11 orlowski lunch-symposium_final
TRANSCRIPT
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?