A Phase II Study of Bortezomib (Velcade®),
Cyclophosphamide (Cytoxan®), Thalidomide
(Thalomid®) and Dexamethasone as First-
Line Therapy for Multiple Myeloma
Sundar Jagannath1, Bill Bensinger2, Robert Vescio3, Elber
Camacho4, Jeffrey Wolf 5, David Irwin 6, Gerardo Capo7,
Marti McKinley8, David H. Vesole1, Amitabha Mazumder1,
John Crowley9, Dixie Esseltine10, Brian G.M. Durie3
1St. Vincent's Comprehensive Cancer Ctr, NY, NY, USA; 2Fred Hutchinson Cancer
Research Center, Seattle, WA, USA; 3Hematology-Oncology Cedars-Sinai Outpatient
Cancer Center, Los Angeles, CA, USA; 4Comprehensive Cancer Center of the Desert,
Palm Springs, CA, USA; 5University of California, San Francisco, CA, USA; 6Alta Bates
Summit Comprehensive Cancer Center, Berkeley, CA, USA; 7Trinitas Comprehensive
Cancer Center, Elizabeth, NJ, USA; 8Aptium Oncology Research Network, Beverly Hills,
CA, USA; 9Ctr for Research and Biostatistics, Seattle, WA USA; 10Millennium
Pharmaceuticals, Inc., Cambridge, MA, USA
1
Disclosures
In compliance with ACCME policy, ASH requires the following disclosures to the activity audience:
Research Support/P.I.
Millennium Pharmaceuticals, Inc.,
a
Employee
N/A
Georgi
Atlanta,
Consultant
Millennium Pharmaceuticals, Inc., Celgene, Inc.
eetingM
Major Stockholder
N/A
Annual
Speakers' Bureau
Millennium Pharmaceuticals, Inc., Celgene, Inc.
ASHth49
Scientific Advisory Board
N/A
Presentation includes discussion of the following off-label use of a drug or medical
device: frontline use of bortezomib in MM
2
Introduction
The aim of frontline therapy is to reduce tumor burden and achieve
prolonged remission
Better response to frontline therapy
improves survival
Obviates need for second transplant
Phase II Trials:
Bortezomib and dexamethasone is effective induction therapy
CR/nCR 18% and CR + PR 88% - Jagannath Br J Haematol 2005
CR/nCR 21% and CR + PR 66% - Harousseau Haematologica 2006
Phase III Trials:
BD is superior to VAD as induction therapy
CR/nCR 20% and CR + PR 82% - Harousseau ASH 2006
3
Background
Goal: Double the CR/nCR rate from 20% to 40%
Achieve by combining all four classes of active agents
Dexamethasone most potent glucocorticoid
Cyclophosphamide alkylating agent with less stem cell
toxicity
Bortezomib - a first-in-class proteasome inhibitor
Thalidomide an IMiD approved for frontline use
4
A Phase II Multicenter Trial in Newly Diagnosed MM
BCD x 3 Followed by BTD x 3
Objectives
Primary Objectives
To assess the response rate to BCD x 3 / BTD x 3 in newly
diagnosed myeloma patients
Primary target to achieve > CR/nCR of > 40%
Secondary Objective
To determine the safety and tolerability of BCD/BTD
To assess VGPR rate versus Bortezomib/dexamethasone
5
Patient Eligibility
Patients with newly diagnosed MM requiring treatment
Inclusion criteria
No previous chemotherapy; KPS 50%
Measurable disease
Age 18 years
Exclusion criteria
HIV
Hemodialysis
Plasma cell leukemia
6
Protocol Flow Diagram
Newly Diagnosed Symptomatic Myeloma
Bortezomib / Cyclophosphamide / Dexamethasone
(1.3 mg/m2)*
(300mg/m2)**
(40mg)***
Three 21 day courses
*Bortezomib days 1, 4, 8, 11
** Cyclophosphamide iv 300mg/m2 days 1and 8
*** Dexamethasone 40mg days 1, 2, 4, 5, 8, 9, 11, 12
Bortezomib / Thalidomide / Dexamethasone
(1.0 mg/m2)
(100mg daily)
(40mg)
Three 21 day courses
*Bortezomib days 1, 4, 8, 11
** Thalidomide 100 mg daily
*** Dexamethasone 40mg days 1, 4, 8, 11
7
Baseline Patient Characteristics (N = 30)
Characteristic
Mean age, years (range)
58 years (38-78)
Male, %
67 %
Median KPS, % (range)
90 (60100) %
-microglobulin 4 mg/L, %
38 %
2
Serum creatinine, > 2mg/dl ("B")
13 %
DurieSalmon stage III, %
73 %
Type of myeloma (%)
IgG
71 %
IgA
11 %
Light-chain disease
18 %
8
Cumulative Best Response (N = 26)**
** 4 patients too early for full response assessment
BCD
BCD + BDT
100
92%*
92%*
90
19
80
)
70
42
%
54%
(
60
te
CR/nCR
35
61%
ar 50
VGPR
es 40
19
n
PR
30
espoR 20
38
31
10
0
36
Cycles
*2 patients "stable" throughout 6 cycles
9
Current Follow-Up
All evaluable patients completed > 4 cycles; 85%
completed 6 cycles.
7 patients have undergone transplantation
Harvest/transplant has proceeded smoothly, without
any harvesting or other issues.
10
Safety: First 26 Patients
Bortezomib related neuropathy Gd > 2: 20% (5 pts)
Neuropathy after starting Thalidomide (Gd > 2): : 15% (4 pts)
15% patients discontinued Bortezomib or Thalidomide
Dexamethasone toxicities (Gd > 2)(Insomnia/Hyperglycemia): 15%
Cytoxan® toxicities (Neutropenia/Pneumonia) (Gd > 2): : 12%
Cytoxan® held in 1 patient
There were no DVT/PE (aspirin prophylaxis after thalidomide)
There were no treatment-related mortality
However, 1 patient died while on no therapy 2 months after
achieving nCR and completing all therapy. Died suddenly
(unknown cause) post-op elective hernia repair
11
Comparison With Prior Study
Bortez/Dex
BCD/BTD
N=49
N=26
100%
88%
92%
90%
80%
19%
)
70%
> CR/nCR
42%
(%
60%
20%
te
> CR/nCR
CR/nCR
ar 50%
> VGPR
VGPR
e
19%
s
40%
n
PR
o
> VGPR
p
30%
se
49%
R
20%
PR
31%
10%
PR
0%
BD
BCD/BTD
12
Conclusion
Bortezomib, cyclophosphamide, dexamethasone followed by
bortezomib, thalidomide and dexamethasone was effective
Response rate was >90%, with VGPR >60%
CR/nCR = 42% (exceeds goal of > 40%)
Improved over Btz-Dex alone
The combination was well tolerated with 85% completing all 6
cycles
Adverse events were predictable and manageable
CTC gr > II Neurotoxicity encountered in 35%
Discontinued therapy from toxicity 15%
Painful neuropathy completely resolved
Stem cell harvest was successful and engraftment was prompt
13
Collaborators
Bill Bensinger
Fred Hutchinson Cancer Research Center, Seattle, WA
Robert Vescio
Cedars-Sinai Cancer Center, Los Angeles, CA
Comprehensive Cancer Center of the Desert, Palm
Elber Camacho
Springs, CA
Jeffrey Wolf
University of California, San Francisco, CA
David Irwin
Alta Bates Summit Comprehensive Cancer Center,
Gerardo Capo
Berkeley, CA
David H. Vesole
Trinitas Comprehensive Cancer Center, NJ
St. Vincent's Comprehensive Cancer Ctr, NY,
Amitabha Mazumder
John Crowley
Ctr for Research and Biostatistics, Seattle
Dixie Esseltine
Millennium Pharmaceuticals, Inc.,
Marti McKinley
Aptium Oncology Research Network
Brian G.M. Durie
14