM Pts: Continuous Variables 3.36.0001 P Value IgA 0.51.0 Risk Ratio 2.03.0 Reduced risk of death Increased risk of death.003 2.76.020 1.03 Prior SRE Age (per 1 yr  ) 4.0 (6.2).206 1.49 Lt chain/IgM/nonsecreting Paraprotein vs IgG.010 1.93.006 2.24 Hb < 10* (6.4) NTX (per 100  ) *Inverse continuous variable for Hb. Data from Protocol 10 analyzed by Richard Cook, PhD.

13. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Management of Bone Disease in Cancer Requires a Multidisciplinary Approach  Oncologist  Surgeons –Orthopedist –Neurosurgeon  Radiation therapist  Nuclear medicine specialist  Pain specialist  Rehabilitation/physical medicine –Physician –Physical therapist

14. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology  Radiotherapy  Radioisotopes  Surgery –Vertebroplasty/kyphoplasty  Analgesia  Bisphosphonates ↓Bone pain ↓Neurologic complications from spinal cord compression ↓ Bone pain ↓Healing of pathologic fracture ↓Neurologic complications from spinal cord compression ↑ Stability ↓ Bone pain ↓ Incidence of SREs Current Treatment Options for Bone Lesions

15. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Surgical Treatment of Vertebral Compression Fractures in Cancer Patients  Operative management –Vertebral column reconstruction –A or P decompression with internal fixation –Oncology patients are generally poor candidates for open surgery due to soft bone/tumor mass and comorbidities  Minimally invasive procedures –Vertebroplasty –Balloon kyphoplasty

16. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Tumor-Related VCFs: Vertebroplasty Fourney DR, et al. J Neurosurg. 2003;98(1 suppl):21-30. Reproduced with permission from the American Association of Neurological Surgeons.

17. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Tumor-Related VCFs: Balloon Kyphoplasty Introduction  Allows precise, minimally invasive access to the vertebral body  Provides working channel Balloon inflation  Reduces the fracture  Compacts the bone  May elevate endplates Removal  Leaves a defined cavity and trabecular dam that can be filled with an approved bone void filler of the physician’s choice

18. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Balloon Kyphoplasty for Cancer Patients With VCFs: Interim Phase IV Data  Randomized trial of balloon kyphoplasty vs nonsurgical management in patients with cancer-related VCFs  Patients enrolled within 3 months of diagnosis of VCF  1 year follow-up; optional crossover at 1 month  Data are from preplanned 1 month interim analysis of this ongoing phase IV study Berenson JR, et al. Clin Lymphoma Myeloma. 2009;28:Abstract 204.

19. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Balloon Kyphoplasty Improves Disability Scores and Pain  For patients with cancer-related VCFs –Balloon kyphoplasty showed marked reduction in back disability and pain at 1 month compared with nonsurgical treatment –Improvements were both statistically and clinically significant –Improvements were achieved without significant increase in serious adverse events Berenson JR, et al. Clin Lymphoma Myeloma. 2009;28:Abstract 204.

20. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Bone-Seeking Radiopharmaceuticals  Composition –Radioactivity: samarium-153, strontium-89 –Targets bone especially areas of increased activity –Ethylenediaminetetramethylenephosphonic acid (EDTMP) with samarium-153 –Strontium (acts like calcium)  Radiopharmaceuticals are approved for relief of pain for patients with osteoblastic metastatic bone lesions that enhance on radionuclide bone scan  Major toxicity is hematologic –Proximity to bone marrow

21. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology All Patients (n = 118) Prostate Cancer (n = 78) Breast Cancer (n = 21) Lung and Other Cancers (n = 19) -20 -16 -12 -8 -4 0 4 Change in AUPC Placebo 0.5 mCi/kg 1.0 mCi/kg Change in AUPC-VAS* at Week 4 Among Primary Tumor Subgroups Serafini AN, et al. J Clin Oncol. 1998;16:1574-1581. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Samarium-153 Lexidronam

22. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Bisphosphonates Relative R 1 R 2 potency EtidronateOH– CH 3 1 ClodronateCl– Cl 10 TiludronateH– S – – Cl 10 PamidronateOH–(CH 2 ) 2 – NH 2 100 AlendronateOH–(CH 2 ) 3 – NH 2 1000 RisedronateH–CH 2 – N 5000 Ibandronate OH (CH 2 ) 2 -N-(CH 2 ) 4 -CH 3 10,000 CH 3 Zoledronic acidOH –N N 100,000 OHR1R1 R2R2 PCPO O  Inhibitors of bone loss  Potency varies greatly depending upon R1 and R2 side chains no N N

23. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology  Monthly IV pamidronate 90 mg in patients with advanced MM (N = 392) Berenson JR, et al. N Engl J Med. 1996;334:488-493. Pamidronate Effect on SREs in MM: A Phase III Trial Proportion of Patients With Skeletal Events at 9 Months Skeletal Morbidity at 9 Months P <.001 PamidronatePlacebo 0 10 20 30 40 50 0 1 2 3 24 41 1.10 2.05 Patients (%) Events/Year

24. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology TrialN Zoledronic Acid 4 mg and 8 mg vs Patient Population Duration, Mos 0101648Pamidronate 90 mg MM, breast cancer 25 011773Placebo Other solid tumors 21 039643PlaceboProstate cancer24 Zoledronic Acid for Bone Lesions: Phase III Trials 3 Randomized, International, Parallel, Double-Blind Trials

25. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology  Patients received oral vitamin D 400 IU and calcium 500 mg  8 mg zoledronic acid reduced to 4 mg after enrollment completed Pts with bone lesions secondary to advanced breast cancer or MM (N = 1648) Pamidronate 90 mg every 3-4 weeks, 120-min infusion (n = 558) Zoledronic Acid 4 mg every 3-4 weeks, 15-min infusion (n = 564) Zoledronic Acid 8 mg every 3-4 weeks, 15-min infusion (n = 526) Treatment for 24 months Rosen LS, et al. Cancer. 2003;98:1735-1744. Zoledronic Acid in MM and Breast Cancer Patients: Protocol 010 Design

26. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Zoledronic Acid vs Pamidronate in Breast Cancer and MM: Efficacy *Hypercalcemia of malignancy is included as a skeletal-related event. Rosen LS, et al. Cancer. 2003;98:1735-1744. Proportion With SRE, % Time to First SRE, Median* Mean Skeletal Morbidity* Multiple-Event Analysis HR* Zoledronic acid 4 mg473761.040.841 Pamidronate 90 mg513561.39-- P value.243.151.084.030

27. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Summary: IV Bisphosphonate Trials for Pts With Bone Disease of Malignancy  Both pamidronate and zoledronic acid administered every 3-4 weeks reduce development of new SREs for patients with osteolytic disease from breast cancer and MM  Only zoledronic acid has shown this benefit for patients with metastatic bone cancer –From all types of other primary solid tumors –With lytic or blastic bone lesions  Infusion time is much shorter with the more potent zoledronic acid (15 mins) than with pamidronate (120 mins)

28. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Other Treatment Recommendations  Reduce risk of falls  Encourage weight-bearing exercise (eg, walking)  Physical therapy  Oral vitamin D (≥ 800 U) and calcium (≥ 1000 mg/day) –Many cancer patients are deficient –Check vitamin D levels on all patients! –If deficient, replace with higher amounts daily or weekly

29. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Monoclonal Gammopathy of Undetermined Significance (MGUS)  Definition –Serum monoclonal protein ≤ 3 g/dL –< 10% plasma cells in the bone marrow –Absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the plasma cell proliferative process  Incidence –3% of individuals older than 50 years of age –5% older than 70 years of age  Risk of bone-related problems –Elevated rate of bone resorption –Increased prevalence of osteopenia/osteoporosis –Heightened risk of fractures especially vertebral compression fractures Kyle RA, et al. N Engl J Med. 2006;354:1362. Pecherstorfer M, et al. Blood. 1997;90:3743-3750. Melton LJ 3rd, et al. J Bone Miner Res. 2004;19:19:25-30.

30. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Phase II Study of ZOL for MGUS Patients With Osteopenia/Osteoporosis  Treatment –Zoledronic acid 4 mg administered IV over 15 minutes at 0, 6, and 12 months  Efficacy –Primary endpoint: BMD –DEXA scans and skeletal surveys were conducted at screening and 1 month after the final zoledronic acid infusion (13 months) Berenson J, et al. Clin Cancer Res. 2008;14:6289-6295.

31. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Zoledronic Acid for MGUS Patients With Osteopenia/Osteoporosis: Responses ParameterPatients, n Result Median Δ L-spine T score (range)44+0.30 (-0.38 to +3.91)* % L-spine improvement (range)44+22% (-18% to +1140%) Median Δ hip T score (range)44+0.19 (-2.40 to +2.03) % hip improvement (range)44+8% (-350% to +150%) Median Δ serum M-protein, g/dL (range)540 (-2.50 to +2.10) Patients with new fractures, n540 Patients progressing to myeloma, n540 *P =.0001 Berenson J, et al. Clin Cancer Res. 2008;14:6289-6295.

32. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Zoledronic Acid for MGUS Patients With Osteopenia/Osteoporosis: Summary  Zoledronic acid administered at 4 mg every 6 months (at 0, 6, and 12 months) –Significantly improves BMD for MGUS patients with bone loss (osteopenia or osteoporosis) –Is safe and well tolerated –Is likely to be an effective treatment to prevent the development of new fractures in this high-risk population Berenson J, et al. Clin Cancer Res. 2008;14:6289-6295.

33. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Bisphosphonates: Adverse Effects  Oral: GI intolerance (in up to 1/3 of patients) especially esophagitis and esophageal ulcers  Intravenous (pamidronate or zoledronic acid) –Flu-like symptoms (fever, myalgias, arthralgias) –Occurs usually 12-48 hrs following the infusion –Lasts 6-24 hrs –Occurs in a minority of patients (10% to 20%) –Not observed with continued dosing –Similar frequency with different drugs –Steroids may help reduce risk and intensity –Ocular effects –Anemia –Renal dysfunction –Osteonecrosis of the jaw

34. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Bisphosphonates: Antibone Resorption Potency vs Renal Dysfunction  Bisphosphonates infrequently associated with renal dysfunction –Occurs with all bisphosphonates –Related to backbone of bisphosphonates, not the R 2 side chain that produces the antibone resorptive potency O- O=P O- C P=O O- Bisphosphonate R1R1 R2R2

35. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Renal Function: The Use of Bisphosphonates  Changes in kidney function are related to C max –ie, the highest level of BP is in the blood –As a result, rate of infusion is the key factor in prevention of kidney problems –Rates faster than 0.3-0.7 mg/min are associated with problems  Importantly, rate of infusion has no impact prevention of skeletal complications –Efficacy related to AUC (how much remains in patient)  Zoledronic acid and pamidronate affect different parts of the kidney –Zoledronic acid: tubular –Pamidronate: glomerular  Reduce the risk of renal dysfunction –Monitor serum creatinine prior to each infusion –Make sure patient is hydrated at time of treatment

36. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Kidney Function and the Use of Bisphosphonates  Since kidney deleterious effects occur at similar rates of infusion (mg/min) among different BPs, more potent BPs such as zoledronic acid (4 mg) can be given safely much more rapidly (over 15 mins) than weaker BPs such as pamidronate (90 mg) (≥ 2 hrs)  Small changes in dose (as recommended for zoledronic acid based on creatinine clearance) make little sense when infusion time is the factor that determines renal risk

37. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Breast Cancer and MM Estimates of First Serum Creatinine Increase*  Zoledronic acid 4 mg renal safety profile is comparable to pamidronate *Post 15-min infusion amendment. † After start of study drug. 0 0 20 40 60 80 100 120240360480600720 Days † Without Increase (%) n Hazard ratio P Value 272 268 1.057.839ZOL 4 mg Pam 90 mg Rosen LS, et al. Cancer. 2003;98:1735-1744.

38. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Use of BPs for Pts With Renal Dysfunction  If serum creatinine < 3 mg/dL, no change to dose, infusion time, or schedule is required  Use among patients with worse function minimally assessed –Pamidronate [1] –Zoledronic acid (ongoing studies)  However, if on dialysis (irreversibly), may use either zoledronic acid or pamidronate at same dose, infusion time, and interval  If renal dysfunction reverses with anticancer therapy, IV BPs may be initiated  If myeloma patients have poor renal function at diagnosis, do not have hypercalcemia or severe bone disease, wait until renal function improves with antimyeloma therapy, then initiate monthly IV BPs  If hypercalcemia, use zoledronic acid even with renal dysfunction 1. Berenson J, et al. J Clin Pharmacol. 1997;37:285-290.

39. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Osteonecrosis of the Jaw: Clinical Features and Working Diagnosis  Clinical features of suspected ONJ –Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing  Working diagnosis of ONJ –No evidence of healing after 6 weeks of appropriate evaluation and dental care –No evidence of metastatic disease in the jaw or osteoradionecrosis Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62:148-152.

40. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Frequency of ONJ in Malignant Bone Disease StudyStudy Type Pts Treated With BP, n Pts With Suspect or Proven ONJ, n Frequency, % Hoff et al, MDACC ASCO 2006 [1] Chart review4019340.8 Durie et al [2] Web-based survey120315212.6 Pozzi et al, Italian Multicenter study [3] Chart review888161.8 Badros et al [4] Chart review/ observational 340113.2 Tosi et al, analysis of Bologna 2002 trial [5] Retrospective review of trial database 25962.7 Zervas et al [6] Observational2542811.0 Dimopoulos et al [7] Chart review202157.4 Cafro et al [8] Chart review1181411.9 Berenson et al [9] Chart review 300 144.7 1. Hoff AO, et al. ASCO 2006. Abstract 8528. 2. Durie GM, et al. N Engl J Med. 2005;3531:99-102. 3. Pozzi S, et al. Blood. ASH 2005. Abstract 5057. 4. Badros A, et al. J Clin Oncol. 2006;24:945-952. 5. Tosi P, et al. ASH 2005. Abstract 3461. 6. Zervas K, et al. Br J Hematol. 2006;134: 620-623. 7. Dimopoulos M, et al. Hematologica. 2006;91:968-971. 8. Cafro A, et al. ASH 2005. Abstract 5152. 9. Berenson J, et al. Clin Lymphoma Myeloma. 2009;28:204.

41. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Osteonecrosis of the Jaw  14 patients (4.7%) developed ONJ –13 patients with ONJ remain alive and currently are in remission or with stable disease –1 patient with ONJ died while in remission from a myocardial infarction  Course of ONJ (4-49 mos from diagnosis of ONJ) –7 improved or resolved –5 remained stable –2 showed some worsening  Patients with ONJ showed an improved OS using both landmark and time-dependent analysis Berenson JR, et al. Clin Lymphoma Myeloma. 2009;28:Abstract 204.

42. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Relative Risk Factors for ONJ  Cancer  Radiation therapy  Corticosteroids  Poor dental hygiene  Poor diet  Dental work  Trauma  Ethanol or tobacco use  Coagulopathy  Chemotherapy  Infection  Bisphosphonates  Antiangiogenic therapies?

43. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Minimizing the Risk of ONJ  Excellent oral hygiene is the best prophylaxis  Limit EtOH and tobacco use  Patients who are starting IV BPs should have a dental assessment first –Dental procedures (extensive) should be done before starting IV BPs if possible  Avoid dental procedures once start IV BPs

44. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Managing ONJ  Make a diagnosis –Get someone to evaluate who knows the entity  Assess its severity –It takes on a wide spectrum!  Maintain excellent dental hygiene and regular exams  Keep surgical intervention to a minimum  There is no standard treatment –Antibacterial and antifungal rinses (chlorhexidine gluconate and nystatin) –Systemic oral antibacterial, antiviral, and antifungal treatments  Hyperbaric oxygen has not proven useful  No evidence that discontinuing IV BPs is necessary or changes the course of ONJ

45. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology IV BPs for MM Patients: Effects of Changes in Schedule on ONJ and Skeletal Risk  No evidence that discontinuing IV BPs changes the risk of ONJ –In fact, risk of ONJ may be not related to number of doses but to time from first dose –Whether pt receives 5 or 50 doses, pt may be at the same risk after 50 mos  Less frequent dosing (every 3 mos) schedules not yet evaluated for –Safety or efficacy –Only every 3- to 4-wk dosing shown to be effective in reducing skeletal complications –Bone resorption marker data show enhanced bone loss occurs 4 wks after dose of IV BP –Changing the risk of ONJ

46. New Targets for Metastatic Bone Disease

47. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Proliferation and differentiation Prefusion osteoclasts RANK OPG RANK RANKL OPG Activated osteoclasts Survival and fusion VEGF VEGFR C-fms M-CSF Monocytes 1 , 25(OH) 2 DC 3, PTH, IL-11 Osteoclasts Osteoblasts/stromal cells RANK Interferon  Hofbauer LC, et al. Arthritis Rheum. 2001:44:253-259. Osteoclastogenesis

48. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Mean ± SEM Study Day 1815222936435057 Change in Urine N-Telopeptide/Creatinine (%) -80 -60 -40 -20 0 20 40 Pamidronate (n = 8) 0.1 mg/kg (n = 4) 0.3 mg/kg (n = 2) 1.0 mg/kg (n = 6) 3.0 mg/kg (n = 6) Body JJ, et al. Cancer. 2003;97(suppl 3):887-892 Phase I Clinical Trial of OPG Analogue in Myeloma Patients With Lytic Disease 50

49. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Inhibiting RANK in Metastatic Bone Disease  Limitations of OPG analogues –Anti-OPG response led to enhanced bone resorption in postmenopausal patient –OPG binds to TRAIL and blocks its activity –Apoptotic ligand for MM and other tumors  Denosumab –Fully human monoclonal antibody to RANKL –IgG2 with long serum half-life –In healthy postmenopausal females –Single SC dose produces sustained inhibition of bone resorption markers

50. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Denosumab in Cancer Patients With Lytic Bone Disease  Double-blind, double-dummy phase I trial  Single dose of –Denosumab SC at 0.1, 0.3, 1.0, or 3.0 mg/kg –Pamidronate IV 90 mg  Assess bone resorption markers –Urine and serum N-telopeptide levels for 84 days following dose Body JJ, et al. Clin Cancer Res. 2006;12:1221-1228.

51. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Time PointUrinary NTX/creatinine, % Change PAMDES 0.1*DES 0.3*DES 1.0*DES 3.0* Day 2-31-16-19-53-39 Day 8-47-35-59 -51 Day 29-19-11-55-56-34 Day 5736-24-64-78-27 Day 85-24-25-45-77-38 *mg/kg Body JJ, et al. Clin Cancer Res. 2006;12:1221-1228. Denosumab in Cancer Patients With Lytic Bone Disease: Phase I Trial Results

52. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Potential Benefits of New Antimyeloma Drugs on Myeloma Bone Disease  Bortezomib, thalidomide, and arsenic trioxide are NF-kB inhibitors –As a result, these drugs block RANK signaling –Inhibit osteoclast function  Bortezomib –Increases in the bone formation marker, bone alkaline phosphatase, among responding patients –Stimulates osteoblast function –Increases BMP production –Blocks DKK1 expression –Bone resorption markers suppressed in responding patients Ma MH, et al. Clin Cancer Res. 2003;9:1136-1144. Zangari M, et al. Br J Haematol. 2005;131:71-73. Shimazaki C, et al. Leukemia. 2005;19:1102-1103. Oyajobi. et al. Br J Haematol. 2007;139:434-438.

53. Bone Health and Skeletal Complications in Multiple Myeloma clinicaloptions.com/oncology Summary  Bone-related problems occur commonly in cancer patients  New minimally invasive surgical techniques such as kyphoplasty are providing rapid palliation for patients with VCFs  IV bisphosphonates reduce skeletal morbidity for patients with metastatic bone disease  Bone-seeking radiopharmaceuticals provide relief of bone pain  Newer antimyeloma drugs may also improve bone strength for cancer patients  New targets for inhibition of bone loss are leading to new therapies including denosumab

54. Go Online for More Information on Bone Health in Cancer! Interactive Virtual Presentations including illustrative cases in multiple myeloma, breast cancer, and prostate cancer clinicaloptions.com/BoneMgmt