The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016

Patient Case Introduction

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

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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 2009. Elevated total protein detected on routine exam.

History and Labs on Diagnostic Physical Presentation Evaluation

• Past medical history: MVA in Total protein 12.0 (6.3–8.2) • Bone marrow biopsy: 1985; melanoma in 1995 to Calcium 9.3 (8.4–10.2) − 80% plasma cells, CD38 right shin Creatinine 1.3 (0.7–1.2) antigen expression on flow • Past surgical history: cytometry tonsillectomy in 1980 Hgb 11.6 (13–16) IgG 7,912 (700–1,600) • Family history: paternal • Skeletal survey: grandmother with breast cancer, died at age 90 − Multiple bone lesions • Social history: recent marriage (5 months), no children, never smoked, social drinker • Physical exam: mildly cushingoid, some nausea, still menstruating

Staging: Durie-Salmon stage IIIA

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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

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Consultation With Myeloma Specialist

R Continue bz/dex for three more cycles to achieve e maximum benefit of treatment and best possible c remission o m Patient proceeded to ASCT, December 2009, and had a m small M spike of 0.1 g/dL (near CR) e n Maintenance therapy prescribed 6 months post- d transplant: len/dex (prophylaxis with baby aspirin and a acyclovir) t i o Response: April 2011 (16 months post-ASCT), near CR with negative SPEP and trace IgG kappa spike n

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

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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

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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

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Definitions

Relapsed Myeloma • Previously treated myeloma patients who, after a period of being off- therapy, 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):5-14.

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Treatment Selection for Relapsed/Refractory Myeloma

Disease Characteristics Patient Characteristics

• How deep was the patient’s • What is the patient’s response to prior therapy? performance status? • How long was the duration of • Does the patient have pre- response to the previous existing toxicities from either therapy? myeloma or previous treatment • How aggressive is the disease? regimens? • Is the patient eligible for a • What are the patient’s clinical trial? 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 Immunomodulator HDAC Inhibitor

• Carfilzomib • Pomalidomide • Panobinostat •Ixazomib

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Carfilzomib

Approval Date • 2012

Drug Class • Second-generation proteasome inhibitor (IV)

• Irreversibly binds to the N-terminal threonine-containing active Mechanism sites of the 20S proteasome of Action • Has antiproliferative and pro-apoptotic activities in tumor cells • Delays tumor growth in myeloma

• 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 FDA-Approved of therapy Indication • 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; 2016.

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)

PFS = 26.3 ORR = KRD (N=396) ≥CR = 32% months 87%

PFS increased by 9 months with KRd; N=792 higher ORR, deeper response, and longer median duration of response with KRd

PFS = 17.6 ORR = RD (N=396) ≥CR = 9% months 67%

Stewart AK et al. N Engl J Med. 2015;372:142.

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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

PFS = 18.7 ORR = KD (N=464) ≥CR = 13% months 77%

Doubled the PFS with Kd; Higher ORR, deeper response, and longer N=929 median duration of response with Kd; PFS benefit was extended whether prior treatment with a PI or not

PFS = 9.4 ORR = VD (N=465) ≥CR = 6% months 63%

Dimopoulos MA et al. Lancet Oncol. 2016;17:27.

Carfilzomib/Lenalidomide/ Dexamethasone (KRd)

KRd Cycles 1–12 Cycles 13–18 Cycles 19+ Carfilzomib 27 mg/m2 IV Carfilzomib 27 mg/m2 IV Carfilzomib discontinued Days 1, 2, 8, 9, 15, 16 Days 1, 2, 15, 16 after Cycle 18 (20 mg/m2 Days 1, 2, Cycle 1 only, to assess tolerability to carfilzomib)

Lenalidomide 25 mg: Days 1 to 21

Dexamethasone 40 mg: Days 1, 8, 15, 22

Stewart AK et al. N Engl J Med. 2015;372:142.

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Carfilzomib Monotherapy (K) Carfilzomib/Dexamethasone (Kd)

CYCLE 1 Carfilzomib Carfilzomib Carfilzomib 20 mg/m2 56 mg/m2 56 mg/m2 NO CARFILZOMIB DOSING 1 2 34567 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Week Week Week Week 1 2 3 4 Dexamethasone, Dexamethasone, Dexamethasone, Dexamethasone, 20 mg 20 mg 20 mg 20 mg

CYCLES 2-on, until disease progression or unacceptable toxicity Carfilzomib Carfilzomib Carfilzomib 56 mg/m2 56 mg/m2 56 mg/m2 NO CARFILZOMIB DOSING 1 2 34567 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Week Week Week Week 1 2 3 4 Dexamethasone, Dexamethasone, Dexamethasone, Dexamethasone, 20 mg 20 mg 20 mg 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 m2

Carfilzomib [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc; 2016.

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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; 2016.

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

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Ixazomib

Approval Date • 2015

Drug Class • Second-generation oral proteasome inhibitor

• Reversibly and preferentially binds and inhibits the 20S proteasome Mechanism • Induces apoptosis of multiple myeloma cell lines of Action • The combination of ixazomib and lenalidomide demonstrates synergistic cytotoxic effects

FDA-Approved • In combination with dexamethasone and lenalidomide for the treatment of patients with multiple myeloma who have received at Indication least one prior therapy

Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc; 2015.

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

PFS = 20.6 ORR = IRD (N=360) ≥CR = 12% months 78%

40% decrease in risk of progression; N=722 PFS extended to patients with high-risk cytogenetics (overcomes high risk)

Placebo PFS = 14.7 ORR = ≥CR = 7% RD (N=362) months 72%

Moreau P et al. Blood. 2015;126: Abstract 727.

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Ixazomib/Lenalidomide/ Dexamethasone

Starting dose is 4 mg 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 1 2–7 Day 8 9–14 Day 15 16–21 Day 22 23–28 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; 2015.

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; 2015.

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Ixazomib: Adverse Reactions Occurring ≥20% • Diarrhea • Constipation • Thrombocytopenia • Peripheral neuropathy • Nausea/vomiting • Back pain • Peripheral edema

Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc; 2015.

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

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Pomalidomide

Approval Date • 2013

Drug Class • Immunomodulator (oral)

• Inhibits proliferation, induces apoptosis and antiangiogenic activity in tumor cells and models Mechanism • Enhances T-cell– and natural killer cell–mediated immunity, of Action inhibits the production of pro-inflammatory cytokines • Works synergistically with dexamethasone to overcome lenalidomide resistance

• In combination with dexamethasone for patients with multiple FDA-Approved myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated Indication disease progression on or within 60 days of completion of the last therapy

Pomalidomide [package insert]. Summit, NJ: Celgene Corporation; 2015.

Pomalidomide 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

PFS = 4.0 ORR = PD (N=302) PR = 26% months 31%

55% reduced risk of progression N=455 or death with PD; Significant OS advantage

PFS = 1.9 ORR = D (N=153) PR = 9% months 10%

San Miguel J et al. Lancet Oncol. 2013;14:1055.

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Pomalidomide/Dexamethasone

Sunday Monday Tuesday Wednesday Thursday Friday Saturday

Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide 4 mg 4 mg 4 mg 4 mg 4 mg 4 mg START START CYCLE

Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide 4 mg 4 mg 4 mg 4 mg 4 mg 4 mg

Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide 4 mg 4 mg 4 mg 4 mg 4 mg 4 mg

Off Off Off Off Off Off

Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide Pomalidomide 4 mg 4 mg 4 mg 4 mg 4 mg 4 mg NEXT NEXT START START CYCLE

San Miguel J et al. Lancet Oncol. 2013;14:1055.

Pomalidomide: 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.

Pomalidomide [package insert]. Summit, NJ: Celgene Corporation; 2015.

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Pomalidomide: 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

Pomalidomide [package insert]. Summit, NJ: Celgene Corporation; 2015.

Pomalidomide: Adverse Reactions Occurring in ≥30% • Fatigue and asthenia • Neutropenia • Anemia • GI distress: constipation, nausea, diarrhea • Dyspnea • Upper respiratory tract infections • Back pain • Pyrexia

Pomalidomide [package insert]. Summit, NJ: Celgene Corporation; 2015.

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Pomalidomide: 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 • 2015: accelerated approval based on PFS

Drug Class • Nonselective histone deacetylase inhibitor (oral)

• Inhibition of histone deacetylase activity results in cell cycle arrest Mechanism and apoptosis of some transformed cells and cytotoxicity of Action • Helps to turn on tumor suppressor genes

• In combination with bortezomib and dexamethasone for the FDA-Approved treatment of patients with multiple myeloma who have received at Indication least two prior regimens, including bortezomib and an immunomodulatory agent

Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.

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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

PFS = 12 ORR = CR/nCR = FVD (N=387) months 60.7% 27.6%

83% improvement with FVD and maintained across all subgroups; maybe more so N=768 with prior V and IMiD; CR nearly doubled with clinically meaningful median duration of response

Placebo PFS = 8.1 ORR = CR/nCR = VD (N=381) months 54.6% 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 oralV Bortezomib 1.3 mg/m2 by injectionD Dexamethasone 20 mg oral CYCLES 1–8 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Week 1 F V D D F V D F D Week 2 F V D D F V D F 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 F V D D F F Week 2 F V D D 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; 2015.

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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; 2015.

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; 2015.

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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; 2015.

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

.

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Summary • Myeloma is a disease characterized by phases of remission and relapse • Choice of treatment at relapse is based on patient- specific 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

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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 • Oncology nurses – Orthopedic surgeon • Pharmacists – Nephrologist • Pain team – Radiation oncologist • Social workers – Cardiologist • Counselors – Psychiatrist – Dentist • Dietitians • Nurse practitioners • Physical therapy • Physician assistants • Home healthcare

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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.

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Case Study Continued • December 2015: elevated M spike on carfilzomib • Patient chose to continue carfilzomib and dose was escalated to 56 mg/m2 – 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

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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 870.4 mg/L – Hgb 8.8 mg/dL • Goals of therapy: – Rapid control – Maintain quality of life

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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):5-14.

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Are the Goals Different?

Target the tumor Refractory relapse

Target the tumor Relapsed Disease Restoration of function

MRD, clonal control Newly diagnosed

Prevention/Microenvironment

Premalignant

Continuing Evolution of Multiple Myeloma Treatment: New Classes and Targets

Novel Therapies and Immunotherapy Atezolizumab

Lenalidomide Nivolumab Carfilzomib Ixazomib

Thalidomide Elotuzumab Vaccines

Pomalidomide CAR-T

Bortezomib PLD Panobinostat Isatuximab

Daratumumab

2003 2006 20072012 2013 2015 2016+

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

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Monoclonal Antibody Therapy

• It is an injection of antibodies that can What is it? directly bind to the surface of a myeloma cell

How does • Antibodies bind to it work myeloma cells then kill against them using different myeloma? mechanisms

Excitement of Monoclonal Antibodies

Advantages Disadvantages

• Novel mechanism of action • Infusion reactions can limit therapy − Additive or synergistic effects with in some current anti-MM drugs • No biomarkers for response to • Generally well tolerated predict who may most benefit − Toxicity profile non-overlapping • Few long-term survivors 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

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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

Lonial S et al. N Engl J Med. 2015;373:621. NK, natural killer; ADCC, antibody-dependent cellular cytotoxicity Dimopoulos MA et al. Blood. 2015;126: Abstract 28.

Phase 1/2 Elotuzumab + Len/Dex: Efficacy

Pts w/o Best Confirmed All Pts Prior Len Response, n (%) (n=28) (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; 30:1953.

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Study Design

Elotuzumab 10 mg/kg IV P R + Len/dex R A n=36 O N G D R Phase 1 Phase 2 O E n=28 n=73 M Elotuzumab 20 mg/kg IV S I + Len/dex S Z I E n=37 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 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 28 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

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Best Response From the Phase 2 Cohort

Phase 2 Phase 2 Elotuzumab Elotuzumab 10 mg/kg 20 mg/kg Total Patients, n 36 37 73 ORR (≥PR), n (%) 33 (92) 28 (76) 61 (84) (95% CI)* (78–98) (59–88) (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)

*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 Elo + Len/dex (E-Rd) schedule (n=321) Assessment criteria Elo (10 mg/kg IV): Cycle 1 and 2: weekly; • Tumor response: • RRMM Cycles 3+: every other week every 4 weeks until • 1–3 prior lines of Len (25 mg PO): days 1–21 progressive therapy Dex: weekly equivalent, 40 mg disease • Prior len exposure • Survival: every permitted in 10% of 12 weeks after study population Len/dex (Rd) schedule (n=325) disease (patients not Len (25 mg PO): days 1–21; progression refractory to len) Dex: 40 mg PO days 1, 8, 15, 22

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;373:621.

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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

E-Ld (n=318) Events, n (%) Grade Grade Grade 1/2 3 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;373:621.

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Daratumumab

Anti-CD38 mAb

Active as single agent and in combination with lenalidomide1-3

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 effect4

Potential impact on both standard- and high-risk disease

1. Lokhorst HM et al. N Engl J Med. 2015;373:1207. 2. Lonial S et al. Lancet. 2016; Jan 6 [Epub ahead of print]. mAb, monoclonal antibody; PI, proteasome inhibitor; 3. Plesner T et al. Blood. 2015;126: Abstract 507. IMiD, immunomodulatory drug 4. Voorhees PM et al. Blood. 2015;126: Abstract 1829.

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 − Pomalidomide − Bortezomib + lenalidomide − Or all 4 agents

Lonial S et al. Lancet. 2016; Jan 6 [Epub ahead of print].

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Overall Response Rate: DARA + LEN/DEX

N=32 100 100 sCR CR VGPR PR Urine M-protein 90 75 ORR = 81% Serum M-protein 80 50 70 34% 25% 25 34%CR or 60 CRbetter or 0 63% 50 9% VGPR63% orVGPR better or -25 ORR, % 40 better From Baseline (%) Baseline From 28% -50 30 Relative Change In Paraprotein Change Relative -75 20 -90 -100 10 19% 0 16 mg/kg • Clinical benefit rate (ORR + minimal response) = 88% N = 32

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%

N=75 ORR = 71% 75 80 PR VGPR Urine M-protein 50 Serum M-protein 70 9% Free light chain CR or 5% 25 60 better 4% 43% 0 50 VGPR 33% or better 40 -25

ORR, % 30 From Baseline (%) Baseline From -50 20

Relative Change In Paraprotein Change Relative -75 28% 10 -100 0 16 mg/kg N = 75

Chari A et al. Blood. 2015;126: Abstract 508.

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The Practical Part: Infusion Reactions

Common Symptoms Treatment

• Anti-CD38 mAb • Recognize early and stop − Sinus/nasal congestion infusion (37% dara, 5% elo) − Throat irritation • Give additional premedications − Cough, dyspnea, wheezing • Restart at ½ the rate − Rare: anaphylaxis, severe HTN, (discontinue if Gr 4 or recurs) CP, arrhythmias • Elotuzumab − 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 Infection Blood Banking

• mAb may be • VZV prophylaxis • Anti-CD38 may interfere with blood bank detectable on tests SPEP/IFE − CD38 on reagent RBCs • Can obscure CR • Positive DAT assessment • Positive antibody screen • Approaches to resolve anti-CD38 interference *Send type and screen BEFORE first dose-DARA IgG k MM − Genotype/phenotype recipient’s RBCs IgG k agent − DTT-treating reagent RBCs (+/- available, give Kell- cells) − Neutralize anti-CD38 in plasma 1 (anti-idiotype, sCD38) ELP G A M K L 1. Chapuy CI et al. Transfusion. 2015;55:1545. 2. Oostendorp M et al. Transfusion. 2015;55:1555.

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Current Clinical Trials of Monoclonal Antibodies in MM

mAb Target Combination Patient Types Phase Elotuzumab SLAMF7 Len/dex New, relapsed 3 Len/dex Daratumumab CD38 New, relapsed 3 Bz/dex Tabalumab BAFF Relapsed/refractory 2 Len/dex Isatuximab CD38 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 Pom/dex Pembrolizumab PD-1 Relapsed/refractory 1/2 Len/dex Elo/pom/dex Relapsed/refractory 3 Nivolumab PD-1 Ipilimumab Relapsed/refractory 1 Lirilumab Atezolizumab PD-L1 Rev Relapsed/refractory 1 Elotuzumab Lirilumab KIR Relapsed/refractory 1 Urelumab Elotuzumab Urelumab CD137 Relapsed/refractory 1 Lirilumab *Immunotoxin conjugate

Case Continued…Treatment History • Bortezomib/dex • ASCT followed by three additional cycles of bortezomib/dex • Maintenance len/dex • Pomalidomide/dex • Carfilzomib/dex

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Next Treatment • Daratumumab/pom/dex – Prospective study on pom and del 17p1 • 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

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

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