Patient Case Introduction

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1 Patient Case Introduction Page Bertolotti, RN, BSN, OCN Clinical Practice Nurse Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center Los Angeles, California 1

2 Disclosure Page Bertolotti, RN, BSN, OCN, has disclosed the following relevant financial relationships: Speakers Bureau: Celgene Corporation and Takeda Pharmaceuticals Case Study 53-year-old woman presents with fatigue and nausea in Elevated total protein detected on routine exam. History and Physical Past medical history: MVA in 1985; melanoma in 1995 to right shin Past surgical history: tonsillectomy in 1980 Family history: paternal grandmother with breast cancer, died at age 90 Social history: recent marriage (5 months), no children, never smoked, social drinker Physical exam: mildly cushingoid, some nausea, still menstruating Labs on Presentation Total protein 12.0 ( ) Calcium 9.3 ( ) Creatinine 1.3 ( ) Hgb 11.6 (13 16) IgG 7,912 (700 1,600) Diagnostic Evaluation Bone marrow biopsy: 80% plasma cells, CD38 antigen expression on flow cytometry Skeletal survey: Multiple bone lesions Staging: Durie-Salmon stage IIIA 2

3 Treatment Options? Is she eligible for an autologous stem cell transplantation? Factors to consider Age and comorbidity Response to induction therapy Risk stratification Social support and insurance coverage Lifestyle, goals, choices Does the patient want a transplant or not? Treatment Plan Induction therapy: Bortezomib/dexamethasone Acyclovir prophylaxis Manage adverse events: peripheral neuropathy Bone health: bisphosphonate every month Response was dramatic; decrease in IgG from 7,912 to 1,863 after 3 cycles 3

4 Consultation With Myeloma Specialist R e c o m m e n d a t i o n Continue bz/dex for three more cycles to achieve maximum benefit of treatment and best possible remission Patient proceeded to ASCT, December 2009, and had a small M spike of 0.1 g/dl (near CR) Maintenance therapy prescribed 6 months posttransplant: len/dex (prophylaxis with baby aspirin and acyclovir) Response: April 2011 (16 months post-asct), near CR with negative SPEP and trace IgG kappa spike Relapse Post-Transplantation and Maintenance Therapy Relapse 3 yrs post transplant Elevated kappa light chain (KLC) 22 to 46 to 69 Elevated M spike 0.1 to 0.2 g/dl 4

5 Relapse: Factors to Consider Retreatment with a prior therapy? Second transplant? Multidrug combination? Synergy? New agents? Clinical trial? Understanding the Next Generation of Novel Agents in Multiple Myeloma Amy Pierre, RN, MSN, ANP-BC Nurse Practitioner John Theurer Cancer Center Hackensack University Medical Center Hackensack, New Jersey 5

6 Disclosure Amy Pierre, RN, MSN, APN-BC, has disclosed the following relevant financial relationships: Speakers Bureau: Amgen/Onyx Objectives Define relapsed/refractory multiple myeloma Review the approved usage, mechanism of action, safety concerns, and toxicity profile of the next-generation proteasome inhibitors, immunomodulators, and HDAC inhibitors Understand the combination regimens commonly utilized in refractory/relapsed multiple myeloma Discuss a patient-centered management plan to minimize the impact of treatment-related side effects 6

7 Definitions Relapsed Myeloma Previously treated myeloma patients who, after a period of being offtherapy, require salvage therapy Refractory Myeloma Disease that is nonresponsive while on therapy or progresses within 60 days of the last therapy Relapsed and Refractory Myeloma Refractory disease in patients who have never achieved a minor response or better that then either becomes nonresponsive while on salvage therapy or progress within 60 days of last therapy Anderson KC et al. Leukemia. 2008;22:231. Disease Phases of Multiple Myeloma Figure 2, page 7 Kurtin SE. Relapsed or relapsed/refractory multiple myeloma. J Adv Pract Oncol. 2013;4(Suppl 1):

8 Treatment Selection for Relapsed/Refractory Myeloma Disease Characteristics How deep was the patient s response to prior therapy? How long was the duration of response to the previous therapy? How aggressive is the disease? Is the patient eligible for a clinical trial? Patient Characteristics What is the patient s performance status? Does the patient have preexisting toxicities from either myeloma or previous treatment regimens? What are the patient s comorbidities? Is the patient transplant eligible? Is the patient eligible for a clinical trial? Lonial S. Hematology Am Soc Hematol Educ Program. 2010;303. Newly Approved Agents for the Relapsed/Refractory Setting Proteasome Inhibitors Carfilzomib Ixazomib Immunomodulator HDAC Inhibitor Panobinostat 8

9 Carfilzomib Approval Date Drug Class Mechanism of Action 2012 Second-generation proteasome inhibitor (IV) Irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome Has antiproliferative and pro-apoptotic activities in tumor cells Delays tumor growth in myeloma FDA-Approved Indication In combination with dexamethasone or with lenalidomide + dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy Carfilzomib [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc; Carfilzomib: ASPIRE Trial The international, randomized, phase 3 superiority trial evaluating carfilzomib with lenalidomide and low-dose dexamethasone (KRd) vs lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory MM who had received one to three lines of therapy. Primary end point: progression-free survival (PFS) KRD (N=396) PFS = 26.3 months ORR = 87% CR = 32% N=792 PFS increased by 9 months with KRd; higher ORR, deeper response, and longer median duration of response with KRd RD (N=396) PFS = 17.6 months ORR = 67% CR = 9% Stewart AK et al. N Engl J Med. 2015;372:142. 9

10 Carfilzomib: ENDEAVOR Trial The phase 3, randomized, multicenter, superiority study comparing carfilzomib and dexamethasone (Kd) to bortezomib and dexamethasone (Vd) in patients with relapsed or refractory MM Primary end point: PFS KD (N=464) PFS = 18.7 months ORR = 77% CR = 13% N=929 Doubled the PFS with Kd; Higher ORR, deeper response, and longer median duration of response with Kd; PFS benefit was extended whether prior treatment with a PI or not VD (N=465) PFS = 9.4 months ORR = 63% CR = 6% Dimopoulos MA et al. Lancet Oncol. 2016;17:27. Carfilzomib/Lenalidomide/ Dexamethasone (KRd) Cycles 1 12 Carfilzomib 27 mg/m 2 IV Days 1, 2, 8, 9, 15, 16 (20 mg/m 2 Days 1, 2, Cycle 1 only, to assess tolerability to carfilzomib) KRd Cycles Carfilzomib 27 mg/m 2 IV Days 1, 2, 15, 16 Cycles 19+ Carfilzomib discontinued after Cycle 18 Lenalidomide 25 mg: Days 1 to 21 Dexamethasone 40 mg: Days 1, 8, 15, 22 Stewart AK et al. N Engl J Med. 2015;372:

11 Carfilzomib Monotherapy (K) Carfilzomib/Dexamethasone (Kd) CYCLE 1 Carfilzomib Carfilzomib Carfilzomib 20 mg/m 2 56 mg/m 2 56 mg/m 2 NO CARFILZOMIB DOSING Week 1 Dexamethasone, 20 mg Week 2 Dexamethasone, 20 mg Week 3 Dexamethasone, 20 mg Week 4 Dexamethasone, 20 mg CYCLES 2-on, until disease progression or unacceptable toxicity Carfilzomib Carfilzomib Carfilzomib 56 mg/m 2 56 mg/m 2 56 mg/m 2 NO CARFILZOMIB DOSING Week 1 Dexamethasone, 20 mg Week 2 Dexamethasone, 20 mg Week 3 Dexamethasone, 20 mg Week 4 Dexamethasone, 20 mg Dimopoulos MA et al. Lancet Oncol. 2016;17:27. Carfilzomib: Administration Precautions Hydration Adequate hydration is required prior to all dosing in Cycle 1 Monitor for fluid overload Premedications Premedicate with dexamethasone Thromboprophylaxis Infection prophylaxis Antiviral Maximum BSA Dosing of 2.2 m 2 Carfilzomib [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc;

12 Carfilzomib: Adverse Reactions Occurring in 20% Hematologic: anemia, neutropenia, thrombocytopenia GI: diarrhea, nausea General: fatigue, pyrexia, insomnia, infusion reactions Infections: URI F/E/N: hypokalemia Musculoskeletal: muscle spasms Respiratory: cough, dyspnea Cardiac: hypertension Carfilzomib [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc; Carfilzomib: Nursing Implications Patient education regarding: Infusion reactions: premedicate, hydration Venous embolus: cough, chest pain, swelling or pain in the legs Thrombocytopenia: bleeding, bruising GI: antidiarrheals, antiemetics Zoster reactivation: painful rash Cardiac: dyspnea, peripheral edema, chest pain, maintain normal blood pressure Infection precautions Risk of TLS: hydration, may need uric acid lowering agent 12

13 Ixazomib Approval Date Drug Class 2015 Second-generation oral proteasome inhibitor Mechanism of Action Reversibly and preferentially binds and inhibits the 20S proteasome Induces apoptosis of multiple myeloma cell lines The combination of ixazomib and lenalidomide demonstrates synergistic cytotoxic effects FDA-Approved Indication In combination with dexamethasone and lenalidomide for the treatment of patients with multiple myeloma who have received at least one prior therapy Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc; Ixazomib: TOURMALINE-MM1 Trial An international, randomized, double-blind, placebo-controlled clinical trial evaluating ixazomib, lenalidomide, and dexamethasone (IRD) compared to placebo with lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma who received 1 3 prior lines of therapy. Primary end point: PFS IRD (N=360) PFS = 20.6 months ORR = 78% CR = 12% N=722 40% decrease in risk of progression; PFS extended to patients with high-risk cytogenetics (overcomes high risk) Placebo RD (N=362) PFS = 14.7 months ORR = 72% CR = 7% Moreau P et al. Blood. 2015;126: Abstract

14 Ixazomib/Lenalidomide/ Dexamethasone Starting dose is oral capsule Dosing Schedule for Ixazomib Taken With Lenalidomide and Dexamethasone 28-Day Cycle (a 4-week cycle) Week 1 Week 2 Week 3 Week 4 Days Days Days Days Day Day Day Day Ixazomib Lenalidomide Daily Daily Daily Dexamethasone For moderate hepatic impairment or severe renal impairment, reduce starting dose to 3 mg. Moreau P et al. Blood. 2015;126: Abstract 727. Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc; Ixazomib: Administration Precautions Take ixazomib at approximately the same day each week Take 1 hour before food or 2 hours after food Ixazomib and dexamethasone should not be taken at the same time Antiviral prophylaxis is required Thromboprophylaxis in combination with lenalidomide Avoid concomitant administration with strong CYP3A inducers Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc;

15 Ixazomib: Adverse Reactions Occurring 20% Diarrhea Constipation Thrombocytopenia Peripheral neuropathy Nausea/vomiting Back pain Peripheral edema Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc; Ixazomib: Nursing Implications Patient education regarding: Thrombocytopenia: bruising, bleeding Take antiemetics and antidiarrheals Monitor for neuropathy: tingling, numbness, pain, burning in feet or hands, or weakness in extremities Swelling or weight gain Development of a rash Antiviral prophylaxis Thromboprophylaxis with lenalidomide 15

16 Approval Date Drug Class 2013 Immunomodulator (oral) Mechanism of Action Inhibits proliferation, induces apoptosis and antiangiogenic activity in tumor cells and models Enhances T-cell and natural killer cell mediated immunity, inhibits the production of pro-inflammatory cytokines Works synergistically with dexamethasone to overcome lenalidomide resistance FDA-Approved Indication In combination with dexamethasone for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy [package insert]. Summit, NJ: Celgene Corporation; Phase 3 Trial Phase 3 multicenter, randomized trial evaluating pomalidomide with low-dose dex therapy (PD) vs high-dose dex (D) in adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy Primary end point = PFS PD (N=302) PFS = 4.0 months ORR = 31% PR = 26% N=455 55% reduced risk of progression or death with PD; Significant OS advantage D (N=153) PFS = 1.9 months ORR = 10% PR = 9% San Miguel J et al. Lancet Oncol. 2013;14:

17 /Dexamethasone Sunday Monday Tuesday Wednesday Thursday Friday Saturday START CYCLE Off Off Off Off Off Off START NEXT CYCLE San Miguel J et al. Lancet Oncol. 2013;14:1055. : Administration Precautions BLACK BOX WARNING: Embryo-Fetal Toxicity: Contraindicated in pregnancy. Must comply with contraception and pregnancy testing. Only available through REMS program (restricted distribution program) Venous and Arterial Thromboembolism: DVT, PE, MI, and stroke occur in patients treated with pomalidomide. Thromboprophylaxis is recommended and choice of regimen should be based on assessment of the patient s underlying risk factors. [package insert]. Summit, NJ: Celgene Corporation;

18 : Administration Precautions Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements (female pregnancy testing and male contraception) Women of reproductive potential must have negative pregnancy testing and use contraception methods before initiating pomalidomide Take with water at least 2 hours before or 2 hours after a meal, at approximately the same time each day Thromboprophylaxis Monitor blood counts [package insert]. Summit, NJ: Celgene Corporation; : Adverse Reactions Occurring in 30% Fatigue and asthenia Neutropenia Anemia GI distress: constipation, nausea, diarrhea Dyspnea Upper respiratory tract infections Back pain Pyrexia [package insert]. Summit, NJ: Celgene Corporation;

19 : Nursing Implications Patient education regarding: Embryo-fetal toxicity: compliance regarding pregnancy testing and contraception, no blood donation, no sperm donation Risk of embolus: provide thromboprophylaxis Cytopenias: fever, infection, bruising/bleeding, fatigue Have supportive GI medications at home Skin rash: antihistamines and topical corticosteroids Panobinostat Approval Date Drug Class 2015: accelerated approval based on PFS Nonselective histone deacetylase inhibitor (oral) Mechanism of Action Inhibition of histone deacetylase activity results in cell cycle arrest and apoptosis of some transformed cells and cytotoxicity Helps to turn on tumor suppressor genes FDA-Approved Indication In combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation;

20 Panobinostat: PANORAMA-1 Trial A multicenter, randomized, placebo-controlled, double-blind phase 3 trial of panobinostat, bortezomib, and dexamethasone (FVD) vs placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens Primary end point = PFS FVD (N=387) PFS = 12 months ORR = 60.7% CR/nCR = 27.6% N=768 83% improvement with FVD and maintained across all subgroups; maybe more so with prior V and IMiD; CR nearly doubled with clinically meaningful median duration of response Placebo VD (N=381) PFS = 8.1 months ORR = 54.6% CR/nCR = 15.7% San Miguel JF et al. Lancet Oncol. 2014;15:1195. Panobinostat/Bortezomib/ Dexamethasone Starting dosage is Panobinostat 20 mg Medication Key F Panobinostat 20 mg oral V Bortezomib 1.3 mg/m 2 by injection D Dexamethasone 20 mg oral CYCLES 1 8 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Week 1 Week 2 F F V V D D D D F F V V D D F F D D Week 3 REST Consider continuing treatment for an additional eight cycles for patients with clinical benefit, unless they have unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks). CYCLES 9 16 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Week 1 Week 2 F F V V D D D D F F F F Week 3 REST For mild hepatic impairment, reduce starting dose to 15 mg. For moderate hepatic impairment, reduce starting dose to 10 mg. San Miguel JF et al. Lancet Oncol. 2014;15:1195. Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation;

21 Panobinostat: Administration Precautions BLACK BOX WARNING: Diarrhea: Severe diarrhea occurred in 25% of patients. Monitor for symptoms, institute antidiarrheal treatment, and interrupt panobinostat and then reduce dose or discontinue. Cardiac: Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated. Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Panobinostat: Administration Precautions Avoid star fruit, pomegranates, and grapefruit If dose is missed, can take up to 12 hours after the specified dose time Ensure antidiarrheals are at home Obtain baseline ECG and monitor throughout therapy Do not initiate panobinostat if QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities Obtain serum electrolytes prior to therapy and weekly or more often if needed Monitor liver function tests and complete blood counts Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation;

22 Panobinostat: Adverse Reactions 20% Diarrhea (68%): severe in 25% Fatigue Nausea/vomiting Peripheral edema Low appetite Pyrexia Myelosuppression Thrombocytopenia 67% Severe neutropenia 34% Electrolyte abnormalities Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Panobinostat: Nursing Implications Patient education regarding: Diarrhea: at first abdominal cramping, loose stool, or diarrhea, take antidiarrheals, monitor electrolytes Antiemetics Cardiac: chest pain, fast/slow heart rate, palpitations, lightheadedness, dizziness, shortness of breath, edema, monitor EKG Bleeding: dark stools, blood in urine, bruising Diet: avoid start fruit, pomegranate, grapefruit; if appetite low, eat small frequent meals Cytopenias: bleeding, bruising, infections, fatigue, short of breath. 22

23 Summary Myeloma is a disease characterized by phases of remission and relapse Choice of treatment at relapse is based on patientspecific and disease-specific factors Treatment goals are to address symptoms, prevent further organ damage, achieve a complete remission, and prolong overall survival Understanding the mechanism of action, safety data, and potential toxicities of relapsed/refractory regimens helps minimize the impact of treatment-related side effects Patient education can improve early detection of treatment-related adverse events Patient Case Continuation Page Bertolotti, RN, BSN, OCN Clinical Practice Nurse Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center Los Angeles, California 23

24 Goals of therapy Individualize care: benefit outweigh risk? What does the patient want? This young woman wanted to maintain as much functional status and quality of life as possible Less trips to the Center and avoid long commute Spa dates and wine tasting with friends Lifestyle choice- oral therapy and avoid steroids Gather the Multidisciplinary Team! Other physicians Orthopedic surgeon Nephrologist Radiation oncologist Cardiologist Psychiatrist Dentist Nurse practitioners Physician assistants Oncology nurses Pharmacists Pain team Social workers Counselors Dietitians Physical therapy Home healthcare 24

25 Relapse Post-Transplantation and Maintenance Therapy Treatment with first relapse Discontinue len/dex and start pomalidomide and weekly dexamethasone Response to treatment Moderate response to pom/dex with reduction in KLC Intolerance to steroid with weight gain despite several dose reductions Second Relapse Second relapse In the fall of 2013, her kappa free light chain started to rise Lifestyle was no longer as significant as before Treatment choice January 2014, she was switched to carfilzomib and dexamethasone Response to treatment Good response with reduction in KLC, M spike In December 2015, her serum M-spike increased consistent with progressive disease. 25

26 Case Study Continued December 2015: elevated M spike on carfilzomib Patient chose to continue carfilzomib and dose was escalated to 56 mg/m 2 Fear of moving on and burning through new options Developed clenching jaw due to prochlorperazine pre-med, changed to dronabinol. Ondansetron was ineffective. March 2016: Time to move on to another therapy Immunotherapy Charise Gleason, MSN, NP-C, AOCNP Chief Advanced Practice Provider Department of Hematology and Medical Oncology Adjunct Faculty The Winship Cancer Institute at Emory University Atlanta, Georgia 26

27 Disclosure Charise Gleason, MSN, NP-C, AOCNP, has disclosed no relevant financial relationships. Relapse Workup Diagnostic workup demonstrates: Skeletal survey with no new lesions Bone marrow biopsy with 60% plasma cells and now with deletion 17p SPEP with M spike of 3.92 g/dl UPEP of 0 FKLC 870./L Hgb 8.8 mg/dl Goals of therapy: Rapid control Maintain quality of life 27

28 Cytogenetics These are the genes of the plasma cells (not the patient) May indicate more about the biology of the disease Most can be found at diagnosis, but others may be acquired later Could well be the most prognostic tool in myeloma, as it may separate high-risk myeloma from standard risk Disease Trajectory: Relapsed/Refractory Disease Figure 2, page 7 Kurtin SE. Relapsed or relapsed/refractory multiple myeloma. J Adv Pract Oncol. 2013;4(Suppl 1):

29 Are the Goals Different? Refractory relapse Target the tumor Relapsed Disease Newly diagnosed Target the tumor Restoration of function MRD, clonal control Prevention/Microenvironment Premalignant Continuing Evolution of Multiple Myeloma Treatment: New Classes and Targets Novel Therapies and Immunotherapy Atezolizumab Lenalidomide Thalidomide Carfilzomib Ixazomib Elotuzumab CAR-T Nivolumab Vaccines Bortezomib PLD Panobinostat Isatuximab Daratumumab IMiD HDAC inhibitor Monoclonal antibody Vaccines Proteasome inhibitor Chemotherapy Adoptive T cell therapy Checkpoint inhibitors PLD, peglylated liposomal doxorubicin; IMiD, immunomodulatory drug; HDAC, histone deacetylase; KSP, kinesin spindle protein, SINE, selective inhibitor of nuclear export 29

30 Monoclonal Antibody Therapy What is it? It is an injection of antibodies that can directly bind to the surface of a myeloma cell How does it work against myeloma? Antibodies bind to myeloma cells then kill them using different mechanisms Excitement of Monoclonal Antibodies Advantages Novel mechanism of action Additive or synergistic effects with current anti-mm drugs Generally well tolerated Toxicity profile non-overlapping with approved anti-mm drugs Can be combined with other immune therapies May be ideally suited to eliminate MRD May be beneficial in all patient groups (SMM, ND, RR, MRD) Many targets possible MM cell Microenvironment Immune signals Disadvantages Infusion reactions can limit therapy in some No biomarkers for response to predict who may most benefit Few long-term survivors 30

31 Elotuzumab Anti-SLAMF7 mab SLAMF7 expressed on both MM cells and NK cells Tags MM cells for ADCC via NK cells and activates NK cells via EAT-2 for MM cell destruction independent of ADCC Activity in combination with lenalidomide led to ELOQUENT trial NK, natural killer; ADCC, antibody-dependent cellular cytotoxicity Lonial S et al. N Engl J Med. 2015;373:621. Dimopoulos MA et al. Blood. 2015;126: Abstract 28. Phase 1/2 Elotuzumab + Len/Dex: Efficacy Best Confirmed Response, n (%) All Pts (n=28) Pts w/o Prior Len (n=22) ORR ( PR) 23 (82) 21 (95) VGPR 8 (29) 7 (32) PR 14 (50) 13 (59) SD 3 (11) 1 (5) PD 2 (7) 0 Lonial S et al. J Clin Oncol. 2012; 30:

32 Study Design Phase 1 n=28 Phase 2 n=73 R A N D O M I Z E Elotuzumab 10 mg/kg IV + Len/dex n=36 Elotuzumab 20 mg/kg IV + Len/dex n=37 P R O G R E S S I O N * Elotuzumab Dosing CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4 CYCLE N-1 CYCLE N Lenalidomide daily dose daily dose daily dose daily dose daily dose daily dose Cycle day Dexamethasone Stratification in phase II: prior therapies (1 vs 2 or 3 lines), prior thalidomide or thalidomide analogs. Len/dex: lenalidomide + low-dose dexamethasone. Assessments were performed once per cycle. *Progression defined by IMWG Criteria. Lonial S et al. J Clin Oncol. 2012; 30:1953. Most Common Treatment-Emerging Grade 3/4 Adverse Events Before and After 18 Months of Treatment Onset Elotuzumab + Len/dex Elotuzumab + Len/dex Grade 3/4 AEs,* 10 mg/kg 20 mg/kg n (%) 18 months >18 months 18 months >18 months n=39 n=20 n=59 n=31 Neutropenia 8 (21) 1 (5) 13 (22) 1 (3) Thrombocytopenia 8 (21) 1 (5) 10 (17) 0 Lymphopenia 10 (26) 1 (5) 5 (9) 0 Anemia 5 (13) 1 (5) 7 (12) 0 Hyperglycemia 2 (5) 0 7 (12) 0 Fatigue 3 (8) 1 (5) 5 (9) 0 Diarrhea 4 (10) 2 (10) 3 (5) 0 Leukopenia 3 (8) 1 (5) 4 (7) 0 Hypokalemia 3 (8) 1 (5) 3 (5) 1 (3) Pneumonia 3 (8) 0 3 (5) 2 (7) *In 5% of patients across elotuzumab 10 and 20 mg/kg. Across dosages, 51 patients received therapy for over 18 months Most treatment-emergent AEs occurred within 18 months of therapy 32

33 Best Response From the Phase 2 Cohort Phase 2 Elotuzumab 10 mg/kg Phase 2 Elotuzumab 20 mg/kg Total Patients, n ORR ( PR), n (%) (95% CI)* 33 (92) (78 98) 28 (76) (59 88) 61 (84) (73 91) CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12) VGPR, n (%) 18 (50) 14 (38) 32 (44) PR, n (%) 10 (28) 10 (27) 20 (27) <PR, n (%) 3 (8) 9 (24) 12 (16) *By Clopper-Pearson method. Richardson PG et al. Lancet Haematol. 2015;2:e516. ELOQUENT-2 Study Design Open-label, international, randomized, multicenter phase 3 trial (168 global sites) Key inclusion criteria RRMM 1 3 prior lines of therapy Prior len exposure permitted in 10% of study population (patients not refractory to len) Elo + Len/dex (E-Rd) schedule (n=321) Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other week Len (25 mg PO): days 1 21 Dex: weekly equivalent, 40 mg Len/dex (Rd) schedule (n=325) Len (25 mg PO): days 1 21; Dex: 40 mg PO days 1, 8, 15, 22 Assessment Tumor response: every 4 weeks until progressive disease Survival: every 12 weeks after disease progression Repeat every 28 days End points: Co-primary: PFS and overall response rate (ORR) Other: OS (data not yet mature); duration of response, quality of life, safety All patients received premedication to mitigate infusion reactions prior to elotuzumab administration Lonial S et al. N Engl J Med. 2015;373:

34 ELOQUENT-2: Key AEs Reported in 30% of Patients E-Ld (n=318) Ld (n=317) Any Any Adverse event, n (%) Grade Grade 3/4 Grade Grade 3/4 Common non-hematologic adverse events Fatigue 149 (47) 27 (8) 123 (39) 26 (8) Pyrexia 119 (37) 8 (3) 78 (25) 9 (3) Diarrhea 149 (47) 16 (5) 114 (36) 13 (4) Constipation 113 (36) 4 (1) 86 (27) 1 (<1) Muscle spasms 95 (30) 1 (<1) 84 (26) 3 (1) Cough 100 (31) 1 (<1) 57 (18) 0 Common hematologic toxicities Lymphocytopenia 316 (99) 244 (77) 311 (98) 154 (49) Neutropenia 260 (82) 107 (34) 281 (89) 138 (44) Infections 259 (81) 89 (28) 236 (74) 77 (24) Exposure-adjusted infection rate was 197 (incidence rate per 100 person-years of exposure) in both arms There was no detriment to overall health-related quality of life with the addition of Elo to Ld ELOQUENT-2: Infusion Reactions Events, n (%) Grade 1/2 E-Ld (n=318) Grade 3 Grade 4/5 Infusion reaction 29 (9) 4 (1) 0 Pyrexia 10 (3) 0 0 Chills 4 (1) 0 0 Hypertension 3 (1) 1(<1) 0 Infusion reactions occurred in 10% of patients 70% of infusion reactions occurred with the first dose No Grade 4 or 5 infusion reactions Elotuzumab infusion was interrupted in 15 (5%) patients due to an infusion reaction (median interruption duration 25 minutes) 2 (1%) patients discontinued the study due to an infusion reaction Lonial S et al. N Engl J Med. 2015;373:

35 Daratumumab Anti-CD38 mab Active as single agent and in combination with lenalidomide 1-3 First mab approved for the treatment of MM patients who have received at least three prior lines of therapy (including a PI and an IMiD) or who are double refractory to a PI and an IMiD Infusion reactions main side effect 4 Potential impact on both standard- and high-risk disease mab, monoclonal antibody; PI, proteasome inhibitor; IMiD, immunomodulatory drug 1. Lokhorst HM et al. N Engl J Med. 2015;373: Lonial S et al. Lancet. 2016; Jan 6 [Epub ahead of print]. 3. Plesner T et al. Blood. 2015;126: Abstract Voorhees PM et al. Blood. 2015;126: Abstract Daratumumab The most clinically advanced of the anti-cd38 monoclonal antibodies A phase 2 study in patients who had already received multiple lines of therapy showed: The majority of patients had reduction in their paraprotein levels compared to their baseline levels Between 21% and 29% overall response rates were observed even in patients who were refractory to: Carfilzomib Bortezomib + lenalidomide Or all 4 agents Lonial S et al. Lancet. 2016; Jan 6 [Epub ahead of print]. 35

36 Overall Response Rate: DARA + LEN/DEX Relative Change In Paraprotein From Baseline (%) N=32 Urine M-protein Serum M-protein ORR, % % 34% CR or CR better or Clinical benefit rate (ORR + minimal response) = 88% scr CR VGPR PR ORR = 81% 25% 9% 28% 19% 16 mg/kg N = 32 63% VGPR 63% or VGPR better or better Plesner T et al. Blood. 2015;126: Abstract 507. Overall Response Rate: DARA + POM-D ORR in double-refractory patients = 67% Clinical benefit rate (ORR + minimal response) = 74% Relative Change In Paraprotein From Baseline (%) N=75 Urine M-protein Serum M-protein Free light chain ORR, % % CR or better ORR = 71% PR VGPR 5% 4% 33% 28% 16 mg/kg N = 75 43% VGPR or better Chari A et al. Blood. 2015;126: Abstract

37 The Practical Part: Infusion Reactions Common Symptoms Treatment Anti-CD38 mab Sinus/nasal congestion Throat irritation Cough, dyspnea, wheezing Rare: anaphylaxis, severe HTN, CP, arrhythmias Elotuzumab Recognize early and stop infusion (37% dara, 5% elo) Give additional premedications Restart at ½ the rate (discontinue if Gr 4 or recurs) Fever, chills Hypertension Less: bradycardia, hypotension Be prepared: Start infusions early Pre-med everyone additional meds likely to be needed Lonial S et al. N Engl J Med. 2015;373:621. Lokhorst HM et al. N Engl J Med. 2015;373:1207. Martin TG et al. Blood. 2014;124. Abstract 83. The Practical Part: Response and Blood Typing Assessing Response mab may be detectable on SPEP/IFE Can obscure CR assessment IgG k MM IgG k agent 1 ELP G A M K L Infection VZV prophylaxis Blood Banking Anti-CD38 may interfere with blood bank tests CD38 on reagent RBCs Positive DAT Positive antibody screen Approaches to resolve anti-cd38 interference *Send type and screen BEFORE first dose-dara Genotype/phenotype recipient s RBCs DTT-treating reagent RBCs (+/- available, give Kell- cells) Neutralize anti-cd38 in plasma (anti-idiotype, scd38) 1. Chapuy CI et al. Transfusion. 2015;55: Oostendorp M et al. Transfusion. 2015;55:

38 Current Clinical Trials of Monoclonal Antibodies in MM mab Target Combination Patient Types Phase Elotuzumab SLAMF7 Len/dex New, relapsed 3 Daratumumab CD38 Len/dex Bz/dex New, relapsed 3 Tabalumab BAFF Relapsed/refractory 2 Isatuximab CD38 Len/dex Pom/dex Relapsed/refractory 1 CyBorD Indatuximab* CD138 Len/dex Relapsed/refractory 1/2 Milatuzumab CD74 Relapsed/refractory 1/2 MOR03087 CD38 Relapsed/refractory 1/2 Pembrolizumab PD-1 Pom/dex Len/dex Relapsed/refractory 1/2 Elo/pom/dex Relapsed/refractory 3 Nivolumab PD-1 Ipilimumab Lirilumab Relapsed/refractory 1 Atezolizumab PD-L1 Rev Relapsed/refractory 1 Lirilumab KIR Elotuzumab Urelumab Relapsed/refractory 1 Urelumab CD137 Elotuzumab Lirilumab Relapsed/refractory 1 *Immunotoxin conjugate Case Continued Treatment History Bortezomib/dex ASCT followed by three additional cycles of bortezomib/dex Maintenance len/dex /dex Carfilzomib/dex 38

39 Next Treatment Daratumumab/pom/dex Prospective study on pom and del 17p 1 Expectations of treatment Effective Potential AEs Reportable signs and symptoms Outcomes Quality of life 1. Leleu X et al. Blood. 2015;125:1411. Concerns for Patients Multiply Relapsed New mutations Older Frailty Comorbidities Residual treatment effects Less response 39

40 Supportive Care Remember we treat the patient, not the disease Bone disease Fatigue and anemia Infections Overall quality of life 40