www.multiplemyeloma.org
Combination Strategies in the
Treatment of Multiple Myeloma
An MMRF Roundtable
January 29-30, 2007
The Westin Tampa Harbour Island Hotel
Tampa, Florida
Supported by grants from
Accelerating the Search for a Cure
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Table of Contents
Welcome
1
Agenda
2
Participants
3
Abstracts
Session I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Session II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Session III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Notes
MM 06-03
27
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
January 30, 2007
Welcome to The Westin Tampa Harbour Island Hotel and the Combination Strategies in the Treatment
of Multiple Myeloma roundtable. The Multiple Myeloma Research Foundation (MMRF) is pleased and
privileged to bring together some of the leading scientists and clinicians in the study of combination
treatment strategies and multiple myeloma.
At this roundtable, we will determine and prioritize optimal combinations for the treatment of multiple
myeloma, as well as how to identify and apply new technologies for determining and testing
combinations preclinically and clinically. A journal article composed of the proceedings of this
roundtable is planned for submission to a leading oncology publication.
This roundtable is made possible by the Multiple Myeloma Research Foundation (MMRF), through
educational grants from Celgene Corporation, Millennium Pharmaceuticals, Inc., Keryx
Biopharmaceuticals, Inc., Kosan Biosciences Incorporated, and Merck & Co., Inc. We would like to
take this opportunity to thank them for their continuing support.
Once again, thank you for joining us. We look forward to working together today and in future endeavors.
Sincerely,
Anne Quinn Young, MPH
Program Director
Multiple Myeloma Research Foundation (MMRF)
MM 06-03
1
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Agenda
MONDAY, JANUARY 29, 2007
6:30
PM
Welcome Dinner
Guest Speaker: James Doroshow, MD, FACP
TUESDAY, JANUARY 30, 2007
7:30
AM
8:30
Introductions & Objectives
Co-Chairs: Kenneth C. Anderson, MD, and William S. Dalton, PhD, MD
8:50
Session I – The Biological Rationale of Combination Therapy for the Treatment of
Multiple Myeloma
Session Chair: Said M. Sebti, PhD
Presenters: Steven Grant, MD; Faith Davies, MBBCh, MD, MRCP, MRCPath;
and Jackson (Jay) Gibbs, MD
10:00
Discussion
10:30
Break
10:45
Session II – The Identification and Application of New Technologies for Determining
and Testing Combinations Preclinically
Session Chair: James Bradner, MD
Presenters: Margaret S. Lee, PhD; Ting-Chao Chou, PhD; and Lawrence H. Boise, PhD
11:55
Discussion
12:25
PM
Lunch
1:25
Session III – The Clinical Design of Combination Trials
Session Chair: Suzanne Trudel, MD, FRCPCC
Presenters: Dixie-Lee Esseltine, MD, FRCPC; Robert C. Kane, MD, FACP; Sagar Lonial,
MD; and Helen Chen, MD
2:55
Discussion
3:25
Roundtable Summary/Next Steps
Determine and Prioritize Optimal Combinations
Co-Chairs: Kenneth C. Anderson, MD, and William S. Dalton, PhD, MD
4:00
MM 06-03
Continental Breakfast
PM
Adjournment
2
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Guest Speaker
James Doroshow, MD, FACP
National Cancer Institute
31 Center Drive
Building 31, Room 3A44
Bethesda, MD 20892
Phone: (301) 496-4291
E-mail: [email protected]
Co-Chairs
Kenneth C. Anderson, MD
William S. Dalton, PhD, MD
Dana-Farber Cancer Institute/
Harvard Medical School
44 Binney Street
Mayer 557
Boston, MA 02115
Phone: (617) 632-2144
Fax: (617) 632-2140
E-mail: [email protected]
H. Lee Moffitt Cancer Center & Research Institute
12902 Magnolia Drive
Tampa, FL 33612
Phone: (813) 615-4261
Fax: (813) 615-4258
E-mail: [email protected]
Session Chairs
James Bradner, MD
Suzanne Trudel, MD, FRCPCC
Dana-Farber Cancer Institute/
Broad Institute of Harvard and MIT
44 Binney Street
Boston, MA 02115
Phone: (617) 632-6629
Fax: (617) 432-3702
E-mail: [email protected]
Princess Margaret Hospital/
University of Toronto
620 University Avenue
8th Floor, Room 204
Toronto, Ontario Canada M5G 2C1
Phone: (416) 946-4566
Fax: (416) 946-2087
E-mail: [email protected]
Said M. Sebti, PhD
H. Lee Moffitt Cancer Center & Research Institute
12902 Magnolia Drive
SRB3-DRDIS
Tampa, FL 33612
Phone: (813) 745-6734
Fax: (813) 745-6748
E-mail: [email protected]
MM 06-03
3
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Faculty
Lawrence H. Boise, PhD
Jackson (Jay) Gibbs, PhD
University of Miami Miller School of Medicine
1600 NW 10th Avenue
Room 3153, Rosenstiel Medical Sciences Building
Miami, FL 33136
Phone: (305) 243-6137
Fax: (305) 243-4623
E-mail: [email protected]
AstraZeneca
35 Gatehouse Drive
Waltham, MA 02451
Phone: (781) 839-4945
Fax: (781) 839-4384
E-mail: [email protected]
Steven Grant, MD
Helen Chen, MD
Virginia Commonwealth University/
Massey Cancer Center
1250 East Marshall Street
Box 980230
Richmond, VA 23298
Phone: (804) 828-5211
Fax: (804) 828-2174
E-mail: [email protected]
National Institutes of Health/
National Cancer Institute
6130 Executive Boulevard
EPN, Room 7131
Bethesda, MD 20892
Phone: (301) 496-1196
Fax: (301) 402-0428
E-mail: [email protected]
Robert C. Kane, MD, FACP
Ting-Chao Chou, PhD
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021
Phone: (212) 639-7480
Fax: (212) 794-4342
E-mail: [email protected]
U.S. Food and Drug Administration
10903 New Hampshire Avenue
Building 22, Room 2109
Silver Spring, MD 20993
Phone: (301) 769-1384
Fax: (301) 769-9845
E-mail: [email protected]
Faith Davies, MBBCh, MD, MRCP, MRCPath
Margaret S. Lee, PhD
Institute of Cancer Research
15 Cotswold Road, Belmont
Sutton, Surrey United Kingdom SM2 5NG
Phone: + 44 20 8643 8901
E-mail: [email protected]
CombinatoRx, Inc.
245 First Street
4th Floor
Cambridge, MA 02142
Phone: (617) 301-7142
Fax: (617) 301-7110
E-mail: [email protected]
Dixie-Lee Esseltine, MD, FRCPC
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139
Phone: (617) 444-3251
E-mail: [email protected]
MM 06-03
Sagar Lonial, MD
Emory University School of Medicine
Winship Cancer Institute, Building C
Suite 4005
Atlanta, GA 30322
Phone: (404) 778-3933
Fax: (404) 778-5530
E-mail: [email protected]
4
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Participants
Melissa Alsina, MD
Daniel E. Greenleaf
H. Lee Moffitt Cancer Center & Research Institute
12902 Magnolia Drive
Tampa, FL 33612
Phone: (813) 903-6886
Fax: (813) 979-7265
E-mail: [email protected]
VioQuest Pharmaceuticals
180 Mount Airy Road
Suite 102
Basking Ridge, NJ 07920
Phone: (908) 766-4400, ext. 115
Fax: (908) 766-4455
E-mail: [email protected]
Peter Atadja, PhD
Lori Hazlehurst, PhD
Novartis Institute for Biomedical Research
250 Mass Avenue
Cambridge, MA 02139
Phone: (617) 381-3447
E-mail: [email protected]
H. Lee Moffitt Cancer Center & Research Institute
12902 Magnolia Drive
Tampa, FL 33612
Phone: (813) 745-3883
E-mail: [email protected]
Robert Birch, PhD
Richard D. Huhn, MD
Keryx Biopharmaceuticals, Inc.
1355 Lynnfield Road
Suite 245
Memphis, TN 38119
Phone: (901) 869-3844
Fax: (901) 869-3842
E-mail: [email protected]
Pfizer, Inc.
50 Pequot Avenue
MS 6025-A3138
New London, CT 06320
Phone: (860) 732-1543
Fax: (860) 686-6326
E-mail: [email protected]
Tom Cavanaugh
Robert Knight, MD
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Phone: (908) 673-9505
Fax: (908) 673-2781
E-mail: [email protected]
MM 06-03
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Phone: (908) 673-9749
Fax: (908) 673-2774
E-mail: [email protected]
5
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
Participants
(continued)
Albert L. Kraus, PhD
Peter Sportelli
Kosan Biosciences
3832 Bay Center Place
Hayward, CA 94545
Phone: (510) 931-5212
E-mail: [email protected]
Keryx Biopharmaceuticals, Inc.
750 Lexington Avenue
20th Floor
New York, NY 10022
Phone: (201) 213-9999
Fax: (212) 531-5961
E-mail: [email protected]
Syed Rizvi, MD
Merck & Co., Inc.
351 North Sumneytown Pike
Mail Stop: UG4D-72
North Wales, PA 19454
Phone: (267) 305-7161
Fax: (267) 305-6537
E-mail: [email protected]
MM 06-03
AN MMRF ROUNDTABLE
Jelena Veljkovic, PhD
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139
Phone: (617) 551-3788
Fax: (617) 444-2180
E-mail: [email protected]
6
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Multiple Myeloma Research Foundation (MMRF)/
Multiple Myeloma Research Consortium (MMRC)
Stephanie Berkowitz, PhD
Anne Quinn Young, MPH
Multiple Myeloma Research Foundation (MMRF)
383 Main Avenue
Fifth Floor
Norwalk, CT 06850
Phone: (203) 652-0221
Fax: (203) 229-0572
E-mail: [email protected]
Multiple Myeloma Research Foundation (MMRF)
383 Main Avenue
Fifth Floor
Norwalk, CT 06850
Phone: (203) 652-0212
Fax: (203) 972-1259
E-mail: [email protected]
Brian Porter
Steven Young
Multiple Myeloma Research Foundation (MMRF)
383 Main Avenue
Fifth Floor
Norwalk, CT 06850
Phone: (203) 652-0206
E-mail: [email protected]
Multiple Myeloma Research Consortium (MMRC)
383 Main Avenue
Fifth Floor
Norwalk, CT 06850
Phone: (203) 652-0213
E-mail: [email protected]
AOI Communications, L.P.
Thomas Burke
Larry Rosenberg, PhD
AOI Communications, L.P.
102 Pickering Way
Suite 404
Exton, PA 19341
Phone: (610) 363-7030, ext. 11
Fax: (610) 363-6922
E-mail: [email protected]
AOI Communications, L.P.
102 Pickering Way
Suite 404
Exton, PA 19341
Phone: (203) 405-1088
Fax: (610) 363-6922
E-mail: [email protected]
Michele Kashmere
AOI Communications, L.P.
102 Pickering Way
Suite 404
Exton, PA 19341
Phone: (570) 339-2523
Fax: (610) 363-6922
E-mail: [email protected]
MM 06-03
7
January 29-30, 2007
AN MMRF ROUNDTABLE
Session I – The Biological Rationale of
Combination Therapy for the Treatment
of Multiple Myeloma
Session Chair:
Said M. Sebti, PhD
MM 06-03
8
SESSION I
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Rational Drug Combinations Designed to Improve Proteasome Inhibitor Activity
in Myeloma and to Circumvent Resistance
Steven Grant, MD
The introduction of the proteasome inhibitor bortezomib (Velcade®) into the therapeutic
armamentarium has had a dramatic impact on multiple myeloma treatment. However, the preexistence
or development of bortezomib resistance represents a major therapeutic challenge. Efforts to
circumvent this problem are hampered by the absence of a clear understanding of the mechanisms
responsible for proteasome inhibitor lethality or resistance. The latter phenomenon may reflect intrinsic
myeloma cell characteristics, or, alternatively, the influence of external factors ie, IGF-1-, IL-6, or
stromal cell-related actions. Despite these uncertainties, several strategies suggest themselves. For
example, preliminary evidence suggests that at least some bortezomib-resistant myeloma cells can
respond to second-generation proteasome inhibitors (eg, PR-171, NPI-0052), raising the possibility that
such agents, either alone, or perhaps in combination with bortezomib, might be effective in resistant
disease. In addition, evidence is accumulating that tumor cells in general, and myeloma cells in
particular, are ill equipped to circumvent the lethal effects of simultaneous interruption of multiple
survival signaling pathways. This concept has stimulated considerable interest in the development of
combination regimens involving bortezomib, particularly those incorporating other targeted agents. For
example, early studies demonstrated potentiation of bortezomib lethality in multiple myeloma by coadministration of MEK1/2 inhibitors, and it was subsequently observed that farnesyltransferase
inhibitors interact synergistically with bortezomib in association with AKT inactivation. Similarly,
perifosine, an alkylysophospholipid which disrupts AKT-related signaling cascades, has also been
shown to promote bortezomib antimyeloma activity.
Another strategy to potentiate bortezomib efficacy in myeloma involves disruption of the NF-κB
pathway. In myeloma, bortezomib is believed to act, at least in part, by disrupting NF-κB activation by
blocking degradation of IκBα. Notably, flavopiridol, a CDK inhibitor that was originally targeted to
myeloma in view of its ability to induce cyclin D1 downregulation, has been shown to act as an IKK
inhibitor. In preclinical studies, flavopiridol and other CDK inhibitors have been shown to interact in a
highly synergistic manner with bortezomib in myeloma and leukemia cells in association with mcl-1
down-regulation and JNK activation. In an ongoing phase 1 trial of flavopiridol and bortezomib in
patients with refractory B-cell malignancies, this regimen has shown evidence of activity in several
myeloma patients refractory to bortezomib alone. Other strategies have attempted to exploit the
observation that bortezomib can kill cells through induction of oxidative damage. Several groups have
shown synergistic interactions in myeloma cells between bortezomib and agents that promote reactive
oxygen species (ROS), including small molecule bcl-2 inhibitors (ie, HA14-1) and the triterpenoid
CDDO. Another approach involves the use of HDAC inhibitors to disrupt aggresome formation, an
action which exacerbates the lethal consequences of interference with protein degradation by
proteasome inhibitors. It would be of great interest to determine which of these strategies would be
effective in the case of second-generation proteasome inhibitors, particularly in the setting of
bortezomib-resistant disease.
MM 06-03
9
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Rational Drug Combinations Designed to Improve Proteasome Inhibitor Activity
in Myeloma and to Circumvent Resistance
(continued)
Finally, a relatively unexplored strategy for the eradication of bortezomib-resistant myeloma involves
the rational combination of agents that disrupt survival pathways downstream of those disrupted by
proteasome inhibitors. For example, it has been shown that the PKC, PDK1, and Chk1 inhibitor UCN01 potently triggers MEK1/2/ERK1/2 activation in myeloma cells, and this effect is dramatically blocked
by MEK1/2 inhibitors, resulting in striking apoptosis. Furthermore, this strategy selectively kills
myeloma cells, is active in vivo, and induces apoptosis in drug-resistant myeloma cells, including those
refractory to bortezomib. In view of the wealth of signal transduction inhibitors currently available as
well as the ongoing development of agents targeting new pathways, it seems very likely that novel
combination strategies capable of improving proteasome inhibitor activity in myeloma and/or
circumventing resistance will emerge in the near future.
Submitted by Steven Grant, MD, Virginia Commonwealth University/Massey Cancer Center, Richmond,
Virginia, USA
MM 06-03
10
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
The Development of Biological Rationales for the Use of Combination Therapies
in the Treatment of Multiple Myeloma
Faith Davies, MBBCh, MD, MRCP, MRCPath
Cancer drug development is leading the way in exploiting molecular biological and genetic
information to develop "personalized" medicine. The new paradigm is to develop agents that target the
precise molecular pathology driving the progression of individual cancers, and to combine agents that
target different pathways to enhance cell kill. Recent examples of this approach in myeloma are the
combination of a proteasome inhibitor or immunomodulatory drugs with dexamethasone. In the
laboratory, these combinations result in an increase in cell death because of their differential effects on
the intrinsic and extrinsic apoptosis pathways, and in the clinic, these combinations result in improved
response rates compared to either agent alone.
The clinical use of small molecules targeting specific pathways requires us to alter our approach to
drug development in a number of ways. The in vivo evaluation of such drugs entails the rational and
efficient discovery, validation, and implementation of informative biomarkers. In this context the
measurement of molecular target status, pharmacokinetic parameters of drug exposure, and
pharmacodynamic endpoints of drug effects on target, pathway, and downstream biological processes
are extremely important, and can be linked to therapeutic effects as part of the "pharmacological audit
trail." Using biomarkers in preclinical drug discovery and development facilitates optimization of PK,
PD, and therapeutic properties so that the best agent is selected for clinical evaluation. As we move
toward the development of rational drug combinations, the use of the informative biomarkers validated
in the preclinical setting becomes more important, ensuring that drug combinations that are moved to
the clinic are effective and are based on sound biological rationale. Applying these biomarkers in early
clinical trials also helps identify the most appropriate patients; provides proof of concept for target
modulation; helps test the underlying hypothesis; informs the rational selection of dose and schedule;
aids decision making, including key go/no go questions; and may explain or predict clinical outcomes.
In addition to these in vivo approaches for the development of small molecules with clean and specific
modes of action, we also need to develop in vitro model systems in which we can develop a full
understanding of the biology of the tumor to enable rational combinations to be selected. This strategy
of selecting multiple combinations active on different and co-operating pathways needs to be
distinguished from the use of small molecules selected to target single cellular activities, the inhibition
of which results in multiple downstream effects within the tumor system of interest. This mode of action
is best illustrated by the clinical effects of bortezomib, which while being highly specific, also disrupt
multiple downstream pathways.
Exploiting the highly targeted nature of some of the novel small molecules demands a conceptual
framework within which to design effective combinations. Evaluating these combinations brings an
absolute requirement for a laboratory program within which to test combinations in well-defined
disease models. Classical chemotherapy targeting DNA relied on the combination of different DNAdamaging agents, largely governed by their side-effect profile. With small molecules the hope is that
their use will be dictated by their targeted mode of action rather than by their side-effect profile. I will
illustrate this in a couple of ways taking into account myeloma biology.
MM 06-03
11
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
The Development of Biological Rationales for the Use of Combination Therapies
in the Treatment of Multiple Myeloma
(continued)
CML is a simple disease model where BCR/ABL is sufficient to cause the disease, and switching it off,
using TK inhibition, is sufficient to abort the phenotype. Myeloma, in contrast, is more complex,
occurring as a result of multiple genetic hits and the deregulation of multiple signaling pathways. As a
consequence of this, a more complex approach to treatment is required, which will demand molecular
diagnostics and multiple combinations of clean small molecules targeting specific pathways.
The t(4;14) deregulates 2 genes; FGFR3 and MMSET. We, and others, have attempted to target FGFR3
and it has been shown that cell lines respond in vitro, but in vivo the effects are much more difficult to
interpret. The other gene, deregulated MMSET, has not been fully evaluated in combination
approaches, yet it is universally deregulated. It is SET domain gene with HMT activity that modulates
gene repression. Transcription factors are difficult to target but modulating the epigenetic make up of
the region of target genes is becoming possible. We know that HDAC1 and 2 bind to the MMSET
transcription complex and so can be targeted, as can the HMT activity of MMSET. Methylation of DNA
is also a consequence of repressive transcription complexes and this too can be targeted, using
demethylating agents. The t(4;14), therefore, provides a good model system in which to test such
combinations in myeloma. It is important to remember, however, that even if the consequences of the
translocation can be effectively targeted, CYLD is deregulated by the 16q deletion leading to
constitutive activity of NF-κB. This occurs frequently in this group of myeloma and confers a poor
prognosis that will also need therapeutic targeting.
The other broad conceptual approach to the treatment of myeloma is to consider the cell biology of
plasma cells as a means of developing rational combinations. Plasma cells can be considered as a
highly specialized cell type designed to produce immunoglobulins. This feature provides a differential
characteristic from other cell types, which can be targeted. The molecular characteristics of secretory
cell types and immunoglobulin secretion in particular are well described and involve the UPR, a
distinct cell response, which can be targeted. This pathway is also relevant in myeloma as it provides a
developmental checkpoint for normal plasma cell development. XBP1 is central in this process and is
frequently dysregulated in myeloma. We have explored targeting this pathway using hsp90 inhibitors,
proteasome inhibitors, and are developing approaches to modulating the UPR by manipulating one of
its major components, IRE1. Designing combinations that modulate this specific feature of myeloma
biology raises a number of relevant questions including: can protein unfolding be manipulated to
deliver a stronger death signal and can a UPR-specific death signal be generated; if the pathway is fully
inhibited by one agent, does further inhibition at a different site in the pathway lead to synergy?
Submitted by Faith Davies, MBBCh, MD, MRCP, MRCPath, Institute of Cancer Research, Sutton, Surrey,
United Kingdom
MM 06-03
12
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Toward Rational Combination Strategies for Molecularly Targeted Therapies in
Multiple Myeloma
Jackson (Jay) Gibbs, MD*, Raj Chopra*, Jeff Brown*, and Paul Smith†
Advances in molecular oncology have been translated into several drugs and numerous clinical
candidates directed against defined targets. Challenges with these new agents include how best to
use them against specific tumor types and also how to define specific combinations with other
therapies. In an effort to shift from empirical to rational approaches, several steps can be taken
including: 1) understanding the relevant pathways that underlie the basis for primary tumor cell
proliferation and survival, 2) defining the strategy for therapy and combination approaches, and 3)
testing these ideas in relevant preclinical models with the anticipation that the results will be
prospective for clinical evaluation. A number of studies have provided details on the genetic
alterations and the gene expression profiles (and by inference the pathways) associated with multiple
myeloma, and these results have identified new candidate drug targets, as well as offer the potential
to guide selection of specific therapies in the clinic (eg, the MEK inhibitor AZD 6244). A challenge
in the selection of combinations falls back to strategic approaches. Should one combine the new
agent with the standard of care? Should agents with broad action (proteasome inhibitor) be
combined with other broad-acting compounds (hsp90, HDAC) or more pathway-specific inhibitors?
Among targeted therapies, should combinations be guided by diverse mechanisms of action (signal
transduction, cell cycle, angiogenesis, etc.) or focus on combinations within particular pathways (in
the case of ras, combining a MEK inhibitor with an AKT or PI3K inhibitor)? Testing these different
strategies in relevant pre-clinical models, and establishing a relationship to the clinical treatment of
multiple myeloma remains a key challenge for the field. These topics and questions will serve as a
basis for discussion during the session.
*AstraZeneca, Waltham, Massachusetts, USA
†
AstraZeneca, Alderley Park, United Kingdom
Submitted by Jackson (Jay) Gibbs, MD, AstraZeneca, Waltham, Massachusetts, USA
MM 06-03
13
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Notes
MM 06-03
14
January 29-30, 2007
AN MMRF ROUNDTABLE
Session II – The Identification and Application
of New Technologies for Determining and
Testing Combinations Preclinically
Session Chair:
James Bradner, MD
MM 06-03
15
SESSION II
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Systematic Screening of Drug Combinations for Multiple Myeloma
Margaret S. Lee, PhD
Clinical experience and theoretical analyses suggest that multi-target approaches are required to
overcome redundant and adaptive oncogenic mechanisms, and cotherapies are indeed the standard of
care for many cancers. Identification of optimal and selective combinations of the many targeted
agents becoming available presents a critical challenge. A platform for combination high throughput
screening (cHTS) has been developed and used to screen combinations of approved drugs for the
discovery of therapeutically relevant synergies in cell-based models. Compound pairs are characterized
over a wide range of concentrations and ratios in a “dose matrix” format in order to distinguish
synergistic interactions from additive ones, as well as to provide possible insights into the network
connectivity of the targets. In addition to providing effective treatments, these chemical synergies can
provide information regarding interactions between targeted pathways, elucidating previously
unappreciated connections between disease mechanisms.
This screening approach is optimally applied to cancers (such as multiple myeloma) for which there are
reasonable phenotypic cellular models with HTS-detectable endpoints. Initial efforts using the RPMI8226 cell line have focused on combinations in which one component is a drug already approved for
multiple myeloma paired with another compound that is not. Numerous synergistic pairs have been
identified – including both some “expected” cases, as well as unanticipated novel interactions.
Submitted by Margaret S. Lee, PhD, CombinatoRx, Inc, Cambridge, Massachusetts, USA
MM 06-03
16
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Combination Strategies Against Multiple Myeloma in Light of the Combination
Index Theorem, Rational Experimental Design, and Computerized Simulation
for Determining Synergism
Ting-Chao Chou, PhD
By merging the mass-action law dynamics and the mathematical induction/deduction, the “unified
theory of dose and effect” for single drug and for drug combinations has been derived1. Its general
equations can serve as algorithms for computerized determination of mass-action law parameters as
well as for simulation of synergism and/or antagonism in terms of combination index (CI), at all doses
or all effect levels, where CI <1, =1, and >1 indicates synergism, additive effect, and antagonism,
respectively. It is shown that “dose” and “effect” are interchangeable, and that the CI plot and
isobologram are two sides of the same coin. This general method may be used for combining drugs
and/or modalities (eg, radiation) regardless of their units (µg/ml, nM, IU, MOI, rad, etc.), the drug
mechanisms (competitive, non-competitive, or uncompetitive), and the target mechanisms (ordered,
sequential, ping-pong, random, transduction, transcription, translation, checkpoints, apoptosis,
pathway, network schemes, system biology, in vitro, in vivo, or epidemiology). By using the massaction-law based “CompuSyn” software2, dose-effect curve, median-effect plot, CI plot, isobologram,
dose-reduction index (DRI) plot and polygonogram (for more than two drugs) can be generated
automatically. DRI values indicate how many folds dose-reduction for each drug are allowed in a
synergistic combination at a given degree of effect (or therapeutic effect). Thus, the dose-reduction
leads to lower toxicity and yet maintains the same efficacy. The proposed experimental design (eg, the
constant ratio combination “diagonal scheme” rather than “checkerboard design”) allows markedly
reduced experimental size (ie, requires many fewer data points) in vitro and in vivo and, therefore,
markedly reduces the cost, time, and animal usage and yet provides the above-mentioned computergenerated graphics and conclusions.
The combination strategies for the treatment of multiple myeloma will be discussed in light of the
above theoretical basis and method. The items of direct relevance will include the selection of
combination drug entities or modalities, combination ratio, schedule dependency, selection of
measurement, and the endpoints for quantitative evaluations, selection of an appropriate and the most
relevant animal model(s), and the optimal therapeutic conditions, which include dose (below MTD),
route (IV injection, IV infusion, length and frequency of infusion, oral, etc.), schedule and interval of
administration. The “optimal therapeutic conditions” require a lot of background homework to
establish and should not be arbitrarily selected nor be decided for saving cost or for convenience, since
without the optimal conditions (eg, the balancing act of efficacy conditions and toxicity), experimental
data for both single drug and drug combinations will be worthless or useless and therefore, wasteful.
Because multiple myeloma is a unique complicated disease, the logistics of how to determine the
therapeutic effect accurately, quantitatively, and meaningfully in vivo can be a major challenge.
Another main challenge is the therapeutic effectiveness for multiple myeloma. The recent discovery of
the second- and third-generation of epothilones, fludelone and iso-oxazole-fludelone may provide
some promise. These compounds have been shown to achieve de facto “therapeutic cure” against
MM 06-03
17
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Combination Strategies Against Multiple Myeloma in Light of the Combination
Index Theorem, Rational Experimental Design, and Computerized Simulation
for Determining Synergism
(continued)
several human xenograft tumors in nude mice. The “cure” is defined by tumor suppression, tumor
shrinkage, tumor disappearance, and complete remission for over 15% of life-span without any relapse,
or >9 logs of cancer cell kills3,4. Furthermore, there are apparent deficiencies in approaches and designs
in conducting “drug combination clinical trials” in patients, in general, in the past that may lead to
costly clinical trial failure. The rational approaches for improving these conditions will be discussed.
References
1. Chou TC. Theoretical basis experimental design and computerized simulation of synergism and
antagonism in drug combination studies. Pharm. Rev. 2006;58:621-681.
2. Chou TC, Martin N. CompuSyn for drug combinations. 1st ed. Paramus (NJ):ComboSyn; 2005.
3. Chou TC, Doug H, Zhang X, Tong W, Danishefsky SJ. Therapeutic cure against human tumor
xenografts in nude mice by a microtubule stabilization agent, fludelone, via parenteral or oral route.
Cancer Res. 2005;65:9445-9454.
4. Chou TC, Zhang X, Wu N, et al. Pharmacological profile of a microtubule stabilization agent, isooxazole-fludelone and its therapeutic effects against human tumor xenografts in nude mice. Proc.
AACR. 2006;47:115. Abstract 488.
Submitted by Ting-Chao Chou, PhD, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
MM 06-03
18
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Using the Responses of Myeloma Cells to Provide the Rationale for Testing
Drug Combinations
Lawrence H. Boise, PhD, Alejo Morales, Delia Gutman, Esther Obeng, Jennifer McCaffertyCepero, Nizar Bahlis, Kelvin P. Lee
The use of combination therapy has been a mainstay of myeloma treatment for the last several decades;
however, it is not clear that combinations such as VAD were any more effective than dexamethasone
alone or if vincristine even contributed to the efficacy of the combination. These early combinations
may have not been effective in part because it is not clear why cells are sensitive to many agents that
are used for the treatment of myeloma. Therefore understanding why myeloma cells are sensitive to
individual agents would likely lead to more rational approaches to combination therapy. This is
particularly important now with the introduction of so many novel agents into the clinic in the past
several years.
Our work has primarily focused on two such agents – arsenic trioxide (As2O3, Trisenox®) and
bortezomib (Velcade®). As2O3 has displayed modest activity as a single agent or in combination with
ascorbic acid clinically. To optimize the types of agents one would combine with As2O3, we have been
studying cellular responses in cell lines. Gene-expression-profiling studies demonstrate that As2O3
induces an anti-oxidant response that includes up-regulation of genes to increase the levels of reduced
glutathione in the cell. Regulation of cellular glutathione GSH is important for the clinical response to
As2O3 as evidenced by a significant difference in changes or absolute levels of GSH in responders and
non-responders to Trisenox and ascorbic acid therapy. Consistent with these data, a recent study
suggests that melphalan, another drug metabolized in a GSH-dependent fashion, forms an effective
combination with As2O3 and ascorbic acid.
In addition to anti-oxidant responses, gene-expression profiling of the apoptotic response reveals the
up-regulation of several BH3 proteins including Noxa. Noxa is a specific inhibitor of mcl-1 but does
not inhibit bcl-2 or bcl-xL therefore we are also determining the effect of addition of the bcl-2/xL
inhibitor, ABT-737. In addition to studying the response of cell lines in vitro we have been studying
responses in cells from patients treated with As2O3 and ascorbic acid. Interestingly, while patient
responses peak after 1 to 2 cycles of therapy, myeloma cells remain sensitive to As2O3 through 6 cycles
of therapy. These data indicate that resistance to arsenic is not cell intrinsic and therefore provide the
rationale for combination therapies that target the tumor micro-environment.
Currently we do not know what the critical targets for arsenic are in myeloma. In contrast, the
proteasome that is the target for bortezomib is well established. However, proteasomes are found in all
cells, therefore the question becomes why are myeloma cells sensitive to proteasome inhibition? We
have demonstrated that proteasome inhibitors activate an unfolded protein response consistent with
endoplasmic reticulum-induced stress and will discuss the implications of this finding for the design of
combination therapy.
Submitted by Lawrence H. Boise, PhD, University of Miami Miller School of Medicine, Miami, Florida, USA
MM 06-03
19
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Notes
MM 06-03
20
January 29-30, 2007
AN MMRF ROUNDTABLE
Session III –
The Clinical Design of Combination Trials
Session Chair:
Suzanne Trudel, MD, FRCPCC
MM 06-03
21
SESSION III
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Velcade® (bortezomib) Strategy
Dixie-Lee Esseltine, MD, FRCPC
These are interesting, challenging and changing times for drug development in multiple myeloma. Until
recently, there had been few regulatory precedents for the approval of drugs for this indication, no
benchmarks for meaningful single agent activity, and a dearth of new agents. Our thinking has certainly
been challenged by new developments! There are now three new drugs recently approved for multiple
myeloma and many more in the pipeline or in phase 1 – many in development specifically for multiple
myeloma. At major medical meetings, the questions now being asked concern the “standard of care;” the
“standard for comparison” for emerging agents; and the most efficient pathways for new drug development.
My presentation will use the development of Velcade® (bortezomib) in multiple myeloma as a reference
point for recent drug development. With the important chemistry and nonclinical work that led to the IND
for bortezomib, a first-in-class proteasome inhibitor, bortezomib’s clinical development pathway now may
seem relatively straightforward to secure regular approval for the single agent in patients with relapsed
multiple myeloma who have received one prior therapy. Speed and partnerships with many stakeholders
characterized this development program which also incorporated pharmacogenomic biomarkers – first in
the phase 2 trials, and secondly, their validation in a prospective international trial. As we now have moved
our development program to studies in the newly diagnosed patients, the development of effective
combinations is of most importance. How do we evaluate drugs in combination with bortezomib for their
contribution to clinical benefit? There are now potential combinations with bortezomib where CR rates are
additive or even synergistic in the clinic and other examples where there is limited single-agent activity with
the new agent, but in combination, clear anti-tumor effect greater than would be expected with either agent
alone. There are also combinations that impact time-to-event without any additive effect on response.
There are some approaches that may be worth considering in our clinical development programs as we
develop combination therapy. We can sample both patient DNA and tumor RNA to inform us. We can
incorporate different statistical approaches for efficiency, such as adaptive design. We can require that the
evidence for complete absence of multiple myeloma be more compelling, and that the ultimate test be
durability of remissions, and that long-term benefit be shown only by prolonged follow-up. The improved
response rates associated with incorporation of new agents need to translate into incremental benefits over
traditional approaches. The incremental change that is of most benefit has yet to be standardized for
different patient groups.
There have been advances in the care of multiple myeloma patients but we are not close to a standard of
care for the majority of patients, especially on a worldwide basis. The potential of the emerging new agents
is awesome. The definitive test remains in the clinical trial. But the success of our trials will now require
longer follow-up for the time-to-event endpoints, prospective collection of prognostic and predictive
markers (and their subsequent validation), creative statistical designs, and above all, the patience to see
these trials through to completion.
Submitted by Dixie-Lee Esseltine, MD, FRCPC, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA
MM 06-03
22
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Considerations for FDA Drug Approval in Multiple Myeloma
Robert C. Kane, MD, FACP
Since 2003, three new drugs have received US FDA marketing authorization (approval) for the therapy
of multiple myeloma. For approval of a new drug, federal law and regulations require the
demonstration of “substantial evidence of efficacy and safety” from “adequate and well-controlled”
trials. The Agency encourages meetings with sponsors in which trial designs, eligibility requirements,
study endpoints, and appropriate pre-specified analysis plans can lead to study results providing this
substantial evidence of benefit for a well-defined patient population.
FDA follows the clinical science as it is developed by disease experts. The oncologic drugs advisory
committee, a rotating group of clinical experts who undergo clearance for conflicts of interest, has
advised FDA that the most compelling evidence for drug approval in oncology is improvement in
survival and/or reduction in tumor-related symptoms. Both of these endpoints may be challenging to
demonstrate in myeloma. The Agency more recently has relied upon evidence of response, including
complete response and durability of response, along with time to disease progression, as indicators of
treatment effect. In addition to evidence for efficacy, adverse effects have to be well-characterized.
In drug combination studies involving new agents, the trial design is expected to isolate and confirm
the incremental contribution of adding the investigational agent to the “standard” therapy backbone.
Recent examples will be used to illustrate the interplay of trial design, endpoint, and analysis plan
options for advancing the care of patients with myeloma.
Submitted by Robert C. Kane, MD, FACP, Center for Drug Evaluation and Research, Silver Spring, Maryland, USA
MM 06-03
23
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
The Clinical Design of Combination Trials
Sagar Lonial, MD
The use of targeted agents has had a significant impact on myeloma therapy, allowing “chemotherapy
free” induction and relapse regimens to rival those of chemotherapy-containing combinations. Agents
that target specific signaling pathways may be associated with less toxicity, but may also have less
single-agent activity. For this reason rationally designed combinations of targeted agents represent a
potential mechanism by which lower doses of each agent may be used in a synergistic manner to
enhance efficacy and reduce toxicity.
The clinical design of these combination trials is of critical importance in order to exploit observed
mechanisms of synergy and to enhance clinical benefit for patients. Four central points are vital to
keep in mind when designing these trials.
1. Optimal drug combinations. This point forms the scientific basis for most well-designed combination
trials. While laboratory data do not always translate into clinical benefit, preclinical studies can
inform good clinical trial design, are necessary for hypothesis-based trials, and can be vital in
designing appropriate correlative studies.
2. Sequence of administration. Targeted agents can have pleiotropic effects on a number of different
signaling pathways that either enhance or inhibit the efficacy of the second added agent. For this
reason, when targeted agents are combined, sequence administration may be critically important.
This may occur because the first agent results in funneling of activity toward another target, thus
enhancing the combination effect (pathway addiction) or may occur because the first agent’s effects
inhibit the efficacy of the second agent. Lack of attention to these specific order-of-addition
experiments and clinical design may result in an inadvertently negative trial.
3. Novel phase 1 design. While standard modified Fibonacci design for phase 1 studies (3+3 design)
continues to be used widely, it is becoming clear that such studies do not necessarily have adequate
power to support robust phase 2 studies, and may under-dose a significant fraction at patients in any
given phase 1 trial. Novel designs for phase 1 studies allow clinicians to proceed more rapidly
through low doses, and to enroll more patients at pharmacologically active doses. These types of
studies require early and constant interaction with a biostatistician, but also have the potential of
more accurately predicting a safe dose for a phase 2 trial and a higher likelihood of clinical benefit
for patients.
4. Trial-specific lab correlates. This final point is clearly what defines a phase 1 combination trial that is
based upon preclinical data and is hypothesis based. Such correlates may be used to demonstrate
target inhibition as well as to develop potential biomarkers for response. The advantage of welldesigned correlative studies is that they can provide a hypothesis and data for subsequent larger
studies as well as inform the current trial as to why a specific approach is either effective or
ineffective.
Submitted by Sagar Lonial, MD, Emory Winship Cancer lnstitute, Atlanta, Georgia, USA
MM 06-03
24
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Abstracts
Combination of Molecularly Targeted Agents – A Clinical Perspective
Helen Chen, MD
Given the complexity of molecular pathobiology of tumors, it is now well recognized that strategies
aiming at simultaneous blockage of multiple molecular pathways are critical to further therapeutic
success of molecularly targeted agents. Challenges to the evaluation of such novel combinations are,
however, unprecedented, in view of the almost limitless possibilities of combinations and the still
inadequately understood cancer biology and heterogeneity. This presentation will review the critical
elements of a development strategy for targeted agent combinations as well as experience with several
NCI-sponsored clinical trials for novel combination regimens. Scientific, medical, and intellectual
property issues that pose barriers to rational preclinical and clinical evaluations will be described, and
possible means of overcoming these barriers will be discussed.
Submitted by Helen Chen, MD, National Institutes of Health, Bethesda, Maryland, USA
MM 06-03
25
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Notes
MM 06-03
26
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Notes
MM 06-03
27
January 29-30, 2007
COMBINATION STRATEGIES IN THE TREATMENT OF MULTIPLE MYELOMA
AN MMRF ROUNDTABLE
Notes
MM 06-03
28
January 29-30, 2007