Noopur Raje, MD. Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN

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2 Noopur Raje, MD Director, Center for Multiple Myeloma MGH Cancer Center Professor of Medicine Harvard Medical School Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN Department of Hematology and Medical Oncology Cleveland Clinic Taussig Cancer Institute Cleveland, OH

3 International Myeloma Foundation (IMF) Dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure International Myeloma Working Group Nurse Leadership Board Black Swan Research Projects Publications: Brochures, etc IMF Infoline Patient Outreach Support Groups Seminars, Workshops Teleconferences Advocacy Global Outreach 3

4 Overview of Myeloma and Bone Disease Dr. Beth Faiman

5 Effects of MM on Major Body Systems Blood: anemia, abnormal clotting, immunosuppression, infection, hyperviscosity Tired, dizziness, headache, short of breath, growth factor dependency, infection, organ infarction, blood clots Renal: (Kidney) proteinuria, amyloidosis, hypercalcemia, renal impairment or failure High calcium, dialysis **Note: Kidney failure can affect bone health** Bone: lytic lesions, osteopenia, hypercalcemia(commonly skull, vertebrae, ribs, long bones) Pain, immobility, bone fractures Multiple Myeloma Research Foundation Accessed August 30, Durie BGM. Accessed August 16, Snowden JA, et al. Br J Haematol. 2011;154:

6 Tests to Diagnose Multiple Myeloma Lab tests Serum protein electrophoresis (SPEP) Urine protein electrophoresis (UPEP) CBC + differential + chemistry including albumin and 2 microglobulin and LDH Serum FLC ratio of free kappa/lambda Monoclonal protein analysis (MPA) Bone marrow biopsy FISH, cytogenetics, and gene expression profiling (GEP) Imaging Skeletal survey MRI, CT or PET scan Albumin alpha-1 alpha-2 beta gamma CBC = complete blood count; CT = computed tomography; FISH = fluorescent in situ hybridization; FLC = free light chain; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; PET = positron emission tomography. Ghobrial IM, et al. Blood. 2014;124: Rajkumar SV, et al. Lancet Oncol. 2014;15:e Faiman B. Clin Lymphoma Myeloma Leuk. 2014;14: Dimopoulous M, et al. Leukemia. 2009; 23(9):

7 Good News: Patients are Living Longer Due to Expanding Treatment Options for Multiple Myeloma: Mibs, Mids, and mabs Alkylators Steroid Anthracycline Proteasome inhibitors ( mibs ) Immunomodulators ( IMiDs Or mids ) Monoclonal Antibodies ( mabs ) HDAC inhibitor **NEWEST Daratumumab 2015 Ixazomib 2015 Elotuzumab 2015 Panobinostat Melphalan 1962 Prednisone 1983 Auto Transplantation 1986 High-Dose Dex Auto = autologous; Dex= dexamethasone. Tariman, J. Nurs Clin North Am. 2017;52(1): DRUGS@FDA.gov 2003 Bortezomib 2006 Lenalidomide 2006 Thalidomide 2007 Doxorubicin **2018 Denosumab (supportive care) 2013 Pomalidomide 2012 Carfilzomib **Daratumumab + Velcade, Melphalan and Prednisone(2018) 7

8 Multiple Myeloma is a Clonal Disorder and the Clones Change Over Time: The Relapsing Nature of MM ASYMPTOMATIC SYMPTOMATIC REFRACTORY RELAPSE M-Protein g/l MGUS or SMOLDERING MYELOMA ACTIVE MYELOMA PLATEAU REMISSION RELAPSE Clone 1.1 Clone 1.2 Clone 2.1 Clone 2.2 Misc Therapy Time MGUS = monoclonal gammopathy of undetermined significance. Adapted from Dr. Brian Durie and Keats JJ, et al. Blood. 2012;120:

9 Bone Turnover in Myeloma is Altered: Normal Bone Remodeling Process 9

10 Immune Basis for Multiple Myeloma Bone Damage Affects Normal Bone Complex disease involving: Cancerous plasma cell clone(s) with genetic changes Produce abnormal immunoglobin (nonsecretory disease is rare) Produce cytokines Cytokine signaling causes an imbalance between Osteoclasts (too many) Osteoblasts (too few) Results in bone damage Palumbo A, Anderson KC. N Engl J Med. 2011;364(11):

11 Courtesy of Teresa Miceli OAF, IL-1, IL-6, DKK1, MIP-1α, VEGF, MMP, FRP-2, RANKL

12 Bone Disease in Multiple Myeloma A burdensome and frequent complication in MM - Present in up to 80% of patients at diagnosis Osteolytic bone lesions - Increased bone resorption/turnover and impaired bone formation Osteoclasts: Dissolve Bone Osteoblasts: Build bone - Pathological fractures - Osteoporosis - Hypercalcemia - Bone pain - Spinal cord compression SRE, skeletal-related event. Terpos E, et al. Haematologica 2016;101(S1, EHA abstracts): P285 Number of Fractures Spinal Vertebral Fractures (N=309) C1 C2 C3 C4 C5 C6 C7 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 Spinal vertebra SREs at Diagnosis (N=463) Percentage pathological fractures 26% surgery to bone radiotherapy SCC 4.7% 4.5% 4.3%

13 Bone Imaging Methods Historical Gold Standard Skeletal survey* Newer Standard MRI CT PET Scan (± MRI or CT) Whole body low-dose CT (WBLDCT) DXA (DEXA) MGUS *Clinicians should look at actual films as large lesions may be under-emphasized in the report Skeletal Survey X-rays Not Appropriate for evaluation of lytic lesions look for osteoporosis, rapid BMD decline DXA = Dual-energy X-ray absorptiometry (previously DEXA); CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography; WBLDCT = whole body low-dose CT. Miceli TS, et al. Clin J Oncol Nurs. 2011; 15(4):9-23; Roodman GD, et al. Hematology AM Soc Hematol Educ Program. 2008: ; Walker R, et al. Oncol. 2007:25(9) : ; Durie BG, et al. Leukemia. 2006;20(9): ; Tariman JD. Clin J Oncol Nurs. 2004:8(3): ; Guise TA et al. Endocr Rev. 1998:19(1):18-54; Gralow JR, et al. J Natl Compr Canc Netw. 2009:7 Suppl 3:S1-32; Dimopoulous M, et al. Leukemia. 2009; 23(9):

14 Updates in Bone Disease Treatment in Myeloma Dr. Noopur Raje

15 Current Treatment of MM Bone Disease Bisphosphonates or bone-strengthening antibody Surgical procedures Vertebroplasty Balloon kyphoplasty Radiotherapy Treatment of myeloma 15 Roodman GD. Hematology Am Soc Hematol Educ Program. 2008: This Photo by Unknown Author is licensed under CC BY-SA

16 Issues ONJ? Stress Fractures Raje et al. Clin Can Res 2008 Grasko, J et al. Oral Maxillofacial Surg Raje, et al. Clin Can Res 2008.

17 Do Bisphosphonates Have An Anti-Myeloma Effect? Several placebo-controlled, randomized phase III studies showed that subsets of myeloma patients receiving bisphosphonates had a survival advantage MRC-IX Myeloma study ZA reduced SRE risk by 26% vs. clodronate, regardless of the anti-myeloma treatment Benefit in both patients with and without bone disease at diagnosis Nordic MM group study- improved physical function, less ONJ Pamidronate 30mg vs 90mg Denosumab vs Zoledronic Acid Morgan GJ, Child JA, Gregory WM, et al; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol. 2011;12(8): ; Gimsing P, Carlson K, Turesson I, et al. Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. The Lancet. Oncology. Oct 2010;11(10): ; Raje N, Vadhan-Raj S, Willenbacher W, et al. Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial. Blood cancer journal. 01/08/online 2016;6:e378.

18 Zoledronic Acid and Pamidronate in Multiple Myeloma Zoledronic acid 4 mg Patients with SRE (%) % 44% Patients with no event (%) Pamidronate 90 mg 0 Pamidronate 90 mg All SREs Zoledronic acid 4 mg Time after start of drug (days) SRE = skeletal-related event Rosen LS et al. Cancer J. 2001;7(5):

19 MRC Myeloma IX Clinical Trial: ZOL vs CLO N = 1,960 Patients with newly diagnosed MM (stage I, II, III) R A N D O M I Z A T I O N Zoledronic acid (4 mg a IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981) Treatment continued at least until disease progression Clodronate (1,600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Patients were evaluated while on the clinical trial for Efficacy: how well the treatment works Safety: side effects that might be caused by the therapy The two therapies were compared to each other. Which patients did better? Primary Endpoints: PFS OS ORR Secondary Endpoints: Time to first SRE SRE incidence Safety CLO = clodronate; IV = intravenous; MM = multiple myeloma; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PO = oral; SRE = skeletal-related event; ZOL = zoledronic acid. a Dose-adjusted for patients with impaired renal function, per the prescribing information.

20 MRC Myeloma IX Results: ZOL Was Better than CLO Cumulative incidence function, SREs/patient Patients With Bone Lesions at Start of Study Patients, n ZOL CLO Time from randomization, months CLO ZOL Lower = Better Cumulative incidence function, SREs/patient Patients, n ZOL CLO Patients Without Bone Lesions at Start of Study Time from randomization, months So it is better to treat all patients with ZOL (zoledronic acid) not CLO (clodronate) whether or not they have bone lesions at the start CLO ZOL Lower = Better CLO = clodronate; SRE = skeletal-related event; ZOL = zoledronic acid. a SREs 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.

21 Urine NTX Biomarker

22 Z-MARK Clinical Trial: Personalizing ZOL Dosing Based on Urine NTX Biomarker Personalized ZOL Dosing for 2 Years Patients were evaluated for 121 MM patients who received IV bisphosphonate therapy 52 to 104 wk before first ZOL dose on study (N=121) Urine NTX level Tested High (NTX 50) Low (NTX < 50) Zoledronic acid (4 mg a IV) Every 4 Weeks Low (untx < 50) Zoledronic acid (4 mg a IV) Every 12 Weeks Skeletal- related event (SRE) includes fracture, spinal cord compression, etc. Progressive disease (PD) myeloma progressing High urine ntx untx 50 ZOL dosing schedule switched to every 4 weeks if SRE, PD, or high ntx IV = intravenous; MM = multiple myeloma; SRE = skeletal-related event; untx = urinary N-telopeptide; wk = weeks; ZOL = zoledronic acid. Raje, et al. Clin Can Res

23 Z-MARK Clinical Trial Results: Personalized Dosing of ZOL Works Well At Start of Study 121 patients: patients had low NTX every 12 weeks - 4 had high NTX so every 4 weeks when NTX low, all switched to every 12 weeks During the 2 years, 38 patients changed to every 4 weeks - 14 patients had high NTX; 4 patients had SRE; 20 patients had disease progression End of year 1: 7 patients with every 12 weeks had an SRE End of year 2: 5 patients with every 12 weeks had an SRE ONJ: 4 patients Personalized ZOL dosing at every 12 weeks based on NTX biomarker levels had low rate of SRE and ONJ Raje et al, Clin Can Res 2015

24 Denosumab Mechanism of Action: A New Antibody To Treat MM Bone Damage 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 et al. Nature 2003;423:

25 Denosumab vs ZOL Clinical Trial 1700 MM patients who received antimyeloma therapy Denosumab* (120 mg SC) Every 4 Weeks n=850 Patients evaluated for Skeletal- related event (SRE) includes fracture, spinal cord compression, etc. When 676 events *Each group also received either and IV or SC placebo so that both groups so doctors and patients couldn t tell which drug they were getting IV = intravenous; MM = multiple myeloma; SC = subcutaneous; SRE = skeletal-related event; ZOL = zoledronic acid. Raje, et al. Clin Can Res R A N D O M I Z A T I O N Daily Supplements of Calcium and Vitamin D for both groups Zoledronic acid* (4 mg IV; 15 min) Every 4 Weeks N=850 Continue Denosumab YES for 2 years YES Denosumab benefit for patients? NO Follow up at 2 years for survival

26 Denosumab and ZOL Results: Both Work Equally Well Time to First SRE While On the Clinical Trial Overall Survival HR (95% CI) = 0.98 (0.85, 1.14); P=0.01 (Noninferiority) Higher = Better HR (95% CI) = 0.90 (0.70, 1.16); P=0.41 Denosumab 121 Deaths (14.1%) Zoledronic Acid 129 Deaths (15.0%) Higher = Better Since the blue Denosumab and red-dashed ZOL lines overlap, both Denosumab and ZOL were equally good by measures of preventing bone events (like fracture) and how long patients lived

27 Denosumab and ZOL Results: Denosumab Has Slightly Better Progression-Free Survival Progression Free Survival HR (95% CI) = 0.82 (0.68, 0.99); P=0.036 (Descriptive) Higher = Better Median Duration (95% CI), Months Denosumab (34.30, NE) Zoledronic Acid (30.19, NE) Blue Denosumab line higher than red dashed ZOL line indicating Denosumab patients lived longer without their disease getting worse

28 Supportive Care and Patient Education Dr. Beth Faiman

29 Bone Health Supportive Care **Bone-strengthening agents are recommended for all patients receiving anti-myeloma therapy - Updated 2018 guidelines suggest for up to 2 years (Duration is case dependent) Pamidronate, Zoledronic acid or Denosumab Regular dental health monitoring, good hygiene Osteonecrosis of the Jaw Dental procedures Kidney health monitoring Kyphoplasty or vertebroplasty for vertebral compression Other bone interventions include surgery or radiation Report new pain to your health care provider Kyphoplasty for Vertebral Compression 29 Anderson K, Ismaila N, Flynn PJ, et al. Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Mar ;36(8): Terpos E, et al. J Clin Oncol. 2013;31: NCCN Multiple Myeloma Guidelines v Miceli TS, et al. Clin J Oncol Nursing. 2011;15(4)suppl:9-23. Coleman RE. Br J Cancer. 2008;98(11): Morgan GJ, et al. ASH 2010, #311. Witzig T, et al. ASH 2010, #3053. Berenson J, et al. Lancet Oncol. 2011;12: Medtronic, Kyphon Products Division. Amgen press release Jan 5,

30 Key Points in Preventing Bone Complications for Patients, Caregivers Exercise, exercise, exercise! Preferably weight bearing Maintain fitness individual to each level Walking 5-10 mins, twice a day to swimming and other activities can enhance fitness Calcium and vitamin D intake with monitoring is essential Various doses recommended. Absolutely necessary if on bisphosphonates or RANKL drugs cause low blood calcium levels Consult with healthcare team Routine disease, bone health monitoring Annual, biannual skeletal surveys or sooner if disease progression suspected Ask healthcare team if restrictions on exercise Ravenborg N, Udd K, Berenson A, Costa F, Berenson JR. Vitamin D Levels Are Frequently below Normal in Multiple Myeloma Patients and Are Infrequently Assessed By Their Treating Physicians. Blood. 2014;124(21):

31 Additional Resources are Free to You! Website: IMF TV Teleconferences IMF InfoLine CURE 9am to 4pm PST enewsletter: Myeloma Minute Download or order at myeloma.org 31

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