Published by the IC
nternational M I
yeloma FT
oundation
IASHNG
2008
VOLUME V, ISSUE IV S
Q4/2008
VELCADE® (bortezomib) Issue
Welcome to the International Myeloma Foundation's (IMF) special edition of CITINGS,
our premiere publication featuring the most up-to-date information on myeloma treatment.
This issue focuses on VELCADE (bortezomib), the first of a new class of drugs called proteasome
inhibitors. In this issue, we provide a list of selected bortezomib data being presented at the
50th Annual American Society of Hematology (ASH) Meeting to be held December 6­9, 2008.
Furthermore, readers will also find a comprehensive list of references to the latest published studies
on bortezomib from both national and international medical journals and publications published
in the fourth quarter of this year.
We hope that CITINGS provides a detailed and informative update of the VELCADE
literature, as well as assists in navigating the ASH meeting. Please feel free to contact the IMF at
(800) 452-CURE or www.myeloma.org
­ Susie Novis, President, IMF
American Society of Hematology Presentations 2008
Saturday, December 6, 2008
Genetic Origin of Myeloma
Marta Chesi, Peter Leif Bergsagel, and Michael Kuehl
Abstract No.: n/a
Location: 304-306-308 - South (Moscone Center)
Time: 2:00 PM
High-Risk Myeloma (Scientific Program)
The Administration of Bortezomib, Dexamethasone and Thalidomide ( VTD) after ASCT in Myeloma Patients
Who Do Not Receive Bisphosphonates Normalizes sRANKL, Dickkopf-1 and Improves Abnormal Osteoclast Function
and Impaired Angiogenesis
Evangelos Terpos, Efstathios Kastritis, Dimitrios Christoulas, Magdalini Migkou, Maria Gavriatopoulou and Meletios A. Dimopoulos
Time: 5:30 PM ­ 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 1728
Poster Board: I-833
Myeloma ­ Therapy, Excluding Transplantation Poster I
Antitumor Activity in a Human Multiple Myeloma (MM) Model Using Sorafenib, Bortezomib, and Dexamethasone Treatment
Julia Schüler, Dagmar Wider, Dietmar Pfeifer, Martin Wagner, Heinz-Herbert Fiebig and Monika Engelhardt
Abstract No.: 1720
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-825
Myeloma ­ Pathophysiology and Preclinical Studies Excluding Therapy Poster I
www.myeloma.org
(800) 452 - CURE (2873)
Funded by an unrestricted educational grant from Millennium: The Takeda Oncology Company
Bortezomib Improves Endothelial Thromboresistance Via Induction of KLF Transcription Factors
Toyoko Hiroi, Clayton B Deming, Haige Zhao, Baranda S Hansen, Elisabeth K Arkenbout, Thomas J Myers, William J Riordan,
Michael A McDevitt and Jeffrey J Rade
Abstract No.: 1890
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-995
Vascular Wall Biology, Endothelial Progenitor Cells, and Platelet Adhesion Poster I
Bortezomib­Melphalan­Prednisone ( VMP) in Newly Diagnosed Multiple Myeloma Patients with Impaired Renal Function:
Cohort Analysis of the Phase III VISTA Study
Meletios A Dimopoulos, Paul Richardson, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Efstathios Kastritis, Martin H Kropff,
Maria Teresa Petrucci, Michel Delforge, Julia A Alexeeva, Rik Schots, Tamas Masszi, Maria-Victoria Mateos, William Deraedt, Kevin Liu,
Andrew Cakana, Helgi van de Velde and Jesus F San Miguel
Abstract No.: 1727
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-832
Myeloma ­ Therapy, Excluding Transplantation Poster I
Bortezomib Overcomes Cell Adhesion-Mediated Drug Resistance Via Down-Regulation of VLA-4 Expression in Multiple Myeloma
Kaoru Hatano, Jiro Kikuchi, Masaaki Takatoku, Rumi Shimizu, Taeko Wada, Masuzu Ueda, Masaharu Nobuyoshi, Iekuni Oh, Kazuya Sato,
Takahiro Suzuki, Katsutoshi Ozaki, Masaki Mori, Tadashi Nagai, Kazuo Muroi, Yasuhiko Kano, Yusuke Furukawa and Keiya Ozawa
Abstract No.: 1634
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-739
Molecular Pharmacology, Drug Resistance Poster I
Bortezomib Targets Stroma-Mediated APO2L/TRAIL Apoptosis Resistance in Multiple Myeloma
Lia Perez, Nancy Parquet, Claudio Anasetti and William Dalton
Abstract No.: 1665
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-770
Myeloma ­ Biology and Pathophysiology, Excluding Therapy Poster I
Immunomodulatory Effects of Lenalidomide and Bortezomib on Bone Marrow Stroma Cell and CD4 T Cell Interaction
in Multiple Myeloma
Gullu Gorgun, Elisabetta Calabrese, Teru Hideshima, Hiroshi Ikeda, Giulia Perrone, Loredana Santo, Diana Cirstea, Paul G Richardson
and Kenneth C Anderson
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 1690
Poster Board: I-795
Myeloma ­ Biology and Pathophysiology, Excluding Therapy Poster I
Lenalidomide, Bortezomib, and Dexamethasone in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM):
Encouraging Response Rates and Tolerability with Correlation of Outcome and Adverse Cytogenetics in a Phase II Study
Paul Richardson, Sundar Jagannath, Andrzej Jakubowiak, Sagar Lonial, Noopur Raje, Melissa Alsina, Irene Ghobrial, Amitabha
Mazumder, Nikhil C Munshi, David H Vesole, Kathleen Colson, Mary L McKenney, Laura Lunde, Sarah Kennedy, Kara Kosakowski,
Constantine Mitsiades, Teru Hideshima, Robert D Knight, Dixie-Lee Esseltine, and Kenneth C Anderson
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 1742
Poster Board: I-847
Myeloma ­ Therapy, Excluding Transplantation Poster I
Primary Therapy with Bortezomib--the Role of Induction, Maintenance, and Re-Induction in Patients with High Risk Myeloma.
Update of Results from E2A02
Angela Dispenzieri, Susanna Jacobus, David H. Vesole, S. Vincent Rajkumar and Philip R. Greipp
Abstract No.: 1738
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-843
Myeloma ­ Therapy, Excluding Transplantation Poster I
Proteomic Profiling of Multiple Myeloma: Correlation of Protein and Gene Expression Data
Ricky D Edmondson, Sheeno P Thyparambil, Veronica MacLeod, Bart Barlogie, and John D. Shaughnessy Jr.
Abstract No.: 1705
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-810
Myeloma ­ Biology and Pathophysiology, Excluding Therapy Poster I
Reversibility of Renal Impairment of Multiple Myeloma Patients Treated with Bortezomib-Based Regimens:
Identification of Predictive Factors
Meletios A. Dimopoulos, Maria Roussou, Efstathios Kastritis, Maria Gavriatopoulou, Flora Zagouri, Magdalini Migkou,
Charis Matsouka, Despina Barmparousi, Dimitrios Christoulas, Erasmia Psimenou, Irini Grapsa and Evangelos Terpos
Abstract No.: 1725
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: I-830
Myeloma ­ Therapy, Excluding Transplantation Poster I
Treatment of Relapsed and Refractory Multiple Myeloma in Patients with p53 Deletion
Donna E. Reece, Young Trieu, Hong Chang, Wei Xu, Peter Anglin, Christine Chen, Vishal Kukreti, Suzanne Trudel, and Joseph Mikhael
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 1724
Poster Board: I-829
Myeloma ­ Therapy, Excluding Transplantation Poster I
Treatment of Patients with Relapsed/Refractory Multiple Myeloma (MM) with Lenalidomide and Dexamethasone with or with
Bortezomib Depending on Prior Neurotoxicity: Prospective Evaluation of the Impact of Cytogenetic Abnormalities and Assessment
Meletios A. Dimopoulos, Efstathios Kastritis, Dimitrios Christoulas, Magdalini Migkou, Maria Gavriatopoulou, Flora Zagouri and
Evangelos Terpos
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 1726
Poster Board: I-831
Myeloma ­ Therapy, Excluding Transplantation Poster I
Sunday, December 7, 2008
Lenalidomide, Bortezomib, and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma:
Encouraging Efficacy in High Risk Groups with Updated Results of a Phase I/II Study
Paul Richardson, Sagar Lonial, Andrzej Jakubowiak, Sundar Jagannath, Noopur S Raje, David Avigan, Irene M Ghobrial,
Robert L Schlossman, Amitabha Mazumder, Nikhil C Munshi, David H Vesole, Robin Joyce, Deborah Doss, Diane L Warren,
Stephen W Hayes, Sarah Kaster, Carol Delaney, Marisa Lauria, Constantine Mitsiades, Teru Hideshima, Robert D. Knight,
Dixie-Lee Esseltine, and Kenneth C Anderson
Time: 4:45 PM
Location: Halls B and C (Moscone Center)
Abstract No.: 92
Myeloma Therapy: Newly Diagnosed Myeloma
Bortezomib Induces Thrombocytopenia by Inhibiting Proplatelet Formation but Not Proliferation and Endomitosis
in Human Primary Megakaryocytes Clinically Relevant Abstract
Wataru Nogami, Akiko Yamane, Takanori Nakamura, Eri Matsuki, Yasuo Ikeda and Yoshitaka Miyakawa
Abstract No.: 87
Location: 120-121-122-123-124-125 - North (Moscone Center)
Time: 5:00 PM
Inherited and Acquired Platelet Disorders
Safety and Efficacy of Novel Combination Therapy with Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide
in Newly Diagnosed Multiple Myeloma: Initial Results from the Phase I/II Multi-Center EVOLUTION Study
Shaji Kumar, Ian W Flinn, Stephen J. Noga, Parameswaran Hari, Robert M. Rifkin, Natalie Scott Callander, Manish Bhandari,
Jeffrey Lee Wolf, Cristina Gasparetto, Amrita Krishnan, Daren D Grosman, Jonathan Glass, Entezam Asim Sahovic, Hongliang Shi,
Iain J. Webb, Paul Richardson, and S. Vincent Rajkumar
Time: 5:00 PM
Location: Halls B and C (Moscone Center)
Abstract No.: 93
Myeloma Therapy: Newly Diagnosed Myeloma
A Phase II Study of Bortezomib ( VELCADE®), Cyclophosphamide (Cytoxan®), Thalidomide (Thalomid®) and Dexamethasone
as First-Line Therapy for Multiple Myeloma
William Bensinger, Sundar Jagannath, Robert Vescio, Elber S. Camacho, Jeffrey Lee Wolf, David H Irwin, Gerardo Capo III, Marti McKinley,
Phyllis Potts, David H. Vesole, Amitabha Mazumder, Dixie-Lee Esseltine, Pamela Becker, John Crowley, and Brian GM Durie.
Time: 5:15 PM
Location: Halls B and C (Moscone Center)
Abstract No.: 94
Myeloma Therapy: Newly Diagnosed Myeloma
Acquired Resistance to Bortezomib in Human RPMI-8226 Multiple Myeloma Cells: Molecular Characterization,
Cross-Resistance with Other Proteasome Inhibitors but Marked Sensitization to Glucocorticoids
Niels E Franke, Gertjan L Kaspers, Nynke van den Berg, Ina van Zantwijk, Katarina Vojtekova, Uzma Yaqub, Serge Smeets, Bauke Ylstra,
Sonja Zweegman, Gerrit Jansen, and Jacqueline Cloos,
Abstract No.: 2640
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-734
Molecular Pharmacology, Drug Resistance Poster II
Bortezomib and Dexamethasone as Maintenance therapy in Relapse/Refractory multiple myeloma Patients
Giulia Benevolo, Alessandra Larocca, Patrizia Pregno, Francesca Gay, Barbara Botto, Lorella Orsucci, Andrea Evangelista,
Antonio Palumbo, Umberto Vitolo, and Mario Boccadoro
Abstract No.: 2771
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-865
Myeloma ­ Therapy, Excluding Transplantation Poster II
Bortezomib, Intravenous Cyclophosphamide and Dexamethasone ( VelCD) for Previously Untreated Multiple Myeloma:
An Interim Analysis of the German DSMM XIa Trial
Stefan Knop, Peter Liebisch, Hannes Wandt, Martin Kropff, Volker Kunzmann, Katja Weisel, Daniel Franke, Monika Engelhardt,
Lorenz H. Truemper, Nikolaus Kroeger, Burkhard Hennemann, Michael Pfreundschuh, Martin Gramatzki, Bernd Metzner,
Christian Peschel, Herbert G. Sayer, Orhan Sezer, Heinz A Duerk, Bernd Hertenstein, Hans-Guenther Mergenthaler, Hella Gollasch,
Hans-Heinrich Wolf, Georgia Schilling, Claas Frohn, and Hermann Einsele
Abstract No.: 2776
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-870
Myeloma ­ Therapy, Excluding Transplantation Poster II
Bortezomib Retreatment in Relapsed Multiple Myeloma (MM): Results from a Binational, Multicenter Retrospective Survey
Irena Hrusovsky, Berthold Emmerich, Albert von Rohr, Monika Engelhardt, Jerome Voegeli, Christian Taverna, Robert Olie, Harold Pliskat,
Claas Frohn and Georg Hess
Abstract No.: 2775
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-869
Myeloma ­ Therapy, Excluding Transplantation Poster II
CCR1 Inhibition Targets Osteoclast-Myeloma Adhesion and Exerts in Vivo Anti-Osteoclast Activity
Sonia Vallet, Nileshwari Vaghela, Mariateresa Fulciniti, Petter Veiby, Teru Hideshima, Samantha Pozzi, Loredana Santo,
Siddhartha Mukherjee, Diana Cirstea, David T. Scadden, Kenneth C. Anderson, and Noopur Raje
Abstract No.: 2757
Location: Hall A (Moscone Center)
Time: 6:00 PM - 8:00 PM
Poster Board: II-851
Myeloma ­ Pathophysiology and Preclinical Studies Excluding Therapy Poster II
Characterization of Bortezomib Resistance in Multiple Myeloma Cell Lines
Silvia CW Ling, Angela M Nikolic, Ammira Al-Shabeeb, Edwin Lau, Phoebe Joy Ho, Douglas Joshua, and John D Allen
Abstract No.: 2639
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-733
Molecular Pharmacology, Drug Resistance Poster II
Clinical Epidemiological Study on Multiple Myeloma in China: A 18-Year Retrospective Study in a Representative Center
Lugui Qiu, Yafei Wang, Peijing Qi, Dehui Zou, Yaozhong Zhao, and Junyuan Qi
Time: 6:00 PM ­ 8:00 PM
Location: Hall A (Moscone Center)
Abstract No.: 2723
Poster Board: II-817
Myeloma ­ Biology and Pathophysiology, Excluding Therapy Poster II
An Economic Evaluation of Bortezomib-Based Induction Therapy in Double Transplant Protocols
for Newly Diagnosed Multiple Myeloma Patients
Si-Tien Wang, Mei Sheng Duh, Hui Huang, Leigh Ann White, Eva Chang, Dixie-Lee Esseltine, and Jing L. Marantz
Abstract No.: 2386
Location: Hall A (Moscone Center)
Time: 6:00 PM - 8:00PM
Poster Board: II-480
Health Services and Outcomes Research Poster II
Expression Profile Signature to Predict Response to Bortezomib and Dexamethasone Combination Therapy in Newly-Diagnosed
Myeloma: Moving towards Prospective Prediction
Nikhil C. Munshi, Cheng Li, Stephane Minvielle, Samir B Amin, Philippe Moreau, Florence Magrangeas, Kenneth C Anderson, and Hervé
Avet-Loiseau
Abstract No.: 2746
Location: Hall A (Moscone Center)
Time: 6:00 PM - 8:00 PM
Poster Board: II-840
Myeloma ­ Biology and Pathophysiology, Excluding Therapy Poster II
Indirect Comparison of the Efficacy of Melphalan-Prednisone-Bortezomib Relative to Melphalan-Prednisone-Thalidomide and
Melphalan-Prednisone for the First Line Treatment of Multiple Myeloma
Yating Yeh, James Chambers, Sabine Gaugris, and Jeroen Jansen
Time: 6:00 PM - 8:00 PM
Location: Hall A (Moscone Center)
Abstract No.: 2367
Poster Board: II-461
Health Services and Outcomes Research Poster II
Inhibition of eIF2 Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells
Surviving Therapy
Denis M Schewe and Julio A Aguirre-Ghiso
Abstract No.: 2762
Location: Hall A (Moscone Center)
Time: 6:00 PM - 8:00 PM
Poster Board: II-856
Myeloma ­ Pathophysiology and Preclinical Studies Excluding Therapy Poster II
Interactions of the Mdm2/p53 and Proteasome Pathways: Implications for Combination Strategies
to Enhance the Anti-Myeloma Activity of Bortezomib
Melissa G. Ooi, Patrick J. Hayden, Douglas W. McMillin, Joseph M. Negri, Jake Delmore, Noopur S Raje, Nikhil C. Munshi,
Dharminder Chauhan, Teru Hideshima, Paul G. Richardson, Constantine S. Mitsiades, Kenneth C Anderson and Nicholas Mitsiades
Abstract No.: 2651
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-745
Molecular Pharmacology, Drug Resistance Poster II
Non-Proteasomal Targets of Proteasome Inhibitors Bortezomib and Carfilzomib
Shirin Arastu-Kapur, Kevin Shenk, Francesco Parlati and Mark K Bennett
Abstract No.: 2657
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-751
Molecular Pharmacology, Drug Resistance Poster II
Novel Agents Overcome the Adverse Prognosis Imparted by Compromised Renal Function in Patients with Multiple Myeloma
Mehul Patel, Taimur Sher, Sikander Ailawadhi, Terry Mashtare Jr., Wei Tan, Pranay Soni, Gregory Wilding, Kena C Miller, Alice Mohr,
Kelvin P. Lee and Asher Alban Chanan-Khan
Time: 6:00 PM ­ 8:00 PM
Location: Hall A (Moscone Center)
Abstract No.: 2726
Poster Board: II-820
Myeloma ­ Biology and Pathophysiology, Excluding Therapy Poster II
Parathyroid Hormones (PTH) Serum Variations Are Associated with Bortezomib Response in Multiple Myeloma Patients
Maurizio Zangari, Lisa Pappas, Fenghuang Zhan, Naveen Sanath kumar, Federica Cavallo, Larry J Suva, Guido Tricot, Dixie-Lee Esseltine,
and Shmuel Yaccoby
Abstract No.: 2783
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-877
Myeloma ­ Therapy, Excluding Transplantation Poster II
A Phase IB, Multicenter, Open-Label, Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients
with Relapsed Multiple Myeloma
David Siegel, Orhan Sezer, Jesus F. San Miguel, Maria-Victoria Mateos, Ian Prosser, Michele Cavo, Muhammad Jalaluddin,
Katharine Hazell, Priscille M. Bourquelot and Kenneth C. Anderson
Abstract No.: 2781
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board II-875
Myeloma ­ Therapy, Excluding Transplantation Poster II
Results of a Phase II Open-Label Trial of Bortezomib in Patients with Multiple Myeloma Who Have Undergone High-Dose Melphalan
Therapy Followed by Autologous Peripheral Blood Stem Cell Transplantation and Failed to Achieve a Complete Response
Robert M. Rifkin, Gary Spitzer, Andrew Greenspan, John F. Schwerkoske, Romeo A. Mandanas, Joe Stephenson, George T. Kannarkat,
Feng Zhan, Lina Asmar, and Roy Beveridge
Abstract No.: 2780
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board: II-874
Myeloma ­ Therapy, Excluding Transplantation Poster II
Salvage Therapy with Intravenous Liposomal Adryamicin (A), Bortezomib (B), Cyclophosphamide (C), and Dexamethasone (D)
(ABCD) in Previously Treated Myeloma Patients
Francesco Di Raimondo, Alessandra Romano, Ausilia Gorgone, Annalisa Chiarenza, Maide Cavalli, Salvatore Berretta, Paolo Fiumara,
Giovanna Motta and Giuseppe A. Palumbo
Abstract No.: 2779
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board II-873
Myeloma ­ Therapy, Excluding Transplantation Poster II
Superior Outcomes Associated with Complete Response:
Analysis of the Phase III VISTA Study of Bortezomib Plus Melphalan­Prednisone Versus Melphalan­Prednisone
Jean-Luc Harousseau, Antonio Palumbo, Paul Richardson, Rudolf Schlag, Meletios A Dimopoulos, Ofer Shpilberg, Martin H Kropff,
Michel Delforge, Rik Schots, Michele Cavo, Anatoly Golenkov, Mieczyslaw Komarnicki, Maria-Victoria Mateos, Andrew Cakana,
Kevin Liu, William Deraedt, Helgi van de Velde and Jesus F San Miguel
Abstract No.: 2778
Location: Hall A (Moscone Center)
Time: 6:00 PM ­ 8:00 PM
Poster Board II-872
Myeloma ­ Therapy, Excluding Transplantation Poster II
Thalidomide Versus Bortezomib-Based Regimens for Relapsed Myeloma: Meta-Analysis and Indirect Meta-Analysis
Ambuj Kumar, Iztok Hozo, and Benjamin Djulbegovic
Time: 6:00 PM ­ 8:00 PM
Location: Hall A (Moscone Center)
Abstract No.: 2362
Poster Board: II-456
Health Services and Outcomes Research Poster II
Treatment Patterns among Patients with Recently-Diagnosed Multiple Myeloma in a National Registry
Carla M. Van Bennekom, Noopur Raje, Kenneth C. Anderson, Theresa E. Anderson, and David W. Kaufman
Time: 6:00 PM ­ 8:00 PM
Location: Hall A (Moscone Center)
Abstract No.: 2374
Poster Board: II-468
Health Services and Outcomes Research Poster II
VELCADE®, Thalidomide, Dexamethasone ( VTD) Followed by Melphalan, Prednisone, Thalidomide (MPT) Maintenance
as a First Line Treatment Demonstrates High Response Rates for High-Risk Patients with Multiple Myeloma (MM)
Who Are Non-Transplant Candidates: Updated Results of Phase II Trial
HyeonSeok Eom, Yeo-Kyeoung Kim, Joo-Seop Chung, Kihyun Kim, Hyo-Jung Kim, HoYoung Kim, Jong-Youl Jin, Young-Rok Do,
Suk-Joong Oh, Cheolwon Suh, Chu-Myong Seong, Chul Soo Kim, Dong Soon Lee and Jae Hoon Lee
Time: 6:00 PM ­ 8:00 PM
Location: Hall A (Moscone Center)
Abstract No.: 2785
Poster Board: II-879
Myeloma ­ Therapy, Excluding Transplantation Poster II
Monday, December 8, 2008
Bortezomib-Doxorubicin-Dexamethasone as Induction Prior to Reduced Intensity Autologous Transplantation
Followed by Lenalidomide as Consolidation/Maintenance in Elderly Untreated Myeloma Patients
Antonio Palumbo, Patrizia Falco, Francesca Gay, Vittorio Montefusco, Claudia Crippa, Francesca Patriarca, Milena Gilestro,
Anna M. Liberati, Fausto Rossini, Tommaso Caravita, Antonietta Falcone, Federica Cavallo, Paolo Corradini, Giuseppe Rossi,
and Mario Boccadoro
Time: 7:30 AM
Location: 120-121-122-123-124-125 - North (Moscone Center)
Abstract No.: 159
Autologous Transplantation: Myeloma, Amyloidosis and Autoimmune Diseases
Bortezomib (BOR) and High Dose Melphalan (HDM) as Conditioning Regimen Before Autologous Stem Cell Transplantation (ASCT)
for De Novo Multiple Myeloma (MM): Final Results of the IFM Phase II Study VEL/MEL
Murielle Roussel, Anne Huynh, Philippe Moreau, Jean Luc Harousseau, Cyrille Hulin, Denis Caillot, Christophe Fruchart, Gerald Marit,
Brigitte Pegourie and Michel Attal
Abstract No.: 160
Location: 120-121-122-123-124-125 - North (Moscone Center)
Time: 7:45 AM
Autologous Transplantation: Myeloma, Amyloidosis and Autoimmune Diseases
TNF-a Polymorphism Modulates the Outcome of Multiple Myeloma Patients Treated with Bortezomib Clinically Relevant Abstract
Gabriele Buda, Alessandro Martino, Valentina Maggini, Enrico Orciuolo, Sara Galimberti, Massimo Gentile, Marino Brunori,
Fortunato Morabito, Anna Maria Rossi, and Mario Petrini
Abstract No.: 216 Location: Yerba Buena Ballroom Salon 8 (San Francisco Marriott)
Time: 7:45 AM
Genomic Pharmacology And Mechanisms of Drug Resistance
Ninety Percent Sustained Complete Response (CR) Rate Projected 4 Years after Onset of CR in Gene Expression Profiling (GEP)-
Defined Low-Risk Multiple Myeloma (MM) Treated with Total Therapy 3 (TT3): Basis for GEP-Risk-Adapted TT4 and TT5
Bart Barlogie, Elias J. Anaissie, John D. Shaughnessy Jr., Frits van Rhee, Mauricio Pineda-Roman, Jeff Haessler, Klaus A. Hollmig,
Yazan Alsayed, Sarah Waheed, Monica Graziutti, Elias Kiwan, and John Crowley
Time: 8:15 AM
Location: 120-121-122-123-124-125 - North (Moscone Center)
Abstract No.: 162
Autologous Transplantation: Myeloma, Amyloidosis and Autoimmune Diseases
Preclinical Evaluation of CRx-501, a Potent Selective A2A Agonist as a Novel Drug Candidate for the Treatment of Multiple Myeloma
Richard J Rickles, Laura Pierce, Thomas Giordano, William Avery, Melissa Farwell, David Crowe, Winnie F. Tam, Mei Chen,
Vikram Kansra, Douglas W. McMillin, Kenneth C Anderson, Constantine Mitsiades, and Margaret S. Lee
Abstract No.: 252
Location: 2009-2011-2022-2024 - West (Moscone Center)
Time: 8:45 AM
Pathophysiology and Translational Models
Updated Follow-up and Results of Subsequent Therapy in the Phase III VISTA Trial:
Bortezomib Plus Melphalan­Prednisone Versus Melphalan­Prednisone in Newly Diagnosed Multiple Myeloma
Jesus F San Miguel, Rudolf Schlag, Nuriet K Khuageva, Meletios A Dimopoulos, Ofer Shpilberg, Martin H Kropff, Ivan Spicka,
Maria Teresa Petrucci, Antonio Palumbo, Olga S Samoilova, Anna Dmoszynska, Kudrat M Abdulkadyrov, Rik Schots, Bin Jiang,
Maria-Victoria Mateos, Kenneth C Anderson, Dixie-Lee Esseltine, Kevin Liu, Andrew Cakana, Helgi van de Velde and Paul Richardson
Abstract No.: 650
Location: Halls B and C (Moscone Center)
Time: 3:45 PM
Myeloma Therapy: Phase III Trials
Bortezomib ( VELCADE®)-Melphalan-Prednisone ( VMP) Versus VELCADE®-Thalidomide-Prednisone ( VTP) in Elderly Untreated
Multiple Myeloma Patients: Which Is the Best Partner for VELCADE®: An Alkylating or An Immunomodulator Agent?
Maria-Victoria Mateos, Albert Oriol, Joaquín Martínez, Mª Teresa Cibeira, Raquel de Paz, Mª José Terol, José García-Laraña,
Enrique Bengoechea, Rafael Martínez, Alejandro Martin, Felipe de Arriba, Luis Palomera, José Hernández, Jose-Luis Bello,
María-Luisa Martín, Yolanda González, Joan Bladé, Juan José Lahuerta and J.F. San Miguel
Time: 4:00 PM
Location: Halls B and C (Moscone Center)
Abstract No.: 651
Myeloma Therapy: Phase III Trials
A Prospective, Randomized, Phase III Study of Bortezomib, Melphalan, Prednisone and Thalidomide ( VMPT) Versus Bortezomib,
Melphalan and Prednisone ( VMP) in Elderly Newly Diagnosed Myeloma Patients
Antonio Palumbo, Sara Bringhen, Davide Rossi, Valeria Magarotto, Francesco Di Raimondo, Roberto Ria, Massimo Offidani,
Chiara Nozzoli, Francesca Patriarca, Vincenzo Callea, Giulia Benevolo, Roberto Marasca, Tommasina Guglielmelli, Manuela Rizzo,
Mariella Grasso, Maria Teresa Petrucci, Paola Omedè, Gianluca Gaidano, and Mario Boccadoro
Time: 4:15 PM
Location: Halls B and C (Moscone Center)
Abstract No.: 652
Myeloma Therapy: Phase III Trials
First Analysis of HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Adriamycine, Dexamethasone (PAD)
Vs VAD as Induction Treatment Prior to High Dose Melphalan (HDM) in Patients with Newly Diagnosed Multiple Myeloma (MM)
P. Sonneveld, B. van der Holt, I. G.H. Schmidt-Wolf, U. Bertsch, L. el Jarari, Hans-Jürgen Salwender, S. Zweegman, E. Vellenga,
J. Schubert, I. W. Blau, GSK Jie, B. Beverloo, A. Jauch, D. Hose, R. Schaafsma, M. J. Kersten, M. Delforge, O. de Weerdt, R. van der Griend,
P. W. Wijermans, Hans Martin, H. van der Velde, Henk M. Lokhorst and H. Goldschmidt
Abstract No.: 653
Halls B and C (Moscone Center)
Time: 4:30 PM
Myeloma Therapy: Phase III Trials
Thalidomide/Dexamethasone (TD) Vs. Bortezomib( VELCADE®)/Thalidomide / Dexamethasone ( VTD) Vs. VBMCP/VBAD/VELCADE®
As Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM):
First Results of a Prospective Phase III PETHEMA/Gem Trial
Laura Rosinol, Mª Teresa Cibeira, Joaquin Martinez, Maria Victoria Mateos, Mª José Terol, Javier de la Rubia, Luis Palomera,
Felipe de Arriba, Albert Oriol, Adrian Alegre, Juan Besalduch, Raquel de Paz, José Garcia-Laraña, Joaquín Díaz-Mediavilla,
Anna Sureda, Juan José Lahuerta, J.F. San Miguel and Joan Bladé
Time: 4:45 PM
Location: Halls B and C (Moscone Center)
Abstract No.: 654
Myeloma Therapy: Phase III Trials
Improved Survival of Patients with Multiple Myeloma after the Introduction of Novel Agents and the Applicability of the
International Staging System (ISS) An Analysis of the Greek Myeloma Study Group (GMSG)
Efstathios Kastritis, Konstantinos Zervas, Argiris Symeonidis, Evangelos Terpos, Sossana Delimpassi, Nicolaos Anagnostopoulos,
Evridiki Michali, Athanasios Zomas, Irini Katodritou, Dimitra Gika, Anastasia Pouli, Dimitrios Christoulas, Maria Roussou,
Theofanis Economopoulos and Meletios A Dimopoulos
Time: 5:00 PM
Location: Halls B and C (Moscone Center)
Abstract No.: 655
Myeloma Therapy: Phase III Trials
Bortezomib ( VEL) Based Regimens in Multiple Myeloma (MM) Patients with Renal Impairment (RI):
A Preliminary Retrospective Italian Multicenter Study
Massimo Gentile, Stefania Ciolli, Maria Teresa Petrucci, Sara Galimberti, Giuseppe Mele, Antonio Francesco Casulli, Donato Mannina,
Eugenio Piro, Graziella Pinotti, Salvatore Palmieri, Lucio Catalano, Vincenzo Callea, Massimo Offidani, Pellegrino Musto, Sara Bringhen,
Luca Baldini, Patrizia Tosi, Francesco Di Raimondo, Mario Boccadoro, Antonio Palumbo, Michele Cavo, and Fortunato Morabito
Abstract No.: 3681
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-763
Myeloma ­ Therapy, Excluding Transplantation Poster III
Bortezomib-Doxorubicin-Dexamethasone (BDD) for Reversal of Acute Light Chain Induced Renal Failure (ARF) in Multiple Myeloma
(MM). Results from a Phase II Study
Heinz Ludwig, Zdenek Adam, Roman Hajek, Richard Greil, Felix Keil, Niklas Zojer, Josef Thaler, Heinz Gisslinger and Alois Lang
Abstract No.: 3682
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-764
Myeloma ­ Therapy, Excluding Transplantation Poster III
Bortezomib Plus Melphalan and Prednisone as Induction Prior to Transplant or as Frontline Therapy for Non-Transplant Candidates
in Patients with Previously Untreated Multiple Myeloma
Cristina Gasparetto, Jon P Gockerman, Louis F Diehl, Carlos de Castro III, Joseph O Moore, Gwynn D Long, Mitchell Horwitz, John Chute,
Keith M Sullivan, Rachel Neuwirth, Patricia H Davis, Linda M. Sutton, Russell D Anderson, Nelson Chao and David A. Rizzieri
Abstract No.: 3325
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-407
Clinical Results ­ Autologous Transplantation Poster III
Clinical Efficacy of VEL-CTD (Bortezomib, Cyclophosphamide, Thalidomide, and Dexamethasone) Regimen in Patients with
Relapsed or Refractory Multiple Myeloma: A Phase II Study
Yeo-Kyeoung Kim, Je-Jung Lee, Sang-Kyun Sohn, Ho-Jin Shin, Joo-Seop Chung, Young-Jin Choi, Joon-Ho Moon, Yee-Soo Chae,
Jong-Gwang Kim, Jae-Sook Ahn, Deok-Hwan Yang, Hyeoung-Joon Kim and the Korean Multiple Myeloma Working Party (KMMWP).
Time: 5:30 PM ­ 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3693
Poster Board: III-775
Myeloma ­ Therapy, Excluding Transplantation Poster III
Combination of Vorinostat Plus Bortezomib for the Treatment of Patients with Multiple Myeloma
Who Have Previously Received Bortezomib
Donna M. Weber, Sundar Jagannath, Ronald Sobecks, Gary Schiller, Lisa Chiacchierini, David Reiser, Carol Oerth,
Jose Garcia-Vargas and Syed Rizvi
Abstract No.: 3711
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-793
Myeloma ­ Therapy, Excluding Transplantation Poster III
Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Preliminary Results of a Phase 1/2 Trial
of Hydroxychloroquine and Standard Dose Bortezomib for Relapsed or Refractory Myeloma
Dan T. Vogl, Edward A. Stadtmauer, James E. Bradner, Lisa Davis, Martin Carroll, Charles W. Nichols, Doris Shank, Mary Carberry,
Cezary R. Swider, Patricia A. Mangan, Brenda K. Shelly, Craig B. Thompson and Ravi K. Amaravadi
Abstract No.: 3684
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-766
Myeloma ­ Therapy, Excluding Transplantation Poster III
Dietary Supplement Vitamin C Significantly Abrogates Bortezomib-Induced Multiple Myeloma (MM) Cell Growth Inhibition
Giulia Perrone, Teru Hideshima, Hiroshi Ikeda, Yutaka Okawa, Diana Cristea, Loredana Santo, Gullu Gorgun, Elisabetta Calabrese,
Noopur Raje, Michele Baccarani, Michele Cavo and Kenneth C. Anderson
Abstract No.: 3687
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-769
Myeloma ­ Therapy, Excluding Transplantation Poster III
Dimethylaminoparthenolide (DMAPT) in Multiple Myeloma
Colin D. Crean, Genglin Zhang, Karen E. Pollok, Anthony L. Sinn, Peter A Crooks, Sherif Farag, Rafat Abonour and
Attaya Suvannasankha
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3672
Poster Board: III-754
Myeloma ­ Pathophysiology and Preclinical Studies Excluding Therapy Poster III
Efficacy and Safety of Re-Treatment with Bortezomib ( VELCADE®) in Patients with Multiple Myeloma: Results from a Prospective
International Phase II Trial
Maria Teresa Petrucci, Igor W. Blau, Paolo Corradini, Meletios A. Dimopoulos, Johannes Drach, Pilar Giraldo, Adriana Teixeira,
and Joan Bladé
Abstract No.: 3690
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-772
Myeloma ­ Therapy, Excluding Transplantation Poster III
High Response Rates with the Combination of Bortezomib, Dexamethasone and the Pan-Histone Deacetylase Inhibitor Romidepsin
in Patients with Relapsed or Refractory Multiple Myeloma in a Phase I/II Clinical Trial
Simon James Harrison, Hang Quach, Kally Yuen, Andrew Strayer, Michael C. Copeman, S. Peinert, M. Bishton, M. Wolf, H. Januszewicz,
MK Kenealy, K. Herbert, David Westerman, D. Carney, J. F Seymour, R. W Johnstone, David Ritchie, and Miles Prince
Abstract No.: 3698
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-780
Myeloma ­ Therapy, Excluding Transplantation Poster III
Inhibition of Autophag y Promotes Bortezomib-Mediated Cell Death in Myeloma Cells
Terry H. Landowski, Aluvia M Escalante, Andrew Jefferson, Robert T Dorr and Ronald Lynch
Abstract No.: 3677
Location: Hall A (Moscone Center)
Time: 5:30 PM - 7:30 PM
Poster Board: III-759
Myeloma ­ Pathophysiology and Preclinical Studies Excluding Therapy Poster III
Initial Treatment with Bortezomib ( VELCADE®), Doxil®, and Dexamethasone ( VDD) Is Superior to Thalidomide and
Dexamethasone (TD) as Initial Therapy Prior to Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma (MM)
Andrzej Jakubowiak, Tara Kendall, Ammar Al-Zoubi, Yasser Khaled, Shin Mineishi, Christine Brozo, Erica Campagnaro,
Moshe Talpaz and Mark S. Kaminski
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3713
Poster Board: III-795
Myeloma ­ Therapy, Excluding Transplantation Poster III
Long-Term Outcomes of Autologous Transplantation in Multiple Myeloma: Benefit from the Newer Drugs Used
in the Relapsed Setting
Roman Hajek, Marta Krejci, Vlastimil Scudla, Elena Tothova, Martin Mistrik, Jaroslav Bacovsky, Miroslava Schutzova, Vladimir Koza,
Tomas Papajik, Libuse Novosadova, Hana Frankova, Yvetta Stavarova, Frantisek Lehanka, Milena Vranova, Petr Kessler, Marketa
Zemanova, Ivana Meluzinova, Nadezda Seifertova, Elen Sumna, Ludek Pour, Vladimir Maisnar and Zdenek Adam
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3331
Poster Board: III-413
Clinical Results - Autologous Transplantation Poster III
Major Shrinking of Residual Tumor Cell Burden and Achievement of Molecular Remissions in Myeloma Patients Undergoing
Post-Trasplant Consolidation with Bortezomib, Thalidomide and Dexamethasone: A Qualitative and Quantitative PCR Study
Marco Ladetto, Gloria Pagliano, Simone Ferrero, Federica Cavallo, Daniela Drandi, Michela Boi, Loredana Santo, Patrizia Pregno,
Mariella Grasso, Anna Marina Liberati, Tommaso Caravita, Francesco Pisani, Claudia Crippa, Vincenzo Callea, Antonietta Falcone,
Sergio Morandi, Mario Boccadoro, and Antonio Palumbo.
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3683
Poster Board: III-765
Myeloma ­ Therapy, Excluding Transplantation Poster III
A Phase I MMRC Clinical Trial Testing the Combination of Bortezomib and Tipifarnib in Relapsed/Refractory Multiple Myeloma
Sagar Lonial, Dixil Francis, Chatchada Karanes, Suzanne Trudel, Donna E. Reece, Amrita Krishnan, Marc Buacharern, Renee Smith,
Faraz Zaman, Engin Gul, Akari M. Dollard, Donald Harvey and Jonathan Kaufman
Abstract No.: 3706
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-788
Myeloma ­ Therapy, Excluding Transplantation Poster III
Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma
Irene M. Ghobrial, Nikhil Munshi, Robert Schlossman, Stacey Chuma, Renee Leduc, Marybeth Nelson, Amy Sam, Kelly O'Connor,
Brianna Harris, Diane Warren, Akari M. Dollard, Jacob Laubach, Ravi Vij, Erica Campagnaro, Ann Birner, Virginia Dixon-Lipscomb,
Kenneth C. Anderson and Paul G. Richardson
Abstract No.: 3696
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-778
Myeloma ­ Therapy, Excluding Transplantation Poster III
A Randomized Phase I Trial of Melphalan + Bortezomib as Conditioning for Autologous Transplant for Myeloma:
The Effect of Sequence of Administration
Sagar Lonial, Jonathan Kaufman, Claire Torre, Amelia Langston, Mary J. Lechowicz, Christopher Flowers, Stephanie McMillan,
Heather Renfroe, Leonard T Heffner and Edmund K Waller
Abstract No.: 3332
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-414
Clinical Results ­ Autologous Transplantation Poster III
A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib
in Multiple Myeloma
Muzaffar H. Qazilbash, Rima M. Saliba, Matteo Pelosini, Chitra M Hosing, Floralyn L Mendoza, Eric Han, Michael Wang,
Donna M. Weber, Amin M. Alousi, Paolo Anderlini, Partow Kebriaei, Issa F. Khouri, Uday R Popat, Marcos De Lima,
Robert Z. Orlowski, Richard E. Champlin and Sergio A. Giralt
Abstract No.: 3320
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-402
Clinical Results ­ Autologous Transplantation Poster III
Sequential Administration of Bortezomib, Liposomal Doxorubicin and Dexamethasone (BDD) Followed by Thalidomide and
Dexamethasone (TD) Results in Rapid Control of Untreated High-Risk Multiple Myeloma (MM) and Improves Depth of Response
Heather Landau, Hani Hassoun, Adam Cohen, Elizabeth Hoover, Tarun Kewalramani, Adam Boruchov, Virginia Klimek, Lillian Reich,
Elyn Riedel, Neeta Pandit-Taskar, Stephen D. Nimer, and Raymond L. Comenzo
Time: 5:30 PM ­ 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3712
Poster Board: III-794
Myeloma ­ Therapy, Excluding Transplantation Poster III
Sequential VAD ( Vincristine, Adriamycin, Dexamethasone) and VTD (Bortezomib, Thalidomide, Dexamethasone) Induction
Followed by High-Dose Therapy with Autologous Stem Cell Transplantation and Maintenance Treatment with Bortezomib
for Newly Diagnosed Multiple Myeloma: Final Analysis of Phase II Trial
Sung-Soo Yoon, Hye Jin Kim, Joo Seop Chung, HyeonSeok Eom, Jun-Ho Jang, Hye Jin Kang, Cheol Soo Kim, Kihyun Kim, Dongsoon Lee,
Jae Hoon Lee, Junglim Lee, Sang Jae Lee, Yoo Hong Min, Chu-Myong Seong, Sang-Kyun Sohn, Cheolwon Suh and Jong-Ho Won
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3330
Poster Board: III-412
Clinical Results - Autologous Transplantation Poster III
Successful Harvesting of Peripheral Hematopoietic Stem Cells after Induction Treatment with Bortezomib, Adriamycin,
Dexamethasone (PAD) in Patients with Newly Diagnosed Multiple Myeloma (MM)
Hartmut Goldschmidt, Henk M. Lokhorst, Uta Bertsch, Bronno van der Holt, Laila el Jarari, Hans-Jürgen Salwender, Sonja Zweegman,
Edo Vellenga, Jörg Schubert, Igor W. Blau, Asiong Jie, Berna Beverloo, Dirk Hose, Helgi van de Velde, Martyn Ronald Schaafsma,
Marie Jose Kersten, Michel Delforge, Okke de Weerdt, Rene Van der Griend, Pierre Wijermans, Hans Martin, Christof Scheid,
Mathias Hänel, Ingo G.H. Schmidt-Wolf and Pieter Sonneveld for the HOVON and GMMG group
Abstract No.: 3470
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30PM
Poster Board: III-552
Ex Vivo Expansion, Mobilization and Engraftment Poster II
Updated Results of a Phase I/II Trial of Autologous Peripheral Blood Progenitor Cell Transplantation
with VELCADE® Maintenance as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma
Mickey Liao, R Malone, K Bartoni, B Habtemariam, Ronald Paquette, Sven de Vos, Mary C Territo and Gary Schiller
Abstract No.: 3710
Location: Hall A (Moscone Center)
Time: 5:30 PM ­ 7:30 PM
Poster Board: III-792
Myeloma ­ Therapy, Excluding Transplantation Poster III
VAMP/ThaCyDex: VELCADE® (Bortezomib), Adriamycin, Melphalan and Prednisone Alternating with Thalidomide,
Cyclophosphamide and Dexametasone as a Salvage Regimen in Relapsed Multiple Myeloma Patients
Enrique Colado, Maria-Victoria Mateos, Maria-Jose Moreno, Felipe de Arriba, Javier de la Rubia, Juan José Lahuerta, Pastora Iniesta,
Maria Cruz Viguria, Ana Pilar Gonzalez, Ramón García-Sanz, Juan Olazabal, and Jesús F San Miguel.
Time: 5:30 PM - 7:30 PM
Location: Hall A (Moscone Center)
Abstract No.: 3694
Poster Board: III-776
Myeloma ­ Therapy, Excluding Transplantation Poster III
Changes in the Expression of Proteasome Genes in Tumor Cells Following Short-Term Proteasome Inhibitor Therapy
Predicts Survival in Multiple Myeloma Treated with Bortezomib-Containing Multi-Agent Chemotherapy
John D. Shaughnessy Jr., Pingping Qu, Ricky Edmondson, Damir Herman, Yiming Zhou, Erming Tian, Frits van Rhee,
Mauricio Pineda-Roman, Yazan Alsayed, Elias Anaissie, Ya-wei Qiang, Joshua Epstein, Shmuel Yaccoby, David Williams,
Fenghuang Zhan, Owen Stephens, Antje Hoering, John Crowley, and Bart Barlogie
Abstract No.: 733
Location: 2005-2007-2018-2020 - West (Moscone Center)
Time: 6:00 PM
Molecular Targets and Biomarkers in Myeloma
Tuesday, December 9, 2008
Preliminary Results of CNTO 328, An Anti-Interleukin-6 Monoclonal Antibody, in Combination with Bortezomib in the Treatment of
Relapsed or Refractory Multiple Myeloma
Jean-François Rossi, Robert F. Manges, Heather J. Sutherland, Sundar Jagannath, Peter Voorhees, Pieter Sonneveld, Michel Delforge, Brigitte
Pegourie, Adrian Alegre, Javier de la Rubia, David La Police, Rajesh Bandekar, Hong Xie, and Robert Z. Orlowski
Abstract No.: 867
Location: Gateway Ballroom 103 - South (Moscone Center)
Time: 7:45 AM
Novel Therapies for Myeloma and Related Disorders
Significant Activity of Bortezomib-Based Therapy in Patients with Primary Systemic (AL) Amyloidosis
Efstathios Kastritis, Ashutosh D Wechalekar, Meletios A. Dimopoulos, Giampaolo Merlini, Philip N Hawkins, Vittorio Perfetti,
Julian D Gillmore and Giovanni Palladini
Abstract No.: 869
Location: Gateway Ballroom 103 - South (Moscone Center)
Time: 8:15 AM
Novel Therapies for Myeloma and Related Disorders
Bortezomib Induces Osteoblast Differentiation Via Wnt-Independent Activation of Beta-catenin/TCF Signaling
Ya-wei Qiang, Bo Hu, Yu Chen, Ying Zhong, Bart Barlogie and John D. Shaughnessy Jr.
Abstract No.: 846
Location: 2005-2007-2018-2020 - West (Moscone Center)
Time: 8:30 AM
Molecular Pathology of Myeloma
Phase I/II Results of a Multicenter Trial of Perifosine (KRX-0401) + Bortezomib in Patients with Relapsed or Relapsed / Refractory
Multiple Myeloma Who Were Previously Relapsed from or Refractory to Bortezomib
Paul Richardson, Jeffrey Wolf, Andrzej Jakubowiak, Jeffrey Zonder, Sagar Lonial, David H Irwin, John Densmore, Amrita Krishnan,
Noopur Raje, Michael H. Bar, Jeffrey P. Allerton, Robert Schlossman, Irene M. Ghobrial, Nikhil C. Munshi, Thomas Martin, Jacob Laubach,
Kathy Colson, Sarah Dean, Deanna Tocco, Elizabeth Steinfield, Tara Kendall, Kimberly O'Riley, Teru Hideshima, Peter Sportelli,
Lesa Gardner, and Kenneth C. Anderson
Abstract No.: 870
Location: Gateway Ballroom 103 - South (Moscone Center)
Time: 8:30 AM
Novel Therapies for Myeloma and Related Disorders
Vorinostat Plus Bortezomib for the Treatment of Relapsed/Refractory Multiple Myeloma: Early Clinical Experience
Donna Weber, Ashraf Z. Badros, Sundar Jagannath, David Siegel, Victoria Richon, Syed Rizvi, Jose Garcia-Vargas,
David Reiser and Kenneth C. Anderson
Abstract No.: 871
Location: Gateway Ballroom 103 - South (Moscone Center)
Time: 8:45 AM
Novel Therapies for Myeloma and Related Disorders
VELCADE® Publications ­ 4th Quarter, 2008
NBlockage of interleukin-6 signaling with 6-amino-4-quinazoline synergistically induces the inhibitory effect
of bortezomib in human U266 cells.
Park J, Ahn KS, Bae EK, Kim BS, Kim BK, Lee YY, Yoon SS.
Anticancer Drugs. 2008 Sep;19(8):777-82.
:
http://www.ncbi.nlm.nih.gov/pubmed/18690088?ordinalpos=54&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors find that combined treatment with bortezomib and 6-amino-4-quinazoline effectively inhibits the IL-6 and soluble IL-6R-
induced activation of STAT3 and extracellular signal-regulated kinase phosphorylation.
The transcription factor nuclear factor-kappa B (NF-kappaB) regulates the transcription of a number of genes involved in a variety
of cellular responses, including cell survival, inflammation, and differentiation. NF-kappaB is activated by a variety of stimuli,
proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. Aberrant NF-kappaB expression is considered to be
one of the oncogenic factors of cancer and the constitutive activation of NF-kappaB is observed in several hematologic disorders [classic
Hodgkin's lymphoma, diffuse large B cell lymphoma, and multiple myeloma (MM)], and the modulation of NF-kappaB activation
is emerging as a promising novel anticancer therapeutic strategy.Therefore, we focused on the regulation of NF-kappaB activation in
MM. When U266 cells were treated with 6-amino-4-quinazoline, an NF-kappaB activation inhibitor, we determined that it most
effectively blocked the interleukin (IL)-6-induced activation of MAPK and JAK/STAT pathways among different signaling inhibitors.
The results of the luciferase assay indicated that 6-amino-4-quinazoline inhibited NF-kappaB activation with diminished NF-kappaB
protein bound to NF-kappaB DNA binding sites. In addition, 6-amino-4-quinazoline suppressed the production of IL-6, which
affected MM cell proliferation. Furthermore, combined treatment with bortezomib and 6-amino-4-quinazoline effectively inhibited the
IL-6 and soluble IL-6R-induced activation of STAT3 and extracellular signal-regulated kinase phosphorylation. Our data showed that
the inhibition of NF-kappaB activation abrogated MM cell proliferation induced by the IL-6 pathway, and might represent a promising
therapeutic strategy for the treatment of MM.
NThe relationship between quality of response and clinical benefit for patients treated on the bortezomib arm
of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma.
Niesvizky R, Richardson PG, Rajkumar SV, Coleman M, Rosiñol L, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T,
Harousseau JL, Boral AL, Esseltine DL, Anderson KC, Bladé J.
Br J Haematol. 2008 Sep;143(1):46-53. [Epub 2008 Jul 31.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18673366?ordinalpos=56&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus
dexamethasone in relapsed myeloma assesses the relationship between quality of response to bortezomib and clinical benefit. The
authors conclude that bortezomib has substantial activity in relapsed myeloma patients and that complete response may be a surrogate
marker for significant clinical benefit with bortezomib.
Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study
within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone
in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free
interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in
the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n =
31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n =
159). CR was associated with significantly longer median TFI (24.1 vs. 6.9/6.4 months) and TTAT (27.1 vs. 13.6/14 months) versus
VGPR/PR. Median TTP was similar in CR, VGPR and PR cohorts; median OS was not reached. Patients achieving MR appeared
to have prolonged median TFI (3.8 vs. 2.3 months), TTAT (8.7 vs. 6.2 months), TTP (4.9 vs. 2.8 months) and OS (24.9 vs. 18.7
months) versus NR. In conclusion, bortezomib had substantial activity in relapsed myeloma patients; CR may be a surrogate marker
for significant clinical benefit with bortezomib. MR appeared to be valid as a separate response category in this setting.
NThe role of novel drugs in multiple myeloma.
Dimopoulos MA, Kastritis E.
Ann Oncol. 2008 Sep;19 Suppl 7:vii121-7.
:
http://www.ncbi.nlm.nih.gov/pubmed/18790953?ordinalpos=46&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
www.myeloma.org
(800) 452 - CURE (2873)
NSynergistic anti-proliferative and pro-apoptotic activity of combined therapy with bortezomib,
a proteasome inhibitor, with anti-epidermal growth factor receptor (EGFR) drugs in human cancer cells.
Cascone T, Morelli MP, Morgillo F, Kim WY, Rodolico G, Pepe S, Tortora G, Berrino L, Lee HY, Heymach JV, Ciardiello F.
J Cell Physiol. 2008 Sep;216(3):698-707.
:
http://www.ncbi.nlm.nih.gov/pubmed/18381602?ordinalpos=67&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors find that the combined treatment with bortezomib and The epidermal growth factor receptor (EGFR) inhibitors has a
synergistic growth inhibitory and pro-apoptotic activity in different human cancer cells which possess a functional EGFR-dependent
autocrine growth pathway through to a more efficient and sustained inhibition of Akt.
The proteasome plays a pivotal role in the turnover of regulatory transduction proteins induced by activated cell membrane growth
factor receptors. The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human
epithelial cancers. Proteasome inhibition may sensitize human cancer cell lines to EGFR inhibitors. We investigated the growth
inhibitory and pro-apoptotic effects of the proteasome inhibitor bortezomib in combination with anti-EGFR drugs, such as gefitinib,
vandetanib, and cetuximab in EGFR-expressing human cancer cell lines. Bortezomib determined dose-dependent growth inhibition
in a nine cancer cell line panel (IC(50) values, range 6-42 nM). A significant synergistic growth inhibitory effect was observed with
the combination of bortezomib and each EGFR inhibitor in all cell lines (combination index, CI, range 0.10-0.55), which was
accompanied by a significant induction in apoptosis by the combined treatment with bortezomib, cetuximab and vandetanib. In HCT-
116 colon cancer and A549 lung adenocarcinoma cells, bortezomib plus EGFR inhibitor treatment induced a more effective inhibition
of EGFR-activated down-stream signals, including a marked suppression in activated, phosphorylated Akt (P-Akt). In contrast,
overexpression of a constitutively active P-Akt protected A549 cells by cell growth inhibition and apoptosis following treatment with
bortezomib and EGFR inhibitors. The combined treatment with bortezomib and EGFR inhibitors has a synergistic growth inhibitory
and pro-apoptotic activity in different human cancer cells which possess a functional EGFR-dependent autocrine growth pathway
through to a more efficient and sustained inhibition of Akt. Erratum in: J Cell Physiol. 2008 Oct;217(1):290. Tortora, Giampaolo
[added].
NUpdate on recent developments for patients with newly diagnosed multiple myeloma.
Palumbo A, Magarotto V, Gay F, Falco P, Bringhen S, Boccadoro M.
Ann N Y Acad Sci. 2008 Sep;1138:19-21.
:
http://www.ncbi.nlm.nih.gov/pubmed/18837878?ordinalpos=52&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors discuss the use of bortezomib as a new standard of care in elderly patients with myeloma.
Recent studies have demonstrated that novel therapeutic combinations are challenging melphalan and prednisone (MP) as the standard
of care in elderly patients with multiple myeloma. Combination regimens containing bortezomib or thalidomide can achieve response
rates, especially complete response rates, which are superior to those seen with standard MP alone, and offer new possibilities for this
patient population.
NBortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature.
Argyriou AA, Iconomou G, Kalofonos HP.
Blood. 2008 Sep 1;112(5):1593-9. [Epub 2008 Jun 23.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18574024?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This review looks critically at the pathogenesis, incidence, risk factors, diagnosis, characteristics, and management of bortezomib-
induced peripheral neuropathy, and highlights areas for future research.
Bortezomib has demonstrated significant activity in clinical trials, mainly against recurrent or newly diagnosed multiple myeloma
(MM). Peripheral neuropathy is a significant toxicity of bortezomib, requiring dose modification and potential changes in the
treatment plan when it occurs. The mechanism underlying bortezomib-induced peripheral neuropathy (BIPN) is unknown. Metabolic
changes resulting from the accumulation of bortezomib in the dorsal root ganglia cells, mitochondrial-mediated disregulation of Ca(++)
homeostasis, and disregulation of neurotrophins may contribute to the pathogenesis of BIPN. It is increasingly recognized that BIPN
may be a proteasome inhibitor class effect, producing primarily a small fiber and painful, axonal, sensory distal neuropathy. Incidence
of BIPN is mainly related to various risk factors, including cumulative dose and evidence of preexisting neuropathy. Assessment
of BIPN is based primarily on neurologic clinical examination and neurophysiologic methods. To date, apart from the use of dose
reduction and schedule change algorithm, there is no effective treatment with neuroprotective agents for BIPN. Analgesics, tricyclic
antidepressants, anticonvulsants, and vitamin supplements have been used as symptomatic treatment against bortezomib-associated
neuropathic pain with some success. This review looks critically at the pathogenesis, incidence, risk factors, diagnosis, characteristics,
and management of BIPN, and highlights areas for future research.
www.myeloma.org
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NInfiltration of the spinal cord in a patient with multiple myeloma.
Varettoni M, Corso A, Zappasodi P, Calliada F, Castagnola C, Mangiacavalli S, Lazzarino M.
J Clin Oncol. 2008 Sep 1;26(25):4207-9.
:
http://www.ncbi.nlm.nih.gov/pubmed/18757337?ordinalpos=68&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
NComplete remission of psoriasis after autologous hematopoietic stem-cell transplantation for multiple
myeloma.
Braiteh F, Hymes SR, Giralt SA, Jones R.
J Clin Oncol. 2008 Sep 20;26(27):4511-3.
:
http://www.ncbi.nlm.nih.gov/pubmed/18802165?ordinalpos=38&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
NBortezomib in combination with dexamethasone for a young multiple myeloma with t(8; 14).
Li JY, Wang LX, Shen WY, Lu SF, Chen LJ, Lu H.
Leuk Res. 2008 Sep 29. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18829108?ordinalpos=31&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors report a case of a 23-year-old male with myeloma who is treated with a conditioning regimen of melphalan and bortezomib
before a successful autologous peripheral hematopoietic stem cell transplantation.
Multiple myeloma (MM) is an age-related disorder usually occurring in older patients. Now, we report a case of a 23-year-old male
suffering from this disease. The patient was admitted on account of pain in the left arm and a later fracture. Interphase fluorescence
in situ hybridization (FISH) revealed the existence of t(8; 14) (q24; q32). Bortezomib in combination with dexamethasone was
administered as the primary treatment and a complete response was achieved after five cycles of therapy. The conditioning regimen
consisted of melphalan and bortezomib and the following autologous peripheral hematopoietic stem cell transplantation was successful.
NConsolidation Therapy with Bortezomib/Lenalidomide/ Dexamethasone Versus Bortezomib/Dexamethasone
After a Dexamethasone-Based Induction Regimen in Patients with Multiple Myeloma: A Randomized
Phase III Trial.
Fonseca R, Rajkumar SV.
Clin Lymphoma Myeloma. 2008 Oct;8(5):315-7.
:
http://www.ncbi.nlm.nih.gov/pubmed/18854289?ordinalpos=37&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors introduce an upcoming clinical trial that will study the potential role of bortezomib and dexamethasone ( VD) or VD plus
lenalidomide as primary first-line therapy in the treatment of myeloma.
In recent years, we have seen tremendous progress in our ability to achieve durable responses in patients with multiple myeloma. At
the center of this progress, we have the development of 2 unrelated classes of drugs: proteasome inhibitors such as bortezomib and
immunomodulatory drugs such as thalidomide and lenalidomide. The depth and durability of responses attained with these agents in
the first-line setting has raised the possibility that they may be considered primary therapy. The Eastern Cooperative Oncology Group
E1A05 clinical trial addresses the potential role of bortezomib and dexamethasone (VD) or VD plus lenalidomide (VRD) as primary
first-line therapy. This clinical trial enrolls patients who have completed a dexamethasone-based induction (excluding patients using
bortezomib). Assuming that most patients entering this clinical trial have been previously treated with thalidomide or lenalidomide, the
trial will test whether switching to a proteasome inhibitor (VD arm) versus adding a proteasome inhibitor (VRD) results in superior
longterm disease control. Patients entering this clinical trial will have deferred stem cell transplantation until the time of relapse. The
primary endpoint of the trial is progression-free survival. By using an alkylator-free consolidation and reserving stem cell transplantation
until the time of relapse, we hope that these treatment strategies will further prolong the survival of patients with myeloma.
www.myeloma.org
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NHomoharringtonine inhibits the AKT pathway and induces in vitro and in vivo cytotoxicity in human
multiple myeloma cells.
Meng H, Yang C, Jin J, Zhou Y, Qian W.
Leuk Lymphoma. 2008 Oct;49(10):1954-62.
:
http://www.ncbi.nlm.nih.gov/pubmed/18949618?ordinalpos=51&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This study demonstrates that homoharringtonine (HHT), an antileukemic drug first isolated from the Chinese evergreen Cephalotaxus
harringtonia, induces significant cytotoxicity in dexamethasone-sensitive and -resistant and chemotherapy-sensitive multiple myeloma
cell lines in a time and dose-dependent manner. The authors also find an additive antitumor effect in the myeloma cells treated with
HHT and bortezomib concomitantly.
Involvement of phosphatidylinositol 3-kinase/Akt-1 in cell survival and proliferation of multiple myeloma (MM) has been well
established. In this study, we demonstrate that homoharringtonine (HHT), an antileukemic drug first isolated from the Chinese
evergreen Cephalotaxus harringtonia, induces significant cytotoxicity in dexamethasone-sensitive and -resistant and chemotherapy-
sensitive MM cell lines in a time and dose-dependent manner. HHT also triggers apoptosis in chemotherapy-resistant patient's
myeloma cells. Contrary to dexamethasone, the cytotoxicity of HHT on myeloma is independent of interleukin-6. The mechanism of
HHT cytotoxicity is related to down-regulation of Akt phosphorylation/activation and various target genes of Akt including nuclear
factor kappa B, XIAP, cIAP and cyclin D1. Moreover, in vivo antitumor activity of HHT is demonstrated in RPMI8226 myeloma
xenograft model. Importantly, an additive effect of antitumor is confirmed in the myeloma cells treated with HHT and bortezomib
concomitantly with inhibition of phosphorylated Akt. Together, these findings obtained with HHT should give useful insights into a
novel antimyeloma chemotherapy.
NLenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma.
Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C, Chauhan D, Okawa Y, Munshi NC, Richardson PG, Anderson KC.
Leukemia. 2008 Oct;22(10):1925-32. [Epub 2008 Jul 3.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18596740?ordinalpos=21&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors investigate the effect of lenalidomide on osteoclast (OCL) formation and osteoclastogenesis in comparison with bortezomib
and conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the myeloma-OCL- bone
marrow stromal cells activation loop in osteolytic bone disease.
Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast
function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib
has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis
in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and
bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL)
secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of
lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore,
downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant
decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-
inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL,
as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both
agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic
bone disease.
www.myeloma.org
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NRole of thalidomide in previously untreated patients with multiple myeloma.
Musto P, D'Auria F, Pietrantuono G, Bringhen S, Morabito F, Di Raimondo F, Pozzi S, Sacchi S, Boccadoro M, Palumbo A;
Gruppo Italiano Malatte Ematologiche dell'Adulto Multiple Myeloma Working Party; Italian Myeloma Network and Gruppo Italiano
Studio Linfomi.
Expert Rev Anticancer Ther. 2008 Oct;8(10):1569-80.
:
http://www.ncbi.nlm.nih.gov/pubmed/18925849?ordinalpos=43&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors report and discuss the clinical results achieved with thalidomide, including in combination with bortezomib, in previously
untreated myeloma patients.
Thalidomide represents one of the most relevant therapeutic advances for patients with multiple myeloma over the last 10 years.
Despite some toxicities, it has demonstrated significant efficacy in elderly patients, as well as in the setting of younger subjects receiving
autologous stem cell transplantation. Here, we report and discuss the clinical results achieved with thalidomide alone or in combination
with dexamethasone or other drugs, such as melphalan, cyclophosphamide, doxorubicin and bortezomib, in previously untreated
myeloma patients.
NTreatment for multiple myeloma: current status and future strategy in Japan. [Article in Japanese]
Iida S.
Rinsho Ketsueki. 2008 Oct;49(10):1368-73.
:
http://www.ncbi.nlm.nih.gov/pubmed/18833921?ordinalpos=50&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
NTriptolide overcomes dexamethasone resistance and enhanced PS-341-induced apoptosis via PI3k/Akt/
NF-kappaB pathways in human multiple myeloma cells.
Yang M, Huang J, Pan HZ, Jin J.
Int J Mol Med. 2008 Oct;22(4):489-96.
:
http://www.ncbi.nlm.nih.gov/pubmed/18813856?ordinalpos=47&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors find that triptolide is able to enhance the activities of bortezomib in multiple myeloma cell lines.
Human multiple myeloma is a presently incurable hematological malignancy and novel biologically based therapies are urgently needed.
Triptolide (TPL) is a purified diterpenod isolated from the Chinese herb, Tripterygium wilfordii Hook. F that has shown antitumor
activities in various cancer cell types. But its activity in Dex-resistant multiple myeloma cell lines and the main upstream signaling
pathway has not been reported. Here we show that TPL induces apoptosis in dexamethasone-sensitive (MM.1S) and dexamethasone-
resistant (MM.1R) cells, most importantly its main upstream signaling pathway is through the PI3k/Akt/NF-kappaB pathway and is
also associated with MAPK pathway, via mitochondrial apoptotic signaling and is also associated with the caspase and Bcl-2 family
members. Moreover, TPL was able to enhance the activities of dexamethasone or bortezomib/PS-341 in multiple myeloma cell lines.
Collectively, these findings provide the framework for a clinical evaluation of TPL, either alone or in combination with dexamethasone
or bortezomib/PS-341, to overcome drug resistance and improve outcome for patients with this universally fatal hematological
malignancy.
www.myeloma.org
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NMultiple myeloma: diagnosis and treatment.
Nau KC, Lewis WD.
Am Fam Physician. 2008 Oct 1;78(7):853-9.
:
http://www.ncbi.nlm.nih.gov/pubmed/18841734?ordinalpos=32&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors provide an overview of myeloma and its treatment, including discussion of bortezomib.
Multiple myeloma, the most common bone malignancy, is occurring with increasing frequency in older persons. Typical symptoms
are bone pain, malaise, anemia, renal insufficiency, and hypercalcemia. Incidental discovery on comprehensive laboratory panels is
common. The disease is diagnosed with serum or urine protein electrophoresis or immunofixation and bone marrow aspirate analysis.
Skeletal radiographs are important in staging multiple myeloma and revealing lytic lesions, vertebral compression fractures, and
osteoporosis. Magnetic resonance imaging and positron emission tomography or computed tomography are emerging as useful tools
in the evaluation of patients with myeloma; magnetic resonance imaging is preferred for evaluating acute spinal compression. Nuclear
bone scans and dual energy x-ray absorptiometry have no role in the diagnosis and staging of myeloma. The differential diagnosis of
monoclonal gammopathies includes monoclonal gammopathy of uncertain significance, smoldering (asymptomatic) and symptomatic
multiple myeloma, amyloidosis, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, and rare plasma cell leukemia
and heavy chain diseases. Patients with monoclonal gammopathy of uncertain significance or smoldering multiple myeloma should
be followed closely, but not treated. Symptomatic multiple myeloma is treated with chemotherapy followed by autologous stem
cell transplantation, if possible. Melphalan, prednisolone, dexamethasone, vincristine, doxorubicin, bortezomib, and thalidomide
and its analogue lenalidomide have been used successfully. It is important that family physicians recognize and appropriately treat
multiple myeloma complications. Bone pain is treated with opiates, bisphosphonates, radiotherapy, vertebroplasty, or kyphoplasty;
nephrotoxic nonsteroidal anti-inflammatory drugs should be avoided. Hypercalcemia is treated with isotonic saline infusions, steroids,
furosemide, or bisphosphonates. Because of susceptibility to infections, patients require broad-spectrum antibiotics for febrile illness
and immunization against influenza, pneumococcus, and Haemophilus influenzae B. Five-year survival rates approach 33 percent, and
the median survival rate is 33 months.
NBortezomib-induced neurogenic bladder in patients with multiple myeloma.
Shimura K, Shimazaki C, Taniguchi K, Inaba T, Horiike S, Taniwaki M.
Ann Hematol. 2008 Oct 4. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18836719?ordinalpos=33&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
NDrug-induced hypersensitivity syndrome after bortezomib treatment for refractory multiple myeloma.
Hattori N, Adachi D, Nakashima H, Saito B, Nakamaki T, Tomoyasu S.
Leuk Res. 2008 Oct 4. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18838167?ordinalpos=34&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
NA striking response to bortezomib in a patient with pleural localization of multiple myeloma.
Mangiacavalli S, Varettoni M, Zappasodi P, Pica G, Lazzarino M, Corso A.
Leuk Res. 2008 Oct 6. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18842298?ordinalpos=32&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
www.myeloma.org
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NBone marrow microenvironment and the identification of new targets for myeloma therapy.
Podar K, Chauhan D, Anderson KC.
Leukemia. 2008 Oct 9. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18843284?ordinalpos=24&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors discuss new agents, including bortezomib, which mediate myeloma tumor cytotoxicity in the bone marrow milieu.
The development of multiple myeloma (MM) is a complex multi-step process involving both early and late genetic changes in the
tumor cell as well as selective supportive conditions by the bone marrow (BM) microenvironment. Indeed, it is now well established
that MM cell-induced disruption of the BM homeostasis between the highly organized cellular and extracellular compartments
supports MM cell proliferation, survival, migration and drug resistance through activation of various signaling (for example, PI3K/Akt,
JAK/Stat-, Raf/MEK/MAPK-, NFkappaB- and Wnt-) pathways. Based on our enhanced understanding of the functional importance
of the MM BM microenvironment and its inter-relation with the MM cell resulting in homing, seeding, proliferation and survival,
new molecular targets have been identified and derived treatment regimens in MM have already changed fundamentally during recent
years. These agents include thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib,
which mediate tumor cytotoxicity in the BM milieu. Ongoing studies are further delineating MM pathogenesis in the BM to enhance
cytotoxicity, avoid drug resistance and improve patient outcome.
NAnalysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study.
Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H,
Reece D, Neuwirth R, Anderson KC, Richardson PG.
J Clin Oncol. 2008 Oct 10;26(29):4784-90. [Epub 2008 Aug 18.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18711175?ordinalpos=29&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The study aims to determine if bortezomib treatment is associated with increased incidence of varicella-zoster virus ( VZV) reactivation
in patients with relapsed multiple myeloma and concludes that though further studies are needed, for patients treated with bortezomib
or bortezomib-containing regimens, the risk of VZV reactivation should be monitored and routine use of antiviral prophylaxis
considered.
PURPOSE: The aim of this subset analysis was to determine if bortezomib treatment is associated with increased incidence of varicella-
zoster virus (VZV) reactivation in patients with relapsed multiple myeloma (MM). PATIENTS AND METHODS: Incidence of
herpes zoster was evaluated in 663 patients with relapsed MM from the phase III APEX trial comparing single-agent bortezomib with
high-dose dexamethasone. RESULTS: Bortezomib was associated with a significantly higher incidence of herpes zoster compared with
dexamethasone treatment (13%, 42 of 331 v 5%, 15 of 332; P = .0002). Most herpes zoster infections were grade 1/2; incidences of
grade 3/4 events (1.8% v 1.5%) and infections considered serious adverse events (1.5% v 0.9%) were similar between treatment arms,
and no herpes zoster-related deaths occurred. Neither the time to onset of the herpes event nor the patients' absolute lymphocyte
counts at baseline differed significantly between arms. VZV reactivation was the only herpes viral event noted to be significantly
elevated in the bortezomib treatment group compared with the dexamethasone treatment group (P = .0002). The incidence of non-
VZV-related herpes viral infections was comparable between arms. No additional risk factors for herpes zoster reactivation were
identified. CONCLUSION: Further studies are needed to explain these observations and their implications; however, for patients
treated with bortezomib or bortezomib-containing regimens, the risk of VZV reactivation should be monitored and routine use of
antiviral prophylaxis considered.
www.myeloma.org
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NPhase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory
multiple myeloma.
Reece DE, Rodriguez GP, Chen C, Trudel S, Kukreti V, Mikhael J, Pantoja M, Xu W, Stewart AK.
J Clin Oncol. 2008 Oct 10;26(29):4777-83. [Epub 2008 Jul 21.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18645194?ordinalpos=30&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors seek to improve the efficacy of the combination of oral weekly cyclophosphamide and alternate day prednisone in relapsed/
refractory myeloma by adding bortezomib to the regimen. They find that weekly bortezomib 1.5 mg/m(2) plus oral cyclophosphamide
and prednisone produces an unprecedented response rate and encouraging 1-year survival in relapsed/refractory patients with myeloma
and conclude that further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease.
PURPOSE: The combination of oral weekly cyclophosphamide and alternate day prednisone is a convenient regimen for relapsed/
refractory multiple myeloma (MM), and we sought to improve its efficacy by adding bortezomib, a proteasome inhibitor with proven
antimyeloma activity. PATIENTS AND METHODS: We conducted a phase I-II trial evaluating six dose levels to define the maximum
tolerated dose (MTD) of this combination in relapsed/refractory MM. An additional 10 patients were evaluated at the highest dose
level reached. RESULTS: Thirty-seven patients were treated on this study. The MTD was not defined. Both of the highest dose levels
of bortezomib tested (1.3 mg/m(2) on days 1, 4, 8, and 11 and 1.5 mg/m(2) on days 1, 8, and 15, each on a 28-day cycle) could be
safely given with cyclophosphamide 300 mg/m(2) per week and prednisone. At these dose levels, the overall response rate was 95%
(complete responses [CR] plus partial response plus minimal response), with CR observed in more than 50% of patients. The weekly
bortezomib regimen resulted in fewer instances of grade 3 thrombocytopenia and grade 1 to 2 peripheral neuropathy; the 1-year
progression-free and overall survival probabilities with this dose level were 83% (95% CI, 73% to 96%) and 100%, respectively.
CONCLUSION: Weekly bortezomib 1.5 mg/m(2) plus oral cyclophosphamide and prednisone produces an unprecedented response
rate and encouraging 1-year survival in relapsed/refractory patients with MM. Further evaluation of this promising regimen is
warranted both in relapsed and newly diagnosed disease.
NBortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in
multiple myeloma.
Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, Nobuyoshi M, Oh I, Sato K, Suzuki T, Ozaki K, Mori M, Nagai T,
Muroi K, Kano Y, Furukawa Y, Ozawa K.
Oncogene. 2008 Oct 13. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18850009?ordinalpos=27&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors perform functional screening using short hairpin RNA (shRNA) to define the molecule(s) responsible for CAM-DR of
myeloma. They find that bortezomib is relatively resistant to CAM-DR because of its ability to specifically downregulate CD49d
expression and that the combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of
myeloma.
Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we
performed functional screening using short hairpin RNA (shRNA) to define the molecule(s) responsible for CAM-DR of MM. Using
four bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226 and U266) and primary myeloma cells, we identified CD29
(beta1-integrin), CD44, CD49d (alpha4-integrin, a subunit of VLA-4), CD54 (intercellular adhesion molecule-1 (ICAM-1)), CD138
(syndecan-1) and CD184 (CXC chemokine receptor-4 (CXCR4)) as major adhesion molecules expressed on MM. shRNA-mediated
knockdown of CD49d but not CD44, CD54, CD138 and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib,
vincristine, doxorubicin and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was
relatively resistant to CAM-DR because of its ability to specifically downregulate CD49d expression. This property was unique to
bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of
myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The
combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.
www.myeloma.org
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NAdvances in therapy of multiple myeloma.
Bladé J, Rosiñol L.
Curr Opin Oncol. 2008 Nov;20(6):697-704.
:
http://www.ncbi.nlm.nih.gov/pubmed/18841053?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This article summarizes the results of treatment of multiple myeloma in the era of novel agents, including the combination of
bortezomib with melphalan-prednisone or with dexamethasone as highly effective regimens for patients not eligible for high-dose
therapy/stem cell transplantation.
PURPOSE OF REVIEW: To summarize the results of treatment of multiple myeloma in the era of novel agents. RECENT
FINDINGS: Recent publications comparing autologous stem cell transplantation (ASCT) with conventional chemotherapy in the era
of `old' drugs have shown that the contribution of ASCT in the treatment of multiple myeloma has been modest. Five trials comparing
single vs. double ASCT showed an increased progression-free survival in three of them, whereas the overall survival was significantly
prolonged in one. The benefit would be only for patients failing to achieve very good partial response with the first transplant. The
results of allogeneic transplantation with reduced-intensity conditioning, particularly after debulking with an ASCT, are encouraging.
On the contrary, the impact of pretransplant induction regimens with novel agents (thalidomide, bortezomib and lenalidomide) on
the posttransplant outcome is being investigated in several large phase III trials. For elderly patients, the combination of `old' therapies
with thalidomide, bortezomib or lenalidomide has resulted in the melphalan-prednisone-thalidomide, melphalan-prednisone-Velcade,
melphalan-prednisone-Revlimid and lenalidomide/dexamethasone regimens, which are highly effective. SUMMARY: ASCT has
resulted in a modest contribution in the treatment of multiple myeloma. Hopefully, its impact will be increased with the incorporation
of novel agents in the pretransplant induction regimens. The combination of thalidomide, bortezomib or lenalidomide with melphalan-
prednisone or with dexamethasone has resulted in highly effective regimens for patients not eligible for high-dose therapy/stem cell
transplantation.
NArsenic trioxide and 2-methoxyestradiol reduce beta-catenin accumulation after proteasome inhibition and
enhance the sensitivity of myeloma cells to Bortezomib.
Zhou L, Hou J, Fu W, Wang D, Yuan Z, Jiang H.
Leuk Res. 2008 Nov;32(11):1674-83. [Epub 2008 May 15.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18485479?ordinalpos=16&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This study shows that beta-catenin protein levels are negatively associated with myeloma cells' sensitivity to bortezomib. As(2)
O(3)/2ME2 can reduce cytoplasmic beta-catenin accumulation after proteasome inhibition and enhance myeloma cells' sensitivity to
bortezomib. This finding can preliminarily help to optimize the new therapeutic regimens for myeloma treatment in the future.
Beta-catenin, the key protein in canonical Wingless/int (Wnt) pathway, degrades via ubiquitin-proteasome pathway. Recently, it proved
important roles in the proliferation of myeloma cells. But little is known about whether cytoplasmic beta-catenin content is associated
with myeloma cell's sensitivity to Bortezomib. We examined the constitutive expression of beta-catenin in five myeloma cell lines and
primary cells from patients. Meanwhile, the effect of Bortezomib combined with arsenic trioxide (As(2)O(3))/2-methoxyestradiol
(2ME2) on beta-catenin accumulation, myeloma cells' survival, apoptosis and their sensitivity to Bortezomib were also investigated.
Our study proved that beta-catenin protein levels are negatively associated with myeloma cells' sensitivity to Bortezomib. As(2)
O(3)/2ME2 can reduce cytoplasmic beta-catenin accumulation after proteasome inhibition and enhance myeloma cells' sensitivity to
Bortezomib. This will preliminarily help to optimize the new therapeutic regimens for MM treatment in the future.
NBortezomib directly inhibits osteoclast function in multiple myeloma: implications into the management
of myeloma bone disease.
Terpos E.
Leuk Res. 2008 Nov;32(11):1646-7. [Epub 2008 Jul 9.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18614229?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
Comment on: Leuk Res. 2008 Nov;32(11):1661-8.
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NFrontline treatment of multiple myeloma in elderly patients.
Moreau P, Hulin C, Facon T.
Blood Rev. 2008 Nov;22(6):303-9. [Epub 2008 Jun 11.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18550234?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors discuss highly active new treatment options available to treat elderly patients with myeloma, including melphalan and
prednisone in combination with bortezomib.
Until 2007, frontline chemotherapy with melphalan and prednisone (MP) was considered as the standard of care in the treatment
of elderly patients with multiple myeloma (MM). Recently, several prospective randomized studies comparing MP with the same
combination plus new agents such as thalidomide (MPT) or bortezomib (MPV) clearly showed that MPT and MPV were superior to
MP in terms of progression-free and overall survival. Melphalan-prednisone-lenalidomide (MPR) is currently compared to MP in one
prospective trial and will also probably be superior to MP. Lenalidomide plus low-dose dexamethasone is a promising combination.
Thus, at least four highly active new treatment options are now available to treat elderly patients with MM. The goal of future trials
will be to determine the best treatment strategy in this group of patients.
NImmune-mediated neuropathies in myeloma patients treated with bortezomib.
Ravaglia S, Corso A, Piccolo G, Lozza A, Alfonsi E, Mangiacavalli S, Varettoni M, Zappasodi P, Moglia A, Lazzarino M, Costa A.
Clin Neurophysiol. 2008 Nov;119(11):2507-12. [Epub 2008 Oct 1.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18829381?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors report a series of patients treated with bortezomib who develop a peripheral damage possibly related to immuno-mediated,
rather than toxic, mechanisms. They conclude that, in some instances, the peripheral damage associated with bortezomib may recognize
immuno-mediated mechanisms and that this form of bortezomib-associated neuropathy needs to be recognized as treatable condition,
as it may respond to immune therapies.
OBJECTIVE: Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple
myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic
effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is
peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage,
however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly
related to immuno-mediated, rather than toxic, mechanisms. METHODS: Five patients who developed a peripheral neuropathy
with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations.
RESULTS: Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent
motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5
patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). CONCLUSIONS: In some instances, the peripheral
damage associated with bortezomib may recognize immuno-mediated mechanisms. SIGNIFICANCE: This form of bortezomib-
associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of
neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may
be the clues to this complication.
NMultiple myeloma--an update on diagnosis and treatment.
Caers J, Vande broek I, De Raeve H, Michaux L, Trullemans F, Schots R, Van Camp B, Vanderkerken K.
Eur J Haematol. 2008 Nov;81(5):329-43. [Epub 2008 Sep 13.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18637123?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This myeloma treatment update addresses the optimalization of different treatment options and schedules, including the use of
bortezomib.
Multiple myeloma is a plasma cell (PC) malignancy characterized by the accumulation of monoclonal PCs in the bone marrow and the
production of large amounts of a monoclonal immunoglobulin or paraprotein. In the past years, new approaches in the diagnosis and
treatment were introduced aiming to identify high-risk patients who need proper anti-myeloma treatment. Intensive therapy including
autologous hematopoietic stem cell transplantation and the new agents bortezomib, thalidomide, and lenalidomide have improved
patients' responses. Further optimalization of the different treatment schedules in well-defined patient groups may prolong their
survival. Patient stratification is currently based on patient characteristics, extent of myeloma disease, and associated cytogenetic and
laboratory anomalies. More and more gene expression studies are introduced to stratify patients and to individualize therapy.
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NNovel targets for myeloma bone disease.
Roodman GD.
Expert Opin Ther Targets. 2008 Nov;12(11):1377-87.
:
http://www.ncbi.nlm.nih.gov/pubmed/18851694?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This article reviews the pathophysiolog y underlying bone remodeling and discusses potential new strategies to treat myeloma bone
disease, including the use of bortezomib.
BACKGROUND: Multiple myeloma (MM) is a plasma cell malignancy in which osteolytic bone lesions develop in over 80% of
patients. The increased bone destruction results from increased osteoclast formation and activity, which occurs adjacent to marrow
sites involved with MM cells. This is accompanied by suppressed or absent osteoblast differentiation and activity, resulting in severely
impaired bone formation and development of purely osteolytic lesions. OBJECTIVE: The pathophysiology underlying this bone
remodeling is reviewed, and potential new strategies to treat MM bone disease are discussed. RESULTS: Recent advances in our
understanding of factors involved in pathogenesis of MM bone disease have identified novel therapeutic targets. Several of these
are or will be in clinical trials soon. CONCLUSION: Agents which target the tumor and bone-destructive process, such as the
immunomodulatory drugs (IMiDs) or bortezomib, in combination with novel anti-resorptives should be effective. These combinations
should be in clinical trials in the next few years. It is unclear if these treatments will be able to `heal' bone lesions in MM patients.
NPulse treatment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity in clinically
relevant conditions.
Boissy P, Andersen TL, Lund T, Kupisiewicz K, Plesner T, Delaissé JM.
Leuk Res. 2008 Nov;32(11):1661-8. [Epub 2008 Apr 18.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18394701?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors test bortezomib on cultured osteoclasts in conditions mimicking the pulse treatment used in the clinic, thereby avoiding
continuous proteasome inhibition and unselective toxicity. Their study demonstrates a direct inhibition of osteoclasts by bortezomib in
conditions relevant to treatment of myeloma.
Myeloma bone disease is due to bone degradation by osteoclasts, and absence of repair by bone forming osteoblasts. Recent
observations suggest that the anti-myeloma drug bortezomib, a proteasome inhibitor, stimulates bone formation and may inhibit
bone resorption. Here, we tested bortezomib on cultured osteoclasts in conditions mimicking the pulse treatment used in the clinic,
thereby avoiding continuous proteasome inhibition and unselective toxicity. A 3 h pulse with 25 nM bortezomib followed by a 3-day
culture in its absence markedly inhibited osteoclast activity as evaluated through bone resorption, TRAcP release, and RANKL-induced
NF-kappaB translocation into nuclei, an event dependent on proteasomes and critical for osteoclast function. The effect on TRAcP
was maximal during the first 24 h post-pulse, and then tended to subside. Importantly, applying this pulse treatment to cultured
myeloma cells drastically reduced their survival. We measured next the levels of two bone resorption markers in patients during the 3
days following five and seven therapeutic bortezomib administrations, respectively. These levels decreased significantly already 1-2 days
after injection, and then increased, showing temporary inhibition of osteoclast activity and paralleling the in vitro effect on TRAcP. Our
study demonstrates a direct inhibition of osteoclasts by bortezomib in conditions relevant to treatment of myeloma.
NDietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib.
Liu FT, Agrawal SG, Movasaghi Z, Wyatt PB, Rehman IU, Gribben JG, Newland AC, Jia L.
Blood. 2008 Nov 1;112(9):3835-46. [Epub 2008 Jul 16.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18633129?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors review the data that indicate dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid
is able to reverse this. They conclude that the complex interactions between quercetin, tumor cells, and bortezomib mean caution is
required when giving dietary advice to patients.
Dietary flavonoids have many health-promoting actions, including anticancer activity via proteasome inhibition. Bortezomib is
a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but is not effective in chronic
lymphocytic leukemia (CLL). Although CLL cells are sensitive in vitro to bortezomib-induced apoptosis when cultured in medium,
the killing activity was blocked when cultured in 50% fresh autologous plasma. Dietary flavonoids, quercetin and myricetin, which are
abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner.
This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH)2, in bortezomib.
The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The
protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a
direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary
flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions
between quercetin, tumor cells, and bortezomib mean caution is required when giving dietary advice to patients.
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NA phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in
patients with refractory solid tumors.
Dees EC, O'Neil BH, Lindley CM, Collichio F, Carey LA, Collins J, Riordan WJ, Ivanova A, Esseltine D, Orlowski RZ.
Cancer Chemother Pharmacol. 2008 Dec;63(1):99-107. [Epub 2008 Mar 8.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18327587?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors conduct a phase I trial of bortezomib and peg ylated liposomal doxorubicin (PLD) in patients with refractory solid tumors
and conclude that a regimen of bortezomib, 1.3 mg/m(2) on days 1, 4, 8, and 11 with PLD, 30 mg/m(2), on day 4 of a 21-day cycle, is
safe in this study, and merits further investigation.
PURPOSE: Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-
tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory
solid tumors. METHODS: Patients received bortezomib, 0.9-1.5 mg/m(2), on days 1, 4, 8, and 11 of every 21-day cycle, along with
PLD, 30 mg/m(2), on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and
to investigate pharmacokinetic and pharmacodynamic interactions of the combination. RESULTS: A total of 37 patients with four
median prior therapies were treated. Frequent grade 1-2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia,
constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib
at 1.2 mg/m(2), and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m(2). Grade 3 toxicities
in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of
frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m(2) levels, bortezomib at 1.3 mg/m(2) and
PLD at 30 mg/m(2) are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit.
Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs. CONCLUSIONS: A
regimen of bortezomib, 1.3 mg/m(2) on days 1, 4, 8, and 11 with PLD, 30 mg/m(2), on day 4 of a 21-day cycle, was safe in this study,
and merits further investigation.
NA phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients
with advanced cancer.
Loconte NK, Thomas JP, Alberti D, Heideman J, Binger K, Marnocha R, Utecht K, Geiger P, Eickhoff J, Wilding G, Kolesar J.
Cancer Chemother Pharmacol. 2008 Dec;63(1):109-15. [Epub 2008 Mar 6.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18322686?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This phase I trial seeks to define the toxicity, maximally tolerated dose and pharmacodynamics of a combination of bortezomib and
doxorubicin in patients with advanced malignancies, and concludes that bortezomib and doxorubicin can be administered safely. This
combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease.
PURPOSE: This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination
of bortezomib and doxorubicin in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-six patients were
treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both
in a 21-day cycle. Dosing ranged from 1.0 mg/m(2) of bortezomib with 15 mg/m(2) of doxorubicin to 1.5 mg/m(2) of bortezomib
with 20 mg/m(2) of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and
ubiquitin-protein conjugates. RESULTS: The combination of bortezomib and doxorubicin was generally well tolerated. There were two
dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m(2) bortezomib, 20 mg/m(2) doxorubicin) and 2 DLT at dose cohort 3a (1.5
mg/m(2) bortezomib, 15 mg/m(2) doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one
patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer
had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was
observed in peripheral blood mononuclear cells of most patients. CONCLUSIONS: Bortezomib and doxorubicin can be administered
safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m(2 )intravenously on days 1, 4, 8 and 11, and
doxorubicin 20 mg/m(2) intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the
activity of both drugs in that disease.
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