MMRF Patient Summit West Palm Beach, FL 2/11/2017

Management of : The Changing Paradigm

Promising Clinical Trials in Multiple Myeloma Ajay Nooka, MD Assistant Professor Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University Atlanta, Georgia

Impact of Clinical Trials in Myeloma: Dramatic Improvements in Survival in <10 Years

Bortezomib Lenalidomide

Thalidomide Pomalidomide Melphalan Panobinostat ASCT Ixazomib Corticosteroids

1958 1962 1983 1999 2002 2012 2013 2015

Median OS 72 mo 64 mo

29.9 mo <12 mo ? 1958 1971–1998 2001–2005 2006–2011 2015–

Kumar SK et al. Leukemia. 2014;28:1122. Kumar SK et al. Blood. 2008;111:2516.

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Targets in Myeloma Plasma Cell

Ocio EM et al. Leukemia .2014;28:525.

Goal of Clinical Trials: Making Progress Against Myeloma • Increase understanding of the disease – Improve the way we use currently available drugs – Identify new treatments • Develop new medications that improve, and potentially lengthen, the lives of patients with cancer • Reduce toxicities/side effects • No placebos!

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Pertinent Research Questions • How can treatments be matched to patients’ subtypes/genomics (personalized medicine)?

Venetoclax Monotherapy for Relapsed/ Refractory Multiple Myeloma: Safety and Efficacy Results From a Phase 1 Study

Venetoclax Pro-apoptotic BCL-2 protein BCL-2 Apoptosis initiation

Pro-apoptotic BIM protein BAX

BAK Cancer Cell Cancer Cell Death BAX Survival

Activation of caspases Cytochrome c

BCL-2 overexpression allows cancer Venetoclax binds selectively to BCL-2, freeing cells to evade apoptosis by pro-apoptotic proteins that initiate programmed sequestering pro-apoptotic proteins.3-5 cell death (apoptosis).6-8

1. Touzeau C et al. Leukemia 2014;28:210. 5. Plati J et al. Integr Biol (Camb). 2011;3:279. 2. Punnoose E et al. Mol Cancer Ther 2016. 6. Certo M et al. Cancer Cell. 2006;9:351. 3. Leverson JD et al. Sci Transl Med 2015. 7. Souers AJ et al. Nat Med. 2013;19:202. 4. Czabotar PE et al. Nature Reviews. 2014;15:49. 8. Del Gaizo Moore V et al. J Clin Invest. 2007;117:112.

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Objective Response Rates in All Patients and by t(11;14) Status

50 sCR CR VGPR PR

ORR 40% 40 4%

10% 30

ORR 21% 20 3% 13% 4% Percentage of Percentage Patients 10 8% 13% ORR 6% 3% 6% 3% 0 All Patients t(11;14) non-t(11;14) N=66 n=30 n=36

Data cutoff of 19Aug2016

Kumar S et al. J Clin Oncol. 2016;34: Abstract 8032.

Pertinent Research Questions • How can treatments be matched to patients’ subtypes/genomics (personalized medicine)? • What are the best drugs and drug combinations for multiple myeloma at all stages of disease?

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Efficacy of Daratumumab, , and Versus Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma Based on Prior Lines of Therapy: Updated Analysis of CASTOR

MV Mateos, J Estell, W Barreto, P Corradini, C-K Min, E Medvedova, M Qi, J Schecter, H Amin, X Qin, W Deraedt, T Casneuf, C Chiu, AK Sasser, and A Nooka

Mateos MV et al. Blood. 2016;128: Abstract 1150.

Updated Efficacy

P<0.001 100 12-month PFSa ORR=84% 100 90 80 7% ≥CR 80 70 19% ORR=63% 60% 26% ≥CR 2% 60 10% 8% 60 DVd 50 ≥VGPR ≥VGPR 62%b 19% 29%

ORR, % 40 35% 40 22% 30

Progression Median: 20 7.1 months 20 34% % Surviving Without Vd 10 22% HR: 0.33 (95% CI, 0.26–0.43; P<0.0001) 0 DVd (n=240) Vd (n=234) 03691215182124 Months No. at risk sCR CR VGPR PR Vd 247 182 129 73 23 9 0 0 0 DVd 251 215 198 160 91 33 5 1 0 • Median (range) follow up: 13.0 (0–21.3) months • An additional 7% of patients receiving DVd achieved ≥CR with longer follow up Responses continue to deepen in the DVd group with longer follow-up

ITT, intent to treat. Note: PFS: ITT population; ORR: response-evaluable population. aKaplan-Meier estimate; bP<0.0001 for DVd vs Vd. Mateos MV et al. Blood. 2016;128: Abstract 1150.

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PFS: Prior Lines of Treatment

1 prior line 2 to 3 prior lines 100 12-month PFSa 100 12-month PFSa

80 77% 80 DVd Median: 9.8 months 60 60 44%

40 40 DVd 25% 22% Vd 20 20 Median: 6.3 months Median: 7.9 months % Surviving WithoutProgression % Surviving WithoutProgression HR: 0.22 (95% CI, 0.14–0.34; P<0.0001) HR: 0.51 (95% CI, 0.36–0.73; P<0.0002) Vd 0 0 0 3 6 9 1215182124 0 3 6 9 12 15 18 21 Months No. at risk Months Vd 113 91 69 43 11 5 0 0 0 106 73 50 27 11 4 0 0 DVd 122 109 104 99 59 19 3 1 0 107 87 77 51 27 10 1 0 DVd is superior to Vd regardless of prior lines of therapy, with greatest benefit observed in 1 prior line aKaplan-Meier estimate Mateos MV et al. Blood. 2016;128: Abstract 1150.

Question 1 Which of the following statements is not correct? A. Enrollment in clinical trials using investigational agents is voluntary. B. Once you sign the consent form, you are bound to continue the study even if you change your mind. C. The goal of clinical trials is to develop new therapeutic choices.

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Misconceptions About Cancer Clinical Trials

Misconceptions Facts

I may get a sugar pill (placebo) instead of No placebos are given—every real therapy. patient receives treatment.

I’ll be treated like a guinea Most patients receive care pig. that exceeds expectations.

Clinical studies are Many involve an for people with no adjustment to a standard other options. of care that may improve outcome or quality of life.

The greater the number of people who participate, the faster drug development can proceed.

The Cleveland Clinic. 10 Biggest Cancer Clinical Trial Myths Busted. Available at http://health.clevelandclinic.org/2014/04/10-biggest-cancer-clinical-trial-myths-busted/.

New Drug Development

Identify a Confirm the Clinical trials target for anti-cancer (human therapy in the activity in studies) laboratory laboratory and to determine animal studies safety, dosing, and effectiveness

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Clinical Trial Types

Phase 1 Phase 2* Phase 3† Objectives • Optimal dose • Preliminary • Definitive efficacy • Side effects efficacy and safety • Metabolism • Additional safety Treatment • Single arm (all • Single arm • Two arms: patients receive • Two arms of patients experimental different randomly therapy) treatments or assigned to doses: patients receive randomly experimental assigned to an therapy or arm standard therapy Study Small (<50) Varies >200 Size

*When no standard treatment is available, FDA may approve drugs based on trial results †Conducted to receive FDA approval of new drugs, in most cases

Other Types of Clinical Trials

Longitudinal Registry Expanded Access Studies Studies Programs • Long-term studies • Patients are treated • Allow early access with a large number using available to experimental of patients therapies therapies when no alternatives are • The MMRF • Efficacy and safety available CoMMpassSM Study are analyzed following treatment • Typically involve a large number of patients

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Question 2 Which of the following statements is true? Please select the best answer from the following statements. A. All adverse events are closely monitored in a clinical trial. B. The efficacy of the investigational agents is closely monitored and confirmed in a clinical trial. C. Both A and B are true. D. Both A and B are false.

Commonly Asked Questions

• How does the study work? How often will I need to see my doctor or visit the cancer center? • Will I need to undergo additional tests? • What is currently known about the new drug or combination? • What benefits can I expect? • What side effects should I expect? Who should I notify if I have side effects? • Can I take my vitamins or other medications? • Can I get the treatment with my local doctor? • Will my insurance pay for my participation in the clinical trial?

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Participating in the Study • Tell study personnel about what medications, vitamins, or dietary supplements you are taking, including the dose • Keep a diary of any side effects you experience • Take study medications as directed; keep days and times the same • Keep your appointments • Ask questions

Drugs in Development: Phase 3 Trials

Drug Administration Type Trials Side Effects Newly diagnosed MM • Myelosuppression • Revlimid + dex ± • Pneumonia Monoclonal pembrolizumab • Infection Pembrolizumab IV antibody RR MM • Pomalyst + dex ± pembrolizumab RR MM • Fatigue Monoclonal Nivolumab IV • Nivolumab, Empliciti, •Skinrash antibody Pomalyst, and dex • Muscle pain Newly diagnosed MM • Myelosuppression Monoclonal Daratumumab IV • VTD vs VTD+dara • IRRs antibody • Infection Newly diagnosed MM • Hypocalcemia Xgeva* Bone- • Xgeva vs Zometa (denosumab, IV targeted • Nausea, anemia, AMG 162) antibody dyspnea, fatigue, constipation

RRMM, relapsed/refractory multiple myeloma; IRR, infusion-related reaction *FDA-approved for non-MM indication

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Drugs in Development: Phase 2 Trials

Small Molecule Monoclonal Inhibitors Antibodies

• Ibrutinib • Tabalumab • Palbociclib • Dinaciclib • Erismodegib • Filanesib • Selumetinib • Tivantinib • Nelfinavir • Selinexor

Bold = treatments studied in MMRC trials

Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib & anti-CD38 mAb Refractory MM: STORM Study

DT Vogl, D Dingli, RF Cornell, CA Huff, S Jagannath, D Bhutani, R Baz, A Nooka, J Richter, C Cole, R Vij, A Jakubowiak, R Abonour, G Schiller, TL Parker, LJ Costa, D Kaminetzky, J Hoffman, AJ Yee, A Chari, D Siegel, R Fonseca, S VanWier, G Ahmann, I Lopez, M Kauffman, S Shacham, JR Saint-Martin, C Picklesimer, C Choe-Juliak, and A. Keith Stewart

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Selinexor Mechanism of Action

Vogl DT et al. Blood. 2016;128: Abstract 491.

Treatment-Related Adverse Events ≥10%

Total AE Team Grade 3 Grade 4 (N=79) Gastrointestinal Nausea 8% — 73% Anorexia 3% — 49% Vomiting 4% — 44% Diarrhea 5% — 43% Dehydration 3% — 11% Dysgeusia — — 11% Constitutional Fatigue 15% — 63% Weight Loss 1% — 33% Hematologic Thrombocytopenia 25% 34% 73% Anemia 27% 1% 49% Leukopenia 13% 1% 32% Neutropenia 11% 6% 24% Lymphopenia 9% 1% 14% Other Hyponatremia 22% — 42% CPK Increase 3% — 10% Dizziness — — 10% Fever 1% — 10%

Vogl DT et al. Blood. 2016;128: Abstract 491.

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Time on Study and Duration of Response Among Responders

Penta Quad Penta Quad Penta Quad Penta Quad Penta • Median time to Quad response: 1

Refractory Status Refractory Quad month • Median Penta VGPR patients Quad duration of PR patients response: 5 Quad On study months Quad On study Quad

02468 Months Following Initiation of Selinexor Treatment Vogl DT et al. Blood. 2016;128: Abstract 491.

A Phase II Study of Pembrolizumab, Pomalidomide and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma

A Badros, M Kocoglu, N Ma, A Rapoport, E Lederer, S Philip, P Lesho, C Dell, N Hardy, J Yared, O Goloubeva, and Z Singh University of Maryland Baltimore, MD

Investigator initiated study supported partially by Merck ClinicalTrials.gov # NCT02289222

Badros AZ et al. Blood. 2016;128: Abstract 490.

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Efficacy and Safety (n=48)

• The median age of participating patients was 64 years • Patients had a median of three lines of prior therapy (range, 2–5) • Toxicities – Hematologic toxicities (≥grade 3): neutropenia, anemia, lymphopenia, and thrombocytopenia. – Nonhematologic: hyperglycemia, upper respiratory tract infections, fatigue, and rash; pneumonitis occurred in 6 patients • Response rates – ≥ partial response: 29 (60%): stringent complete response: 3 (6%) very good partial response (VGPR): 10 (21%); and partial response: 16 (33%), 3 (6%) patients had minimal response, 11 (23%) had stable disease, 2 progressed, and 3 were not evaluable for response • DOR and PFS – Median DOR for responding patients was 16.3 months; progression-free survival was 17.4 months

Badros AZ et al. Blood. 2016;128: Abstract 490.

Drugs in Development: Phase 1/2 Trials

Small Molecule Monoclonal Inhibitors Antibodies

• AT7519M • Indatuximab • Ricolinostat • Milatuzumab • Romidepsin • MOR03087 • KW-2478 • TH-302 • Linsitinib • KPT-8602 • Idasanutlin • Oprozomib • Marizomib • VLX1570 • Veliparib

Bold = treatments studied in MMRC trials

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Drugs in Development: Phase 1

Small Molecule Monoclonal Inhibitors Antibodies

• Afuresertib • Atezolizumab • Venetoclax • Ulocuplumab • Quisinostat • DFRF4539A • BMS 833923 • Isatuximab • Ganetespib •Durvalumab • CB-5083 • Lorvotuzumab mertansine • 90Y-BC8-DOTA • ABBV-838

Bold = treatments studied in MMRC trials

Question 3 Which of the following statements is true of a phase 3 trial? A. Safety is established in a phase 3 trial. B. Preliminary efficacy is established in a phase 3 trial. C. Both safety and preliminary efficacy are established in early phase trials. Phase 3 trial compares the investigational agent or its combination to the current standard of care.

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Immune Cell Therapy

• It is an infusion of autologous What is it? MM-directed T cells

In two main ways: 1. Patient’s T cells are harvested How are the and then engineered in a lab to T cells be able to identify specific surface directed to markers on MM cells MM cells? 2. These engineering T cells are then stimulated in a lab to make them more active and to proliferate and grow

How does it • Infused, MM-directed T cells work against myeloma? directly kill MM cells and stimulate T-cell immunity

Types of Immune Cell Therapy • Chimeric antigen receptor (CAR) T cells • T-Cell Receptor (TCR) engineered T cells • Marrow-infiltrating lymphocytes (MILs)

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Engineered T Cell Therapy

TCR transgene Myeloma- specific TCR eg MAGE-A3 TCR

OR

Peripheral blood T cells Tumor-specific CAR Chimeric antigen (for example, receptor (CAR) anti-CD19) transgene

T cells kill myeloma cells In vitro T cell expansion Adoptive T cell therapy

CAR T Cell Therapy in Multiple Myeloma • CART T cell therapy: CTL019 Myeloma patients with • MM precursor cell surface disease progression within 1 yr of prior ASCT target: CD19 • Preliminary results of phase 1 study – 10 patients treated Second ASCT – 6 patients with ongoing responses

CTL019 infusion – 1 patient (so far) attained minimal residual disease (MRD)- negative sCR for > 1 year Patient outcome evaluated

Garfall AL et al. N Engl J Med. 2015;373:1040. sCR, stringent complete response

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Immune Cell Therapy in Development

Study Type Trial Patient Types Phase Site(s) Relapsed/ CART-19 for multiple myeloma 1 University of Pennsylvania refractory Safety study of CAR-modified T cells targeting Relapsed/ 1 Dana-Farber Cancer Institute CAR T NKG2D-ligands refractory

Study of T cells targeting B-cell maturation antigen Relapsed/ National Cancer Institute 1 (BCMA) for previously treated multiple myeloma refractory University of Pennsylvania

Tadalafil and lenalidomide maintenance with or Newly diagnosed; Sidney Kimmel without activated marrow infiltrating lymphocytes relapsed (without 2 Comprehensive Cancer (MILs) in high-risk myeloma prior ASCT) Center

MILs Adoptive immunotherapy with activated marrow- infiltrating lymphocytes and cyclophosphamide graft- Sidney Kimmel Relapsed/ versus-host disease prophylaxis in patients with 1 Comprehensive Cancer refractory relapse of hematologic malignancies after allogeneic Center hematopoietic cell transplantation Affinity- Engineered autologous T cells expressing an Relapsed/ City of Hope enhanced affinity-enhanced TCR specific for NY-ESO-1 and 1/2 refractory University of Maryland T cells LAGE-1

CD3/CD28 activated Id-KLH primed autologous DLI Post-transplant 2 University of Pennsylvania lymphocytes

Therapeutic Vaccines in Development

Patient Study MM Vaccine Types Phase Sites Dendritic cell fusion Beth Israel Deaconess Medical Post- vaccine + CT-011 2 Center/ transplant* (monoclonal antibody) Dana-Farber Hiltonol (MAGE-A3 vaccine Post- 2 University of Pennsylvania Poly-ICLC) transplant* Oncolytic measles virus RR 1 Mayo Clinic (Rochester, MN) (MV-NIS) Oncolytic measles virus RR 2 University of Arkansas (MV-NIS) Emory/Illinois Cancer Specialists/ Beth Israel Deaconess Medical PVX-410 SMM 1/2 Center/Massachusetts General Hospital/MD Anderson Cancer Center Post- PVX-410 2Emory University transplant

*Goal of eliminating any remaining cancer cells

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Smoldering Multiple Myeloma: Drugs in Development • Monoclonal antibodies are in phase 2 trials: – Empliciti – Darzalex – Nivolumab – Siltuximab (CNTO328)

• Other drugs currently used for active/ symptomatic myeloma are also being studied: – Revlimid, phase 3 – Kyprolis, phase 2

Summary: Clinical Trials in Multiple Myeloma • Clinical trials advance multiple myeloma care and speed new drug development • No one receives a placebo • EVERYONE who is eligible should participate in clinical trials – The greater the number of participants, the faster new treatments and new uses for existing treatments are developed To find a clinical trial, contact the MMRF Call 1-866-603-(MMCT) 6628 or visit www.myelomatrials.org

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