Multiple Myeloma Bone Disease - PDF Free Download

The 4th World Congress on CONTROVERSIES IN MULTIPLE MYELOMA May 3-5, 2018 Paris, France Multiple Myeloma Bone Disease Evangelos Terpos MD, PhD Plasma Cell Dyscrasias Unit,, National & Kapodistrian, School of Medicine, Athens, Greece 1 SC IC CARFILZOMI 00079

Speaker 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 2

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 Bone Disease in Multiple Myeloma At diagnosis, lytic lesions by WBXR: Vertebrae in 65% of patients Ribs in 45% Skull in 40% Shoulders in 40% Pelvis in 30% Long bones in 25% 1. Terpos E, et al. J Clin Oncol. 2011;29:1907 1915; 2. Dimopoulos M, et al. Leukemia. 2009;23:1545 1556. 3

Bone Involvement in Myeloma Leads to Skeletal Related Events 60% 50% 51 n = 179 40% 37 34 30% 20% 10% 5 3 0% Total SREs Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Berenson JR, et al. J Clin Oncol. 1998;16:593 602. 4

SREs Are a Serious Problem for Patients With Multiple Myeloma (Our Experience) SREs at Diagnosis (%) 0 5 10 15 20 25 30 SREs at 1st Relapse (%) 0 10 20 30 Pathological fractures Surgery to bone 5.5 26.0 Bortezomib based regimens 10.0 Radiotherapy 5.2 IMiD based regimens 22.0 SCC 5.0 n = 284 Terpos E, et al. Presented at: American Society of Hematology Annual Meeting. December 7 10, 2013. New Orleans, LA. 5

Bone Metabolism: A Balance Between Osteoblasts and Osteoclasts Blood Vessel Matrix Matrix formation maturation Proliferation & mineralization Osteoblast pregenitors OSTEOBLAST DIFFERENTIATION Early osteoblast Mature osteoblast Lining cell Apoptosis Osteocytes Lining cells Local factors Sclerostin Osteoid Osteoblasts Osteoclasts New bone Microcrack Cement line Osteocyte apoptosis Old bone New osteocytes 1. Seeman E, et al. N Engl J Med. 2006;354:2250 2261; 2. van Bezooijen RL, et al. Cytokine Growth Factor Rev. 2005;16:319 327. 6

Images courtesy of Dr. Terpos.

Jilka RL, et al. Bone. 2013;54:264 271.

Images courtesy of Dr. Terpos.

RANK Ligand: An Essential Mediator of Osteoclasts RANKL RANK Growth factors Hormones Cytokines CFU-M CFU-M Prefusion Prefusion osteoclast osteoclast Multinucleated Multinucleated osteoclast osteoclast Mature Mature osteoclast osteoclast Osteoblast lineage Bone Boyle WJ, et al. Nature. 2003;423:337 342. 11

Increased Bone Density Associated With Absence of RANKL Preclinical Experiments Normal RANKL Knockout Li J, et al. Proc Natl Acad Sci U S A. 2000;97:1566 1571. 12

Osteoprotegerin: The Decoy Receptor of RANKL Osteoclast Formation, Function, and Survival Inhibited by OPG RANKL RANK OPG Growth factors Hormones Cytokines CFU M Prefusion osteoclast Multinucleated osteoclast Inactive osteoclast Osteoblast lineage Bone Boyle WJ, et al. Nature. 2003;423:337 342. 13

Reduced Bone Density Associated With Absence of OPG 100 50 40 BV%TV 30 20 10 0 * * 10 OPG +/+ OPG +/ OPG / *P < 0.001 (compared with OPG +/+). Bucay N, et al. Genes Dev. 1998;12:1260 1268. 14

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 Promotes OC activation Osteoclast activity Prevents OC activation 1. Hofbauer LC, et al. JAMA. 2004;292:490 495; 2. Lacey DL, et al. Cell. 1998;93:165 176; 3. Boyle WJ, et al. Nature. 2003;423:337 342. 15

Myeloma Microenvironment and Bone Disease Myeloma cells RANKL OPG ( ) CD138 Osteoblasts balp, osteocalcin IL 6, IGF 1 BAFF, APRIL Dkk 1, sfrp 2 sclerostin, activin A α4β1integrin RANKL RANKL OPG VCAM 1 VCAM 1 ( ) RANKL RANK IL 6 IL 11, IL 1b, βfgf TNFα, M CSF BMSCs MIP 1α, MIP 1β, SDF 1α, IL 3, HGF, OPN Osteoclast precursor Collagen type 1 degradation products: NTX, ICTP, CTX TRACP 5b Activated osteoclasts Bone resorption Bone matrix 16 1. Terpos E, et al. Ann Oncol. 2005;16:1223 1231; 2. Moreaux J, et al. Blood. 2011;117:1280 1290.

srankl/opg in newly diagnosed myeloma 2.0 1.5 30 121 36 1.0.5 52 0.0 Log srankl/opg -.5-1.0-1.5 N = 159 149 134 158 45 10 28 83 68 Control A B C Bone Disease 17 Terpos E, et al. Blood. 2003;102:1064 9.

RANKL inhibition and survival in mice with multiple myeloma Paraprotein (g/dl) 4.0 3.5 3.0 2.5 2.0 0 100 0 3.5 * P < 0.02 * 2.4 Survival 1.0 0.8 0.6 0.4 Control P < 0.02 OPG % Myeloma cells 90 85 80 75 0 0 Control 84.7 5T33MM + Vehicle * P < 0.02 * 75.8 5T33MM + OPG 0.2 0 0 5 10 15 20 25 30 35 40 Days 18 Vanderkerken K, et al. Cancer Res. 2003;63:287 9.

Prognostic value of srankl/opg in multiple myeloma Probability of survival (%) 100 80 60 40 20 20 srankl/opg < 1 89% srankl/opg 1 3 srankl/opg > 3 32% 0 12 24 36 48 60 Months post diagnosis 19 Terpos E, et al. Blood. 2003;102:1064 9.

Osteoclasts: Key for Myeloma Cell Growth Without Osteoclasts With Osteoclasts Myeloma cell culture after 14 days Abe M, et al. Blood. 2004;104:2484 2491. 20

Osteoclasts and Osteoblasts: Antagonists of Myeloma Cell Growth? P < 0.002 7 6 5 P < 0.0003 P < 0.02 P < 0.04 MM MM + OC MM + OB MM + OC + OB BrdU (%) 4 3 2 1 0 BrdU = bromodeoxyuridine; OB = osteoblast; OC = osteoclast; MM = multiple myeloma. Yaccoby S, et al. Haematologica. 2006;91:192 199. 21

Treatment of Myeloma Related Bone Disease 22

Therapies for Myeloma related Bone Disease VCAM1 CD40 MUC1 MULTIPLE MYELOMA PLASMA CELL BONE MARROW STROMAL CELL VLA 4 CD40L ICAM1 BHQ880 MLN3897 LY2127399 Wnt receptor BAFF MIP 1a MESENCHYMAL CELL β Catenin RUNX 2 FMS MAPK OSTEOBLASTS ERK TRAF6 Integrin p38 OPG JNK AP 1 P50/p52 ACTIVIN A OSTEOCLAST BONE Sotatercept Bisphosphonates Adpated from: Raje N et al. Clin Cancer Res. 2011;17:1278 1286. 23

Targeting Osteoclasts With Bisphosphonates Zolendronate stained green 1. Sato G, et al. J Clin Invest. 1991;88:2095 2105; 2. Coxon F, et al. Bone. 2008;42:848 860. 24

ZOL Significantly OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350) Survival Distribution Function Estimate OS (% Patients) 100 90 80 70 60 50 40 30 20 10 0 Clodronate (n = 682) Zoledronic acid (n = 668) + Censored P = 0.0107 HR = 0.82 (95% CI = 0.70 0.96) 10 mo 0 1 2 3 4 5 6 Time Since Initial Randomization (y) ZOL CLO 668 682 544 534 447 437 292 271 165 143 64 53 3 0 Morgan G, et al. Lancet. 2010;376:744 751.. 25

Bisphosphonates Choice: Cochrane Meta Analysis No evidence of superiority in any specific aminobisphosphonate (zoledronate, pamidronate, or ibandronate) for any outcome However, zoledronate appears to be superior to placebo and etidronate in improving OS IMWG Recommendations for BPs Choice 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 1. Mhaskar R, et al. Cochrane Database Syst Rev. 2012;5:CD003188; 2. Terpos E, et al. J Clin Oncol. 2013;31:2347 2357. 26

When Do We Start Treatment With BPs? MRC Myeloma IX: ZOL SREs vs CLO Regardless of Bone Lesions at Baseline Bone Lesions at Baseline No Lesions at Baseline Cumulative Incidence Function, SREs a /Patient 0.5 0.4 0.3 0.2 0.1 0 CLO 43% ZOL 34% P = 0.0038 0 6 12 18 24 30 36 42 Time From Randomization (mo) Cumulative Incidence Function, SREs a /Patient 0.5 0.4 0.3 0.2 0.1 0 P = 0.0068 CLO 17% ZOL 9% 0 6 12 18 24 30 36 42 Time From Randomization (mo) Highlights the importance of treating all patients regardless of skeletal morbidity at presentation asres 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. CLO = clodronate; MRC = Medical Research Council; SRE = skeletal related event; ZOL = zoledronic acid. Morgan G, et al. Lancet Oncol. 2011;12:743 752. 27

BPs Initiation IMWG Recommendations: BPs Initiation and Treatment Duration 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 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/vgPR and further continued at relapse (grade B) For patients in CR/vgPR, the optimal treatment duration of BPs is unclear; 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 2357. 28

BPs Severe Adverse Events: MRC IX Study ZOL (n = 213) Non Intensive Pathway (n = 851) Intensive Pathway (n = 1,111) MP (n = 424) C TDa (n = 427) CVAD (n = 556) C TD (n = 555) CLO (n = 211) ZOL (n = 215) CLO (n = 212) ZOL (n = 278) CLO (n = 278) ZOL (n = 277) CLO (n = 278) ONJ b 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. Lancet. 2010;376:744 751. 29

Osteonecrosis of the Jaw (ONJ) ONJ occurs in approximately 4% 11% of those who receive BPs Risk Factors: Invasive dental procedures (eg, tooth extraction and dental implants); poor oral hygiene; age; duration of BPs administration 1. Terpos E, et al. Expert Rev Hematol. 2014;7:113 125; 2. Melea PI, et al. Int J Dent. 2014;2014:427273. 30

ONJ healed in 75% Natural History of ONJ in Myeloma ONJ did not resolve over a follow up period of at least 9 months in 25 patients (26%) ONJ recurrence followed re initiation of bisphosphonate in 6 of 12 patients Patients in whom ONJ was precipitated by dental procedures were less likely to have recurrence or non healing lesions after BP re initiation following ONJ healing, as compared to those who develop spontaneous ONJ lesions (P = 0.007) Badros A. et al. J Clin Oncol. 2008;26:5904 5909. 31

IMWG Guidelines: BPs and ONJ Preventive strategies should be adopted to avoid ONJ Patients should receive a comprehensive dental examination and be educated regarding optimal dental hygiene (grade C) Existing dental conditions should be treated before initiating BP therapy (grade C; panel consensus) After BP treatment initiation, unnecessary invasive dental procedures should be avoided Temporary suspension of BP treatment should be considered if invasive dental procedures are necessary (grade D). The panel s consensus is to stop BPs for 90 days before and after invasive dental procedures (tooth extraction, dental implants, and surgery to the jaw). BPs do not need to be discontinued for routine dental procedures including root canal Initial treatment of ONJ should include discontinuation of BPs until healing occurs (grade C) Terpos E, et al. J Clin Oncol. 2013;31:2347 2357. 32

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 2357. 33

Cancer Therapy: Clinical Bone Marker Directed dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Results of the Z MARK Study Noopur Raje 1, Robert Vescio 2, Charles W. Montgomery 3, Ashraf Badros 4, Nikhil Munshi 5, Richard Orlowski 6, Joseph T. Hadala 7, Ghulalm Warsi 7, Eliza Argonza Aviles 7, Solveig G. Ericson 7, and Kenneth C. Anderson 8 Clinical Cancer Research Proportion of Patients With 1 SRE 0.062 0.060 0.058 0.056 0.054 0.052 0.050 0.048 0.046 0.044 N Year 1 Year 2 5.8% 4.9% 121 101 Translational Relevance Zoledronic acid is indicated for the treatment of patients with multiple myeloma in conjunction with the standard anti neoplastic therapy. Although standard monthly infusions are effective in reducing the risk of skeletal complications, patients with normal bone metabolism may not require as intense a treatment schedule as patients with accelerated bone resorption. A reduced dosing schedule of every 12 weeks may be adequate for patients with normal bone metabolism and may mitigate long term toxicity. This study evaluated a tailored approach to zoledronic acid therapy that aimed at maximizing the benefit risk ratio and allowing an effective, less frequent dosing based on bone turnover marker, urinary N telopeptide of type I collagen. In this study, the low skeletal related event rate maintained for every 12 week dosing supports the efficacy of less frequent zoledronic acid dosing in patients with multiple myeloma who have already received 1 to 2 years of prior intravenous bisphosphonate therapy.

Denosumab Mechanism of Action Denosumab Inhibits Osteoclast Formation, Function, and Survival Denosumab OPG RANKL RANK CFU M Pre Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Mature Osteoclast Bone Boyle WJ, et al. Nature. 2003;423:337 342. 35

Denosumab vs Zoledronic Acid in Myeloma: Study Design Randomization (N = 1,718) 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) Denosumab 120 mg SC + Placebo IV Q4W (n = 859) Placebo SC + Zoledronic acid 4 mg IV Q4W (n = 859) Primary endpoint: Noninferiority for First On Study SRE 676 Events Offered open label denosumab up to 2 years Yes Benefit:Risk positive? No 2 year follow up for survival Raje N, et al. Lancet Oncol. 2018;19:370 381. 37

Primary Methods: Key Endpoints Time to the first on study skeletal related event (non inferiority). Secondary Time to the first on study skeletal related event (superiority). Time to the first and subsequent on study skeletal related event (superiority). Overall survival. Exploratory Progression free survival. Raje N, et al. 38Lancet Oncol 2018;19:370 81

Results: Baseline Patient Demographics and Characteristics Denosumab N = 859; n (%) Zoledronic Acid N = 859; n (%) All Patients N = 1718; n (%) Male 462 (53.8) 473 (55.1) 935 (54.4) Female 397 (46.2) 386 (44.9) 783 (45.6) Mean Age (Years) 63.5 63.3 63.4 Median 63.0 63.0 63.0 Min, Max 29, 91 31, 89 29, 91 White 711 (82.8) 699 (81.4) 1410 (82.1) Asian 107 (12.5) 101 (11.8) 208 (12.1) Black or African American 29 (3.4) 36 (4.2) 65 (3.8) Europe 509 (59.3) 513 (59.7) 1022 (59.5) North America 218 (25.4) 227 (26.4) 445 (25.9) Rest of the World 132 (15.4) 119 (13.9) 251 (14.6) Prior SRE History (Yes) 567 (66.0) 577 (67.2) 1144 (66.6) Multiple Myeloma ISS Stage at Diagnosis I 272 (31.7) 275 (32.0) 547 (31.8) II 307 (35.7) 326 (38.0) 633 (36.8) III 257 (29.9) 232 (27.0) 489 (28.5) Not Available 23 (2.7) 26 (3.0) 49 (2.9) Class of the First-Line Therapy Proteasome Inhibitor Only 441 (51.3) 452 (52.6) 893 (52.0) Immunomodulatory Drug Only 133 (15.5) 154 (17.9) 287 (16.7) Proteasome Inhibitor + Immunomodulatory Drug 248 (28.9) 215 (25.0) 463 (26.9) Other 33 (3.8) 36 (4.2) 69 (4.0) Intent to Undergo Autologous PBSC Transplantation: Yes 465 (54.1) 39 465 (54.1) 930 (54.1) Raje N, et al. Lancet Oncol 2018;19:370 81

Results: First On Study SRE Primary Endpoint Met: Noninferiority for First On Study SRE Proportion Of Subjects Without SRE 1.0 0.8 0.6 0.4 0.2 0.0 Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Study Month Denosumab 120 mg Q4W 859 583 453 370 303 243 197 160 127 99 77 50 35 22 Zoledronic Acid 4 mg Q4W 859 595 450 361 288 239 190 152 125 95 69 48 31 18 Raje N, et al. Lancet Oncol. 2018;19:370 381. 40

The Majority of On Study Skeletal Related Event s Occurred Within 3 Months Incidence of on study skeletal related events was high and occurred early 44% of patients had at least one, on study SRE, with 60% of all first skeletal related events occurring within 3 months Multiple myeloma patients have widespread bone loss that may not be detectable and correlates with an increased risk of early vertebral collapse Proportion of Patients Without a Skeletal Related Event 1.0 0.8 0.6 0.4 0.2 0.0 Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859) HR (95% CI) = 0.98 (0.85, 1.14); P = 0.01 (Noninferiority met) P = 0.82 (Superiority not met) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Study Month Denosumab: 859 583 453 370 303 243 197 160 127 99 77 50 35 22 Zoledronic Acid: 859 595 450 361 288 239 190 152 125 95 69 48 31 18 Terpos E, et al. Presented at: 22nd Congress of the European Hematology Association. June 22 25, 2017. Madrid, Spain. Abstract S782. CI Confidence interval; HR Hazard ratio; Q4W every 4 weeks. 41

Post hoc Landmark Analysis at 15 Months Proportion Without a SRE on Study (%) 100 80 60 40 20 0 HR (95% CI) = 0.66 (0.44 0.98); P = 0.039 0 15 18 21 24 27 30 33 36 39 42 Time Since Randomization (months) Number at risk (censored) Denosumab: 450 366 300 238 183 143 98 68 41 16 (0) (72) (58) (53) (50) (36) (44) (30) (26) (25) Zoledronic Acid: 459 367 294 231 176 129 90 58 31 10 (0) (78) (61) (54) (46) (43) (36) (26) (22) (21) Raje N, et al. Lancet Oncol 2018;19:370 381. 42

Results: Type of SRE, Landmark Analysis Total First SREs Total SREs Denosumab, n Zoledronic acid, n Denosumab, n Zoledronic acid, n Fracture 28 37 Fracture 31 43 Radiation to bone 4 11 Radiation to bone 5 12 Surgery to bone 6 13 Surgery to bone 9 13 Spinal cord compression 2 1 Spinal cord compression 2 1 45 45 Events 30 15 Denosumab ZA Events 30 15 Denosumab ZA 0 Pathologic fracture Radiation to bone Surgery to bone Spinal cord compression 0 Pathologic fracture Radiation to bone Surgery to bone Spinal Cord Compression Terpos E, et al. Presented at: 22nd Congress of the European Hematology Association. June 22 25, 2017. Madrid, Spain. Abstract S782.

Results: Progression Free Survival Proportion of Subjects Without Event 1.0 0.8 0.6 0.4 Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859) HR (95% CI) = 0.82 (0.68, 0.99); descriptive P = 0.036 0.2 Denosumab median (95% CI) = 46.09 mo (34.3, NE) Zoledronic acid median (95% CI) = 35.38 mo (30.19, NE) 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Study (mo) Denosumab 120 mg Q4W 859 789 703 583 501 411 329 269 214 157 125 82 57 35 14 Zoledronic Acid 4 mg Q4W 859 806 690 584 495 404 324 252 206 159 112 78 53 30 9 Raje N, et al. Lancet Oncol. 2018;19:370 381. 44

Results: Overall Survival Proportion of Subjects Survived 1.0 0.8 0.6 0.4 Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859) HR (95% CI) = 0.90 (0.70, 1.16); P = 0.41 0.2 Denosumab: 121 deaths (14.1%) Zoledronic acid: 129 deaths (15%) 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Study Month Denosumab 120 mg Q4W 859 809 737 640 565 477 395 344 288 229 175 130 85 48 19 Zoledronic Acid 4 mg Q4W 859 830 737 652 568 488 414 348 289 233 179 127 87 49 15 Raje N, et al. Lancet Oncol. 2018;19:370 381. 45

Results: Adverse Events of Interest Zoledronic Acid (N = 852) n (%) Denosumab (N = 850) n (%) Hypocalcemia 106 (12.4) 144 (16.9) Serious AEs of hypoglycemia 2 (0.2) 8 (0.9) Adjudicated positive osteonecrosis of the jaw 24 (2.8) 35 (4.1) Adjudicated positive atypical femur fracture 0 0 AEs potentially associated with hypersensitivity 189 (22.2) 219 (25.8) Serious AEs potentially associated with hypersensitivity 9 (1.1) 5 (0.6) Musculoskeletal pain 425 (49.9) 407 (47.9) Infections and infestations 500 (58.7) 537 (63.2) Serious AEs of infections and infestations 163 (19.1) 165 (19.4) New primary malignancy 12 (1.4) 22 (2.6) Renal toxicity TEAEs 146 (17.1) 85 (10.0) in patients with baseline CrCl < 60 ml/min 58/220 (26.4) 30/223 (12.9) Creatinine > 2 mg/dl 54/823 (6.6) 31/824 (3.8) in patients with baseline CrCl < 60 ml/min 32/203 (15.8) 20/216 (9.3) Creatinine doubled from baseline 55/840 (6.5) 28/841 (3.3) in patients with baseline CrCl < 60 ml/min 16/220 (7.3) 6/233 (2.6) Raje N, et al. Presented at: American Society of Clinical Oncology Annual Meeting. June 1 5, 2017. Chicago, IL. Abstract 8005. 46

Conclusions for the Management of Myeloma Related Bone Disease Osteolytic bone disease is the main complication of myeloma BPs treatment of choice: zoledronic acid, pamidronate Denosumab is the new standard of care: Non inferiority was demonstrated for the primary endpoint of time to first SRE However, the 15 month landmark analysis demonstrated an improved delay in time to first skeletal related events for patients treated with denosumab Progression free survival for denosumab was longer (10.7 months) compared to zoledronic acid, with an HR (95% CI) = 0.82 (0.68, 0.99), descriptive P = 0.036 There were 35 (4.1%) and 24 (2.8%) positively adjudicated events of osteonecrosis of jaw (ONJ) in the denosumab arm and ZA arm, respectively Hypocalcemia events for denosumab and ZA were 144 (16.9%) and 106 (12.4%), respectively, with no grade 5 events Fewer AEs potentially related to renal toxicity occurred with denosumab than ZA (10% vs 17.1%), as with acute phase reactions (5.4% vs 8.7%) 47

Thank You 48