ROBERT ORLOWSKI, MD, PhDHouston, USA

• Professor, Department of Myeloma/Lymphoma, at the University of Texas MD Anderson Cancer Center

• Dr. Orlowski has published numerous book chapters, articles, and abstracts on cancer therapy, with a focus on the molecular pathogenesis of oncologic disease processes and the mechanisms of action of chemotherapeutics. His clinical research efforts focus on the translation of promising laboratory based findings into novel clinical trials for patients with hematologic malignancies. He has published in, and is a reviewer for, several journals, including Blood, Cancer Research, Journal of Clinical Oncology, and the New England Journal of Medicine. He has received several awards, including The Leukemia & Lymphoma Society Scholar in Clinical Research and the Jefferson-Pilot Fellowship in Academic Medicine.

The Changing Landscape of Treatment of Myeloma and Other

Plasma Cell DyscrasiasRobert Z. Orlowski, Ph.D., M.D.

Director, Myeloma Section

Florence Maude Thomas Cancer Research Professor

Departments of Lymphoma/Myeloma & Experimental Therapeutics

Principal Investigator, MD Anderson SPORE in Multiple Myeloma and MD Anderson Moon Shot in High Risk Myeloma

Chair, SWOG Myeloma Committee

Outline

• Newly diagnosed myeloma• Relapsed and refractory myeloma• Other related plasma cell dyscrasias

2014 ASH Abstract 197

Superior Efficacy of VTD over VCD As Induction Therapy for Autotransplantation-Eligible, Newly

Diagnosed, Myeloma Patients

Michele Cavo, Lucia Pantani, Annalisa Pezzi, Federica Cavallo, Maria Teresa Petrucci, Francesco Di Raimondo, Francesca Patriarca, Anders Waage, Elena

Zamagni, Vittorio Montefusco, Monica Galli, Barbara Gamberi, Giuseppe Rossi, Paola Tacchetti, Mariella Grasso, Sonja Zweegman, Massimo Offidani, Stelvio

Ballanti, Renato Zambello, Anna Marina Liberati, Renato Bassan, Patrizia Pregno, Antonio Palumbo, and Pieter Sonneveld

Retrospective Study Design

Response Data

Safety & Tolerability

2014 ASH Abstract 33

Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy with

Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with

Newly Diagnosed Multiple Myeloma

Jatin J. Shah, Lei Feng, Elisabet E. Manasanch, Donna M. Weber, Sheeba K. Thomas, Francesco Turturro, Raymond Alexanian, Nina Shah, Uday R. Popat, Yago

Nieto, Qaiser Bashir, Muzaffar H. Qazilbash, Richard E Champlin, and Robert Z. Orlowski

Study Design

Response Data

Safety

Epoxyketone Proteasome Inhibitors

Kuhn, DJ et al. Blood 110:3281, 2007.

Binding Selectivity

Kuhn, DJ et al. Blood 110:3281, 2007.

Preclinical Activity

Kuhn, DJ et al. Blood 110:3281, 2007.

Initial Approval

Siegel, DS et al. Blood 120:2817, 2012.

• Relapsed/refractory myeloma after 2 or more prior lines of therapy

Carfilzomib + Thalidomide/Dex

Sonneveld, P et al. Blood 125:449, 2015.

Carfilzomib + Thalidomide/Dex

Sonneveld, P et al. Blood 125:449, 2015.

Durability

Sonneveld, P et al. Blood 125:449, 2015.

• Excellent long-term outcomes

• Similar for standard and high-risk groups

Adverse Events

Sonneveld, P et al. Blood 125:449, 2015.

2014 ASH Abstract 175

Weekly Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple

Myeloma Patients : A Phase I-II Study

Antonio Palumbo, Davide Rossi, Sara Bringhen, Alessandra Larocca, Fabiana Gentilini, Lorenzo De Paoli, Paola Omedè, Stelvio Ballanti, Federica Cavallo,

Roberto Passera, Anna Marina Liberati, Mario Boccadoro, Gianluca Gaidano, Pieter Sonneveld, and Paolo Corradini

Study Design

Patient Characteristics

Treatment Exposure

Conclusions from Phase I

Safety Overview

All Adverse Events

Grade 3 & 4 Adverse Events

Preliminary Response Data

Time to Response

Response & Treatment Duration

Weekly vs. Twice Weekly

Outline

• Newly diagnosed myeloma• Relapsed and refractory myeloma• Other related plasma cell dyscrasias

Carfilzomib/Len/Dex

Wang, M et al. Blood 122:3122, 2013.

Efficacy Data

Wang, M et al. Blood 122:3122, 2013.

2014 ASH Abstract 79

Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients (Pts) with Relapsed Multiple Myeloma : Interim Results

from ASPIRE, a Randomized, Open-Label, Multicenter Phase 3 Study

A. Keith Stewart, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás Masszi, Ivan Spicka, Albert Oriol, Roman Hájek, Laura Rosiñol, David S. Siegel, Georgi G.

Mihaylov, Veselina Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus F. San Miguel, Heinz Ludwig, Naseem

Zojwalla, Margaret E. Tonda, Biao Xing, Philippe Moreau and Antonio Palumbo

ASPIRE Study Design

Key Study Criteria

Patient & Disease Characteristics

Patient & Disease Characteristics II

Progression-free Survival

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

Subgroup Analysis

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

• Most subgroups benefited from CRd to a greater extent

PFS in Risk Groups

Stewart, AK et al. ASH Abstract 79, 2014.

Treatment Response

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

Overall Survival

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

Survival by Response Category

Stewart, AK et al. ASH Abstract 79, 2014.

Adverse Events in at Least 25%

Stewart, AK et al. ASH Abstract 79, 2014.

Other Adverse Events of Interest

Stewart, AK et al. ASH Abstract 79, 2014.

Health-related Quality of Life

Stewart, AK et al. ASH Abstract 79, 2014.

2014 ASH Abstract 32

Phase I Study of the Combination of Carfilzomib and Panobinostat for Patients with Relapsed and

Refractory Myeloma : A Multiple Myeloma Research Consortium (MMRC) Clinical Trial

Jonathan L. Kaufman, Todd Zimmerman, Cara A. Rosenbaum, Ajay K. Nooka, Leonard T. Heffner Jr., R. Donald Harvey, Charise Gleason, Colleen Lewis, Cathy

Sharp, Kenisha W. Barron, and Sagar Lonial

Study Design

DLTs

Adverse Events

Dose Intensity

Efficacy Data

Response Durability

2013 ASH Abstract 690

Phase I/II Dose Expansion of a Multi-Center Trial of Carfilzomib and Pomalidomide with Dexamethasone

(Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

Jatin J. Shah, Edward A. Stadtmauer, Rafat Abonour, Adam D. Cohen, William Bensinger, Cristina Gasparetto, Jonathan L. Kaufman, Suzanne Lentzsch, Dan T. Vogl, Robert Z. Orlowski, Erica L. Kim, Natalia Bialas, David D. Smith, and Brian

GM Durie

Response Data

Outcome Patient Response

≥ VGPR, % 27

ORR, % 70

CBR, % 83

DOR (median), mos 17.7

PFS (median), mos 9.7

OS (median), mos > 18

Long Term Outcomes

2013 ASH Abstract 1982

Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib (Car) in Patients with Relapsed and/or Refractory Multiple Myeloma

(RRMM)

Jatin J. Shah, Lei Feng, Sheeba K. Thomas, Donna M. Weber, Michael Wang, Brandi Hilder, Raymond Alexanian, and Robert Z. Orlowski

Initial Efficacy Data

• All patients were bortezomib-refractory• 63% achieved an MR or better in this phase I• Growth factor support was not needed after

cycles 1 and 2

2013 ASH Abstract 1934

A Phase 1, Dose-Escalation Study (CHAMPION-1) Investigating Weekly Carfilzomib in Combination with Dexamethasone for Patients with Relapsed or

Refractory Multiple Myeloma

James R. Berenson, Leonard Klein, Robert M. Rifkin, Priti Patel, Sandra Dixon, Ying Ou, and Alan Cartmell

Preliminary Data

• Dose limiting toxicities seen at 88 mg/m2 • Dyspnea, vomiting

• Tentative identification of 77 mg/m2 as the dose for further study in combo with dex

• Overall response rate of 67%, with CBR of 87% seen so far• Patients were relapsed or refractory after 1-3

prior lines of therapy

2014 ASH Abstract 34

Clinical Profile of Single-Agent Oprozomib in Patients (Pts) with Multiple Myeloma (MM) : Updated Results

from a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study

Ravi Vij, Michael Savona, David S. Siegel, Jonathan L. Kaufman, Ashraf Badros, Irene M. Ghobrial, Agne Paner, Sundar Jagannath, Andrzej Jakubowiak, Joseph R.

Mikhael, Prashant Kapoor, Linda L. Neuman, Ju RueyJiuan Lee, and Jesus G. Berdeja

Response Data

2014 ASH Abstract 3453

Oprozomib and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma :

Initial Results from the Dose Escalation Portion of a Phase 1b/2, Multicenter, Open-Label Study

Parameswaran N. Hari, Kenneth H. Shain, Peter M. Voorhees, Nashat Gabrail, Muneer H. Abidi, Jeffrey Zonder, Ralph V. Boccia, Paul G. Richardson, Linda L.

Neuman, Sandra J. Dixon, and Claudia Paba Prada

Study Design

• Two schedules being studied• 2/7

– Days 1, 2, 8, 9 of a 14-day cycle• 5/14

– Days 1-5 of a 14-day cycle

• Oprozomib 210 mg starting dose, then + 30 mg• Dex 20 mg po on days 1, 2, 8, 9

DLTs

• 2/7 schedule– No DLTs

• 5/14 schedule– 3 DLTs @ 210 mg cohort

• 1 grade 2 subarachnoid hemorrhage• 1 grade 3 transaminitis • 1 grade 4 thrombocytopenia

Adverse Events

Early Response Data

• 12 pts on 2/7 schedule had 2 assessments for ≥response– 5 pts had PR, 2 pts had MR, 5 pts had SD– ORR of 41.7% and a CBR of 58.3%

• 7 pts on the 5/14 schedule had 2 assessments≥– 3 pts had MR, 2 pts had SD – CBR of 42.9%

Other Ongoing Carfilzomib Studies

• ENDEAVOR– Carfilzomib (20/56 mg/m2)/dex vs. Bortezomib/dex

• S1311– Carfilzomib (20/27 mg/m2) + dex vs. carfilzomib

20/56 mg/m2) + dex

• CLARION– CMP vs. VMP

• E1A11– CRd vs. RVd

Crystal Structure of Bound Carfilzomib

Harshbarger, W et al. Structure 23:1 , 2015.

2014 ASH Abstract 274

Mucin 20 (MUC20) Modulates Proteasome Assembly Chaperones through the c-MET Pathway and Is a Biomarker of Proteasome Inhibitor Sensitivity in

Myeloma

Huihan Wang, Veerabhadran Baladandayuthapani, Heather Yan Lin, Xiaobin Wang, Bingzong Li, Xing-Ding Zhang, Isere Kuiatse, Hua Wang, Dongmin Gu, Liye

Zhong, Wencai Ma, Richard E. Davis, and Robert Z. Orlowski

Understanding of Carfilzomib Resistance?

Outline

• Newly diagnosed myeloma• Relapsed and refractory myeloma• Other related plasma cell dyscrasias

2014 ASH Abstract 35

A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for

Untreated Patients with AL Amyloidosis

Efstathios Kastritis, Xavier Leleu, Bertrand Arnulf, Elena Zamagni, Peter Mollee, M. Teresa Cibeira, Stefan O. Schönland, Philippe Moreau, Roman Hajek, Arnaud Jaccard, Emmanuelle Nicolas-Virelizier, Robin Filshie, Bradley Augustson, Maria-Victoria Mateos, Paolo Milani, Meletios A. Dimopoulos, Eric Hachulla, Jean-Paul Fermand, Andrea Foli, Antonio Palumbo, Pieter Sonneveld, Hans Erik Johnsen,

Giampaolo Merlini, and Giovanni Palladini

Study Design

Response Data

Response Durability

Safety

2014 ASH Abstract 36

A Prospective Phase II Trial of Lenalidomide and Dexamethasone ( LEN-DEX) in POEMS Syndrome

Arnaud Jaccard, Anne Lazareth, Lionel Karlin, Sylvain Choquet, Laurent Frenzel, Laurent Garderet, Mamoun Dib, Lionel Galicier, Olivier Tournilhac, Karim

Belhadj, Philippe Moreau, Olivier Decaux, Lotfi Benboubker, Michel Cogné, Lucile Musset, and Jean Paul Fermand

Study Design

Impact on VEGF Levels

Clinical Responses

Efficacy Follow-up

Conclusions

• Induction regimens are achieving higher response rates and qualities

• Achievement of CR/MRD by flow, and in some cases by molecular testing is more common

• High dose therapy is still the standard of care for post-induction consolidation in transplant-eligible patients

Conclusions II

• Oral proteasome inhibitors & monoclonal antibodies may soon achieve approvals

• These drugs are rapidly being moved to the front-line setting in transplant-ineligible patients

• Triplet regimens are becoming the standards of care for patients with relapsed/refractory disease

• Novel agents are showing efficacy in other plasma cell dyscrasias, such as AL amyloidosis and POEMS syndrome

Remaining Questions

• What is optimal therapy for high-risk myeloma?• Is one induction regimen best for everyone, or

can we individualize therapy?• Do patients who achieve molecular MRD after

chemotherapy or transplant need consolidation and/or maintenance?

• What are the key resistance mechanisms that need to be overcome for patients in the setting of relapsed/refractory disease?