Welcome and Introductions

Myeloma Update on Treatment From the American Society of Hematology (ASH ) Annual Meeting Welcome and Introductions Myeloma Update on Treatment From the American Society of Hematology (ASH ) Annual Meeting William Bensinger, MD Director of the Autologous Stem Cell Transplant Program Fred Hutchinson Cancer Research Center Professor of Medicine University it of Washington Seattle, WA January 13, 2015 2 1

Disclosures Consulting Acetylon, Bristol Myers Squibb, Celgene, Novartis, Onyx, Pharmacyclics, Sanofi Research Funding Acetylon, Bristol Myers Squibb, Celgene, Novartis, Onyx, Pharmacyclics, Sanofi 3 Etiology of Multiple Myeloma (MM) Exact cause unknown 1 Multistepprocess process leads to development of malignant clone 1 Myeloma cells Return to bone marrow 2 Produce monoclonal protein (M protein) 1 Alter cytokine regulation in the bone marrow environment 3 1. McGuire TR. Multiple myeloma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7 th ed. New York, NY: McGraw-Hill; 2008:2295-2307. 2. Tricot G. Lancet. 2000; 355:248-250. 3. Rajkumar SV, et al. Hematology 2005 Am Soc Hematol Educ Program. 2005:340-345 4 2

Epidemiology of MM Prevalence More than 95,800 people in the US 1 Incidence About t 24,000 people are diagnosed d with MM each year in the US 2 Annual age adjusted incidence is 5.56 per 100,000 1 Mortality Nearly 11,000 US MM patients expected deaths in 2014 2 The overall 5 year relative survival rate for 2004 2010 was 46.7% 1 Demographics Median age at diagnosis is 69 years 1 <3.8% 38% of MM patients are younger than 45 years 1 Incidence is more than twice as high in blacks as in whites 1 More frequent in men than women 1 1. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER Web site, April 2014. 2. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014. 5 Spectrum of Clinical Manifestations of MM Renal Impairment M protein Neuropathy Infection Multiple Myeloma Cells Immunodeficiency Bone- Related Signs and Symptoms Hypercalcemia Bone Pain Lytic Lesions Marrow Infiltration Anemia Hb 12 g/dl 1. Ropper AH, et al. N Engl J Med. 1998;338:1601-1607. 2. Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. 3. Bladé J, et al. Hematol Oncol Clin North Am. 2007;21:1231-1246. 6 3

Clinical Presentation As many as 20% of patients with MM may be asymptomatic* at diagnosis 1 Signs & Symptoms 1-4 Lab Parameters 1 Radiographic Parameters 1 Bone Marrow 1 Bone pain Fatigue Weight loss Paresthesias Recurrent infection Renal failure Spinal cord compression Back pain Elevated paraproteins- M peak Low hemoglobin Hypercalcemia Low albumin Elevated β 2 -microglobulin Elevated serum creatinine i Elevated C-reactive protein Lytic lesions Osteoporosis Fractures Increased plasma cells *Some patients may be diagnosed due to incidental abnormalities from comprehensive labs and imaging studies. 5 1. McGuire TR. Multiple myeloma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7 th ed. New York, NY: McGraw-Hill; 2008:2295-2307. 2. Kyle RA, et al. Mayo Clinic Proc. 2003;78:21-33. 3. Bladé J, et al. Hematol Oncol Clin North Am. 2007;21:1231-1246. 4. Nau KC. Am Fam Physician. 2008;78:853-859. 5. Landgren OL, et al. JAMA. 2010;304:2397-2404. 7 Initial Diagnostic Evaluation History and Physical Examination Tests Serum Urine Bone Marrow Aspirate Radiography CBC with differential BUN/creatinine, electrolytes LDH Calcium, albumin Serum free light chain assay Quantitative immunoglobulins β 2 -microglobulin Serum protein electrophoresis (SPEP) Serum immunofixation electrophoresis (SIFE) 24-hr urine total protein Urine protein electrophoresis (UPEP) Urine immunofixation electrophoresis (UIFE) Morphology Histology Cytogenetic analysis Fluorescence in situ hybridization (FISH) Immunohistochemistry +/- flow cytometry Skeletal survey Magnetic Resonance imaging Positron Emission Tomography LDH, lactate dehydrogenase. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma. v.1.2011. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 3, 2011. 8 4

Hallmark of MM Serum Protein Electrophoresis (SPEP) Normal Multiple myeloma M protein Albumin α 1 α 2 β ϒ Reprinted with permission from the American Academy of Family Physicians. 1999. George ED, et al. Am Fam Physician. 1999;59:1885-1894. 9 Diagnostic Criteria for Symptomatic MM Presence of M protein in serum or urine Identification of >10% monoclonal plasma cells in bone marrow Evidence of end organ damage: CRABi CRABi: Symptomatic MM Quintad Calcium Elevation R enal Failure A nemia B one i nfections Serum calcium 11 mg/dl Serum creatinine 2 mg/dl Hemoglobin <12 g/dl Lytic lesions, pathologic fractures, or severe osteopenia Frequent Infections 10 5

International Staging System for MM Stage International Staging System 1 Median Survival 2 I Serum β 2 -microglobulin <3.5 mg/l Serum albumin 3.5 g/dl 62 months II Neither stage I nor stage III 44 months III Serum β 2 -microglobulin 5.5 mg/l 29 months 1. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma. v.1.2011. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 3, 2011. 2. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420. 11 Impact of Genetic Abnormalities on Prognosis in MM Prognosis may vary according to type of chromosomal abnormality 1-7* Chromosomal abnormality (FISH based) Incidence (%) Prognosis Hyperdiploidy 39%-45% Favorable Isolated del 13 48% No significance t(11;14) 7.8%-21% No significance t(14;16) 1.9%-5% Poor t(4;14) 6.5%-15% Poor del 17p 11% Poor del 13 with del 17p t(4;14) 8.6% 11.9% Poor *Chromosomal abnormalities may be found in MGUS patients as well. 5 1. Dewald GW, et al. Blood. 2005;106:3553-3558. 2. Fonseca R, et al. Cancer Res. 2004;64:1546-1558. 3. Avet-Loiseau H, et al. Blood. 2007;109:3489-3495. 4. Fonseca R, et al. Leukemia. 2009;23:2210-2221. 5. Rajkumar SV, et al. Mayo Clin Proc. 2006;81:693-703. 6. Munshi M. Hematology 2008. American Society of Hematology. 2008;298-305. 7. Walker BA, et al. Blood. 2010;116:e56-65. 12 6

Myeloma Treatment: A Historical Perspective Present 1990 Introduction of novel agents 1987 High-dose melphalan and stem cell rescue as standard therapy 1983 Autologous stem cell transplant 1974 1969 1962 1958 1947 1844 Kyle RA, et al. Blood. 2008;111:2962-2972. Combination of carmustine + cyclophosphamide + melphalan + vincristine + prednisone Melphalan + prednisone (MP) established Corticosteroids Melphalan Urethane established as standard of care Rhubarb pill and orange peel infusion Phlebotomy and application of leeches as maintenance 13 Managing Myeloma: The Components Tx Eligible Initial Therapy Autologous Transplant (consolidation) ± Addl. consolid Maintenance Treatment of Relapsed disease Tx Ineligible Consolidation/ Maintenance/ Continued therapy Supportive Care 14 7

Goals of Therapy Control the myeloma disease activity Improve disease symptoms Bone damage (pain and fractures) High calcium, kidney problems (weakness) Anemia (fatigue, shortness of breath) Kidney problems (fatigue) Reduce frequent infections Achieving a remission Minimize treatment related symptoms 15 Current Status of Treatment for MM Therapy has become better thanks to new drugs and the use of autologous stem cell transplantation Survival for many patients now approaches ten years (120 months) Cure is still elusive, thus the interest in consolidation/maintenance Many new drugs and new drug classes are under development 16 8

Drugs for MM Class Steroids Alkylators Vinca alkyloids Anthracyclines IMiDs Proteasome inhibitors Drugs dexamethasone, prednisone cyclophosphamide, melphalan, bendamustine vincristine doxorubicin, PEG-DOX thalidomide, lenalidomide pomalidomide bortezomib, carfilzomib 17 Initial Treatment Transplant Candidates Bortezomib dexamethasone, thalidomide* or lenalidomide Bortezomib dexamethasone* Lenalidomide dexamethasone* Bortezomib, doxil +/ dexamethasone Cyclophosphamide, bortezomib, dex Thalidomide dexamethasone* VAD, DVD, Dexamethasone Non transplant candidates Melphalan prednisone + thalidomide or lenalidomide (MPT/R)* MP + bortezomib (MPV)* Lenalidomide + dexamethasone Bortezomib dexamethasone, cyclophosphamide or lenalidomide * Data from phase III randomized trials that have compared these to other regimens. 18 9

Measuring Treatment Response Remission No sign of disease. Sometimes the terms complete remission (response) or partial remission (response) are used. Complete Response (CR) No sign of M protein in blood and urine. Normal percent of plasma cells or no sign of myeloma cells in marrow (5% plasma cells in bone marrow), stable bones on skeletal survey Very Good Partial Response (VGPR) 90% reduction in blood and (<100 mg) urine proteins Partial Response More than a 50% decrease in M protein in the blood and reduction in 24-h urinary M-protein by 90%. 19 You Need Good Combinations 20 10

Autologous Stem Cell Transplantation Considered important therapy for eligible multiple myeloma patients High rates of CR to VGPR, CR correlates with survival Disease control better in all trials, but there is not always a survival benefit Low mortality (<2%) No donor limitation Less effective for high risk groups Still not curative for most patients (<15%) 21 22 11

ASCT Improves Major Responses After Traditional or Novel Induction Trial Regimens No ncr% GIMEMA IFM Hovon Ludwig VcTD x3 TD x3 VcD x4 VAD x4 VcAD x3 VAD 3 241 239 223 218 371 373 Induction 31* 11 15* 6 11* 5 ASCT 52* 31 35* 18 30* 15 VAD x3 373 5 15 VcTD x4 CVcTD x4 49 48 51 44 85 77 Reeder CyBorD x4 28 46 72 IFM VcRD x3 31 23 42 23 Updates from ASH 2014 #4739 Carfilzomib, Cyclophosphamide & Dexamethasone is an Active Regimen for Induction Therapy Prior to ASCT in the Management of Newly Diagnosed Patients with Multiple Myeloma 28 patients age 44 74, median 64 Carfilzomib 2x weekly ¾ weeks, Cy, dex weekly x6 cycles Maximum Carfilzomib dose 56 mg/m 2 Overall response rate 91%, 2 CR, 10 VGPR 1 patient discontinued for progressive disease #175 Weekly Carfilzomib, Cyclophosphamide, Dexamethasone in Newly Diagnosed Multiple Myeloma 30 patients age >65 or transplant-ineligible, median age 74 Up to 9 cycles + maintenance Overall response rate 86%, complete response 25% Maximum tolerated dose 70 mg/m 2 13% of patients discontinued #79 ASPIRE Study: Lenalidomide + Dexamethasone with or without Carfilzomib in Relapsed Multiple Myeloma 792 patients, median of 2 prior therapies, median age 64 years Overall response rate 87% with CRd v. 67% with Rd Complete response rate 32% CRd, 9% RDd Duration of response 29 months CRd, 21 months Rd Median duration of treatment 22 months CRd, 14 months Rd Progression-free survival median 26 months CRd, 18 months Rd 1. Bensinger WI, et al. 2014 American Society of Hematology. Abstract 4739. 2. Palumbo A, et al. 2014 American Society of Hematology. Abstract 175. 3. Stewart AK, et al. 2014 American Society of Hematology. Abstract 79. 24 12

Novel Agents Under Development Agent Marizomib (NPI-0052), Oprozomib (ONX 0912), Ixazomib (MLN 9708) Daratumumab (CD38) SAR650984 (CD38) Elotuzumab (CS-1) Siltuximab (IL-6) Cetuximab (EGFR) Lucatumumab (CD40) BMS-936564 (CXCR-4) MK-3475 (PD-1) BT062 (CD56) LGH447 BYL719 Vorinostat, Panobinostat, Romidepsin, Rocilinostat (ACY- 1215) Mechanism of Action Proteasome inhibitor Monoclonal antibody Immunotoxin PIM Kinase inhibitor PI3 Kinase inhibitor HDAC inhibitor 25 Updates from ASH 2014 #83 A Phase 1b study of SAR650984 1 (anti-cd38 mab) in combination with lenalidomide + dexamethasone in relapsed/refractory myeloma 31 patients, median prior therapies 7, median age 59 years 84% were resistant to thalidomide, lenalidomide or pomalidomide Overall response rate 58% Duration of response 9 months #84 Safety and efficacy of daratumumab 2 (anti-cd38 mab) in combination with lenalidomide + dexamethasone in relapsed/refractory myeloma 45 patients, median prior therapies 3, median age 61, excluded lenalidomide resistant or intolerant patients Overall response rate 87 100% 1. Martin T, et al. 2014 American Society of Hematology. Abstract 83. 2. Plesner T, et al. 2014 American Society of Hematology. Abstract 84. 26 13

Individualizing Care Important Factors: Age High-risk cytogenetics Renal disease Convenience/location Blood counts Steroid status Previous therapy PATIENT PREFERENCE 27 Role of Clinical Trials Clinical trials are critical to the successes in the treatment of multiple myeloma All the new drugs, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib and pegdoxorubicin were approved as a result of patient participation in key trials Participation is critical to the further development and approval of not yet approved drugs: daratumumab, SAR650984, elotuzumab, ixazomib, oprozomib, and several others. Patients themselves can benefit by obtaining access to potentially lifesaving therapies before the drugs become commercially available 28 14

Multiple Issues Affect Quality of Life Disease-Related Anemia fatigue, short of breath Bone fractures, pain, high calcium levels Kidney failure, dialysis, fatigue Immunosuppression infections Nervous system neuropathy, paralysis Treatment-Related Neuropathy bortezomib, thalidomide Blood clots all IMiDs Kidney function bisphosphonates Osteonecrosis of the jaw bisphosphonates, denosumab 29 Managing Disease Related Symptoms Anemia Transfusions, erythropoetins, disease treatment Bone Bisphosphonates, vertebroplasty, surgery, radiotherapy Kidney Hydration, treat high calcium with bisphosphonates or denosumab, disease treatment Immunosuppression Prophylactic antibiotics, intravenous immunoglobulin Nervous system Avoiding drugs that may worsen neuropathy, surgery or radiotherapy for spinal cord compression symptoms 30 15

Managing Treatment Related Side Effects Neuropathy Adjusting dose, frequency or route of bortezomib, switching to carfilzomib, gabapentin, vitamins, amino acids for pre-existing neuropathy Blood clots Prophylactic aspirin, warfarin or heparins Infections Prophylactic antibiotics, antivirals Kidney function Hydration, monitoring kidney function while on bisphosphonates Osteonecrosis of the jaw Good oral hygiene, avoid tooth extractions while on bisphosphonates Hyperglycemia Reduce or avoid steroids, insulin 31 Communicating With Your Health Care Team Your Health Care Team Physician-medical oncology, radiation therapy, orthopedist Advanced practice providers, Nurse Practitioner or Physician's Assistant Nurses Pharmacist Dietician Physical therapist Social worker-economic, economic social, mental Critical to involve all these professionals in your care; let them know as early as possible about changes in symptoms, work status, appetite 32 16

Resources for Help and Information The Leukemia & Lymphoma Society www.lls.org/myeloma Myeloma Beacon www.myelomabeacon.com Multiple Myeloma Research Foundation www.themmrf.org International Myeloma Foundation www.myeloma.org MMORE www.mmore.org 33 Myeloma Update on Treatment From the American Society of Hematology (ASH ) Annual Meeting Question & Answer Session The speaker s slides are available for download at www.lls.org/programs 34 17

Myeloma Update on Treatment From the American Society of Hematology (ASH ) Annual Meeting The Leukemia & Lymphoma Society (LLS) offers: Live, weekly Online Chats that provide a friendly forum to share experiences and chat with others about anything from the initial phase of diagnosis to treatment and survivorship. Each chat is moderated by an oncology social worker and is password protected. WEBSITE: www.lls.org/chat Question & Answer Session Co-Pay Assistance Program offers financial assistance to qualified cancer patients The to help speaker s with treatment-related slides are available expenses for and download insurance at: premiums. www.lls.org/programs Patients may apply online or over the phone with a Co-Pay Specialist. WEBSITE: www.lls.org/copay TOLL-FREE PHONE: (877) LLS-COPAY For more information about blood cancers and other LLS programs, please contact an LLS Information Specialist. TOLL-FREE PHONE: (800) 955-4572 EMAIL: infocenter@lls.org 35 18