Download Myeloma Frontline Therapy 2004

NOVEL THERAPIES:
Frontline Approaches 2004
Brian G.M. Durie, M.D.
Traditional Frontline Therapy
Transplant Planned
VAD or DEX
No Transplant
MP or variant
Transplant Planned
Consider
Medical Eligibility
Age
Personal Choice
Novel Options
For Frontline
Thalidomide
VELCADE
A Randomized Phase III Trial of
Thalidomide Plus Dexamethasone
Versus Dexamethasone
in Newly Diagnosed Multiple Myeloma (E1A00)
R
A
N
D
O
M
I
Z
A
T
I
O
N
E1A00: 207 patients
Thal + Dex
x4 cycles
CR/PR/
Stable
Dex
x 4 cycles
Prog
anytime
Off Rx @ 4
monthsfor transplant*
Off Rx
*Treatment beyond 4 cycles was permitted at physician
discretion
S. V. Rajkumar et al. Proc ASCO 2004
Dose
Arm A
Thal 200 mg PO daily
plus Dex 40 mg day 14, 9-12, 17-20
Arm B
Dex 40 mg day 1-4, 9-12,
17-20
All pts received pamidronate or zoledronic acid monthly
S. V. Rajkumar et al. Proc ASCO 2004
Results
Best Response* within 4 Cycles
Thal/Dex: 67/98 pts (68%)
Dex:
46/98 pts (46%)
*allowing for using serum M protein levels in patients in whom
measurable urine M protein was unavailable at follow-up
S. V. Rajkumar et al. Proc ASCO 2004
Major Toxicities Within 4 Cycles
Toxicity
Thal/Dex
(N=102)
Dex
(N=101)
DVT (Grade >=3)
16 (16%)
3 (3%)
Rash (Grade >=3)
4 (4%)
0 (0%)
Sinus bradycardia (Grade >=3)
1 (1%)
0 (0%)
Neuropathy (Grade >=3)
6 (6%)
4 (4%)
Toxicity of Any Type (Grade >=4)
34 (33%)
16 (15%)
Total **
45 (44%)
19 (19%)
** Rows do not add to total as patients could have more than one of
toxicity types
S. V. Rajkumar et al. Proc ASCO 2004
these
Conclusions
Thal/Dex is an effective induction therapy in
newly diagnosed multiple myeloma
Response rates with Thal/Dex are superior to
Dex alone but the risk of added toxicity is
higher
Risks/Benefits need to be balanced when
deciding on therapy
Conclusions
Given these results there is little reason to
use VAD as initial treatment for myeloma
DVT prophylaxis needed while using Thal/Dex
Future trials of front-line therapy using more
aggressive oral/intravenous therapy need to
show significant superiority over Thal/dex in
randomized trials
Future ECOG strategy: Phase III with CC5013+Dex (E4A03)
VELCADE (bortezomib) Compared
to high-dose Dexamethasone in
Relapsed Multiple Myeloma:
A Phase III Randomized Study
(APEX)
ASCO Press Briefing
Paul Richardson, M.D.
Dana Farber Cancer Institute
Saturday, June 5, 2004
Study Design
Phase III APEX trial to assess VELCADE
compared to high-dose dexamethasone
International, randomized, controlled
study in patients with relapsed or
refractory multiple myeloma
One-to-three prior lines of therapy
669 patients enrolled at 94 centers
Study Design (cont’d)
End points
Primary: time to progression (TTP)
Secondary: survival, response rate (RR) and
duration, time to skeletal events (TSE), incidence
of ≥ G3 infection, safety
Exploratory: quality of life (QOL),
pharmacogenomics
Companion crossover study provided
VELCADE to patients progressing on
dexamethasone arm
Patients refractory to high-dose
dexamethasone were excluded from the
study
Time to Progression (Interim Analysis)
58% improvement in median TTP with
VELCADE
Bortezomib
(n = 327)
P < 0.0001
Dexamethasone
(n = 330)
Median TTP:
VELCADE arm – 5.7 months
Dexamethasone arm – 3. 6 months
Final Survival Analysis*
(Includes Crossover Patients)
Bortezomib (n = 333)
Dexamethasone (n = 336)
1 year
244 days median follow-up in survivors
-VELCADE: 48 deaths
-Dexamethasone: 81 deaths
Overall survival, P < 0.01
1-year survival, P < 0.01
*January 13, 2004
Risk of death in the first year reduced by ~30 percent in
VELCADE arm
Statistical significance held even with ~50% of patients crossing
over from dexamethasone arm to receive VELCADE
First-line Therapy With Bortezomib
(VELCADE®, Formerly PS-341)
in Patients With Multiple Myeloma
Multi-Institutional Phase II Clinical Trial
Sundar Jagannath,1 Brian G.M. Durie,1 Jeffrey Wolf,1
Elber Camacho,1 David Irwin,1 Jose Lutzky,1 Marti McKinley,1
Eli Gabayan,1 Amitabha Mazumder,1 John Crowley,2
David Schenkein3
1Salick
Health Care Research Network, Los Angeles, CA; 2Center for Research &
Biostatistics, Seattle, WA; 3Millennium Pharmaceuticals, Inc., Cambridge, MA
Treatment Plan
Bortezomib 1.3 mg/m2 2x/week x2 q 3
weeks for a maximum of 6 cycles
Dex 40 mg permitted only on the day of
and after each bortezomib dose
After 2 cycles for patients who achieve less than a PR
After 4 cycles for patients who achieve less than a CR
(immunofixation negative)
Dex dose was twice the dose used in the phase 2
bortezomib trials (SUMMIT/CREST)5,6
Premedication was allowed according to
physician discretion
Current Best Overall Responses
(n = 24)
Response*
CR
NCR
PR
MR
SD
PD
n (%)
2 (8)
4 (17)
13 (54)
4 (17)
0 (0)
1 (4)
Overall 79%
*Responses based on paraprotein.
• Bortezomib alone induced CR/NCR in 6 patients;
2 of these NCR patients received dexamethasone and response
status remained unchanged
Addition of Dexamethasone (n = 14)
Dexamethasone was added to the
treatment of
8 patients at cycle 3
6 patients at cycle 5
Additional response after dexamethasone,
8/14
Response improved by 2 levels:
SD to PR: 2
Response improved by 1 level:
MR to PR: 4
SD to MR: 2
Serum M Protein for First 9 Patients
(≤ 4 Cycles)
Serum M Protein,
% of Baseline
1.25
1
0.75
0.5
0.25
0
0
1
2
3
Cycle
4
5
6
Treatment-Related Adverse Events*
(n = 24)
Neuropathic pain
Sensory neuropathy
Fatigue
Diarrhea
Constipation
Maximum grade: any AE
0
2
4
6
8
10 12 14 16 18 20 22 24
Number of Patients
Maximum toxicity grade:
1
*Adverse events graded per NCI CTC v2.
2
3
4
Ancillary Findings
Stem cell harvesting
Has proceeded without difficulty
Successful harvest: 5/5 (100%)
2 patients transplanted with complete
hematologic recovery
Conclusions
Bortezomib was effective and well tolerated as
front-line therapy in this study
This phase 2 study has demonstrated a 79%
response rate
Combination with dexamethasone provides added
benefit in some patients
Stem cell harvesting and engraftment was
feasible
Development of peripheral neuropathy and
resolution requires further study; monitoring in
the clinical setting is warranted
Accrual ongoing: Currently 36 patients
Multi-Institutional Phase II Clinical Trial
PAD Combination Therapy
(Bortezomib/Formerly PS-341,
Adriamycin and Dexamethasone)
for Previously Untreated Patients
With Multiple Myeloma
J. D. Cavenagh,1 N. Curry,1 J. Stec,2 C. Morris,3 M. Drake,3
S. Agrawal,1 P. Smith,1 D. Schenkein,2 D. Esseltine,2 H.
Oakervee1
1St
Bartholomew’s Hospital, London, UK
2Millennium Pharmaceuticals, Inc., Cambridge, MA, USA;
3Belfast City Hospital, Belfast, UK
Treatment
Induction (4 cycles prior to transplantation)
Bortezomib 1.3 mg/m2 by IV bolus on days 1, 4,
8, and 11
Doxorubicin administered by continuous infusion
or IV push to cohorts at escalating dose levels on
days 1–4
Dexamethasone 40 mg PO
• Cycle 1: days 1–4, 8–11, and 15–18
• All subsequent cycles: days 1–4
Treatment
Day
Cycle 1
1
4
8
11
15
18
21
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Adriamycin
Day
Cycles 2–4
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Adriamycin
1
4
8
11
15
18
21
Level 1: No Adriamycin
CD34+ cells × Response
Response 106/kg (No. of
3 Mo
Patient After 4
harvesting
PostNo.
Cycles
attempts)
Autograft
1
PR
4.2 (1)
VGPR
2
VGPR
2.7 (2)
CR
3
CR
1.6 (2)
NA
Level 2: Adriamycin 4.5
CD34+ cells × Response
Response
Patient
106/kg (No. of
3 Mo
After 4
No.
harvesting
PostCycles
attempts)
Autograft
4
PR
7.4 (1)
VGPR
5
VGPR
2.3 (2)
CR
6
PR
4.7 (1)
PR
7
PR
3.6 (2)
PR
Level 3: Adriamycin 9.0
*After 1–2 cycles.
†After 3 cycles.
na = not available.
Patient No.
Response
After 4 Cycles
CD34+ cells × 106/kg
(No. of harvesting
attempts)
Response 3 Mo
Post-Autograft
8
PR
1.9 (1)
VGPR
9
VGPR*
2.1 (1)
na
10
VGPR
4.7 (4)
VGPR
11
PR
0
na
12
CR
4.3 (4)
na
13
SD
3.7 (2)
na
14
VGPR
2.5 (3)
na
15
VGPR†
2.8 (6)
na
16
VGPR
10.4 (2)
na
17
PR
na
na
18
PR
na
na
19
VGPR*
na
na
20
CR*
na
na
21
PR*
na
na
N = 14
2 CR, 6 VGPR,
5 PR, 1 SD
Outcome After PAD Induction
95% CR/PR rate (3 CR, 8 VGPR, and 9 PR)
after ≥ 1 cycle of treatment (n = 21)
1 CR after PD alone
2 CRs after PAD
94% CR/PR rate (2 CR, 7 VGPR, 8 PR)
after 4 cycles (n = 18)
Serum/Urinary Myeloma Protein Response by PAD Cycle
120
Isotype
IgAκ
IgAλ
Change in Myeloma Protein (%)
110
100
IgGκ
IgGλ
κ-LC
λ-LC
90
80
70
60
Mean ±
SEM
50
40
30
20
10
0
Pre-Rx
#1
#2
#3
#4
Treatment Cycle
• M-protein levels decreased by a mean of 70% following cycle 1 of treatment
Neuropathy
N = 21
Frequency of
Sensory
Neuropathy
(53%)
Frequency of
Painful
Neuropathy
(43%)
Grade
1
9 (43)
8 (38)
3
2 (10)
1 (5)
1–2
4 (19)
2 (10)
3–4
6 (29)
5 (24)
PAD
Cycle
Melphalan
1 (5)
2 (10)
More frequent after 2nd cycle
Neuropathic symptoms improving in all
patients after completion of therapy
Conclusions
PAD combination therapy is an effective
regimen for previously untreated patients
with multiple myeloma
94% CR/PR rate after 4 cycles
15 of 16 patients mobilised, 11/15 transplanted
thus far
All 8 evaluable patients achieved PR or better
following PBSCT (2 CR, 4 VGPR, 2 PR)
Major toxicity was painful neuropathy
A second cohort is being recruited to receive
a reduced dose of bortezomib (1.0 mg/m2)
ORAL MELPHALAN,
PREDNISONE, AND
THALIDOMIDE
FOR NEWLY DIAGNOSED
MYELOMA PATIENTS
A. Palumbo*, A. Bertola*, P. Musto°, M. Nunzi°,
V. De Stefano°, L. Catalano°, T. Caravita°,
C. Cangialosi°, S. Bringhen*, M. Boccadoro*.
Divisione Universitaria di Ematologia, Azienda
Ospedaliera S. Giovanni Battista, Torino–Italy*, and the
Italian Multiple Myeloma Study Group°
Patient Characteristics for MPT Trial (n=42)
Median age
Range
72
61-80
Male
Female
23 (55)
19 (45)
Stage IIA
Stage IIIA
Stage IIIB
18 (43)
17 (40)
7 (17)
ß2-microglobulin < 3mg/L 14 (33)
ß2-microglobulin > 3mg/L 23 (55)
Data missing
5 (12)
IgG
IgA
Bence Jones protein
26 (62)
9 (21)
7 (17)
Response After MPT (42 Patients)
50
%
of
R
e
s
p
o
n
s
e
40
45%
36%
19%
30
20
26%
12%
7%
10
0
CR+nCR
VGPR
(90%–99%)
PR
(50%–89%)
NR
Time to Maximum Response
100
80
%
60
40
20
0
0
1
2
3
4
5
months
6
9
12 15 16
Time to Onset of Adverse Events
40
30
% 20
10
0
0
2
4
6
8
months
10
12
14
16
Conclusions
MPT is very active in previously
untreated patients with multiple
myeloma.
45% of patients achieved CR and nCR
93% of patients achieved a PR or better
MPT was generally well-tolerated
Conclusions (cont’d)
The most serious adverse events with
this regimen were infection and DVT,
suggesting the need for prophylaxis
with antibiotics and anticoagulants
The CR rate was similar to rates
observed after high-dose chemotherapy
followed by stem cell transplantation
(42%)
Conclusions (cont’d)
MPT appears to be a promising
regimen. However, a general
recommendation for its adoption cannot
be made until the following are
determined:
Time to disease progression
Overall survival of these patients
Potential effectiveness of prophylactic
antibiotics and anticoagulants
Current Status
New Trial in Europe
MPT versus MP
Plan to Register MPT
As new standard of care
Frontline Therapy
New Issues
Response rate CR/PR
Length of remission (TTP)/survival (EFS)
Side effects
Time to harvest
WHAT’S NEXT?
Combinations
VELCADE + DOXIL (or ADRIA) + DEX
or
VELCADE + THALIDOMIDE (or REVIMID) + DEX
VELCADE + THALIDOMIDE
Example of Response
PS 341
2.0
2
1.8
M – P r o t e I n g / dL
+ DEX
+ THAL 100 mg
1.6
3
1.4
1.2
Resistant to prior THAL
1
1.0
0.8
0.6
0.4
0.2
0
4
5
6
7
8
C y c l e s o f T r e a t m e n t (1 – 8)
Role of Transplant
A single autotransplant is superior to
standard chemotherapy alone
The benefit in the setting of novel
therapies is unknown.
S9321 Survival in Context of
IFM 90 & MRC VII Trials
Standard Dose Therapy
Single Autotx
S9321
S9321
IFM90
IFM90
MRC VII
MRC VII
IFM 94 vs TT2
Overall Survival
TT1
TT2
IFM94 (2 Transplants)
IFM94 (1 Transplant)
2004 and Beyond
Conduct comparative trials
Stem Cell transplant: 1 or 2?
Novel Combinations
Select based on molecular data??
GEP Predicts Response to Velcade
Response
Actual
No Response
Response
No Response
Predicted
No Response
Response
17
2
3
18