Transcript A Multicenter Prospective Randomized Study Testing Non

Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Welcome and Introduction
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Moderator:
Richard Lutes, MD
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Upfront Therapy
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Lenalidomide/high-dose dexamethasone vs
lenalidomide/low-dose dexamethasone
(ECOG trial E4A03)
Rd
Probability
1
0.8
RD
0.6
0.4
0.2
A
B
Log-rank P=0.0001
0
0
5
10
15
20
25
Overall survival (mo)
Subjects, n
Events, n (%)
Censored,
n (%)
Median survival (95% CI)
A Len/High-dose Dex (RD)
223
41 (18)
182 (82)
NA (23.56, NA)
B Len/Low-dose Dex (Rd)
222
13 (6)
209 (94)
NA (NA, NA)
Rajkumar SV, et al, ASCO 2007, Abstract LBA8025.
Lenalidomide/high-dose dexamethasone vs
lenalidomide/low-dose dexamethasone
(ECOG trial E4A03)
N
Events
Survival
Probability
(95% CI)
Len-High Dex (RD)
223
26
0.87 (0.82, 0.92)
Len-Low Dex (Rd)
222
8
0.96 (0.94, 0.99)
1-year survival rate
Rajkumar SV, et al, ASCO 2007, Abstract LBA8025.
Lenalidomide/high-dose dexamethasone vs
lenalidomide/low-dose dexamethasone
(ECOG trial E4A03)
Len/
High-dose Dex
n=217
Len/
Low-dose Dex
n=216
P value
Any non-Hem toxicity
(Grade ≥3)
52.1
34.3
<0.001
Toxicity of any type
(Grade ≥4)
28.6
18.1
0.003
Early Deaths
(<4 months)
4.5
1.4
0.034
Toxicity, %
Rajkumar SV, et al, ASCO 2007, Abstract LBA8025.
Melphalan-prednisone-thalidomide (MPT) vs
melphalan-prednisone (MP) in patients aged ≥75
years (IFM 01-01 trial)
Best response at
12 months, %
MP
n=100
MPT
n=100
At least PR (50%)
31
61
At least VGPR (90%)
8
23
Complete remission
1
7
P<0.0001
hulin c, et al, ASCO 2007, Abstract 8001.
Melphalan-prednisone-thalidomide (MPT) vs
melphalan-prednisone (MP) in patients aged ≥75
years (IFM 01-01 trial)
Overall survival by treatment (n=200)
Proportion
1
MPT
Median OS = 45.3 mo
[33.3 – Unreached] Y/N=39/100
0.75
0.50
MP Placebo
Median OS = 27.7 mo
[24.6 – 34.9] Y/N=54/100
0.25
0
0
10
20
30
40
50
Time from randomization (mo)
Log-rank P=0.05
Median follow-up time = 24 months
hulin c, et al, ASCO 2007, Abstract 8001.
60
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Upfront Therapy
Discussion
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Moderator:
Richard Lutes, MD
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Transplantation
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Percent of patients (%)
TTIII plus bortezomib
100
PR
nCR
80
CR
60
40
20
0
0
12
24
Months from Start of Induction
Barlogie B, et al, ASCO 2007, Abstract 8020.
36
TTIII plus bortezomib
Endpoint at 24 months
%
Overall survival
87
Event-free survival
84
CR
91
nCR
80
PR
60
Treatment-related mortality
5
Post-relapse survival
34
Barlogie B, et al, ASCO 2007, Abstract 8020.
Alternating bortezomib and dexamethasone as
induction regimen in younger MM patients
Best Response Ever Achieved
(n=40)
8%
End of Induction Treatment
(n=40)
3%
17%
17%
17%
8%
3%
3%
12%
13%
10%
42%
39%
8%
ORR: 82.5%
MR
PR
VGPR
Rosinol L, et al, ASCO 2007, Abstract 8024.
ORR: 77.5%
CR
Non-evaluable
Progression
Stable
Alternating bortezomib and dexamethasone as
induction regimen in younger MM patients
Thrombocytopenia
Neutropenia
Peripheral
Neuropathy
Skin
Grade 1
Grade 2
Gastrointestinal
Grade 3
Fatigue
Liver
0
20
40
60
Percent
Rosinol L, et al, ASCO 2007, Abstract 8024.
80
100
Characteristics of patients relapsing
after autologous stem cell transplant
Early relapse
n=94
Late relapse
n=338
P value
Male
61.7
57.7
NS
PCLI ≥1%
41.9
15.5
<0.001
β2-microglobulin >3.5 mg/dL
28.7
23.1
NS
Bone disease
12.8
15.4
NS
Refractory at transplant
41.5
29.3
0.03
Durie-Salmon: Stage II
27.6
36.2
NS
72.4
63.8
NS
>1 induction regimen
18
8
0.007
Abnormal karyotype
34
14.8
<0.0001
51.1
36.4
0.01
Characteristics, %
Stage III
Circulating PC at collection
Mahmood ST, et al, ASCO 2007, Abstract 8022.
Mel-based autotransplants for MM
• Retrospective analysis of 2836 transplant
patients identified 5 factors that could
influence outcomes
–
–
–
–
–
Type of treatment (tandem transplant or not)
Presence of cytogenetic abnormality
High β2-microglobulin
Low albumin
Low platelet counts
Pineda-Roman M, et al, ASCO 2007, Abstract 8043.
Reduced intensity conditioning
• 32 patients with relapsed/refractory MM
– 19 patients with HLA-identical sibling donor
• 5 patients had disease progression
• 4 patients in complete remission
• 5 patients in PR or VGPR
– 13 patients with no HLA-identical donor
• 11 patients had disease progression
– Overall, 6 patients died from treatment-related
mortality (incidence, 33%)
Mohty M, et al, ASCO 2007, Abstract 8045.
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Transplantation
Discussion
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Moderator:
Richard Lutes, MD
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Treating Relapsed/Refractory Disease
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Pegylated doxorubicin (PLD) and
bortezomib vs bortezomib alone
Response rates,
%
Total
(CR + nCR + PR)
PLD +
Bortezomib bortezomib
n=310
n=303
P value
44
52
CR + nCR
13
17
PR
31
35
CR + VGPR*
20
30
*According to IMWG 2006 criteria.
Harousseau JL, et al, ASCO 2007, Abstract 8002.
0.05
0.007
Percent of Subjects Alive (%)
Pegylated doxorubicin (PLD) and
bortezomib vs bortezomib alone
Overall survival
Median follow-up time: 14 mo
100
PLD + Bortezomib
80
60
40
Censored
Died
20
Bortezomib
PLD +
Bortezomib
Bortezomib
82%
18%
75%
25%
HR (95% CI) 1.41 (1.002, 1.97)
P<0.05
0
0
100
200
300
400
Time (d)
Harousseau JL, et al, ASCO 2007, Abstract 8002.
500
600
700
Effect of prior thalidomide treatment on
efficacy of pegylated doxorubicin (PLD) and
bortezomib
Time to progression
Median, d
Hazard ratio (95% CI)
Log-rank P value)
PLD + bortezomib
(vs bortezomib)
IMiD exposed
PLD + bortezomib
(vs bortezomib)
IMiD naive
270 (vs 205)
295 (vs 189)
1.62 (1.08, 2.41)
P=0.018
2.01 (1.42, 2.84)
P<0.0001
*Treatment by subgroup (IMiD exposed, IMiD naïve) interaction test from the Cox model.
Sonneveld P, et al, ASCO 2007, Abstract 8023.
Heterogeneity
test*
P=0.446
Effect of prior thalidomide treatment on
efficacy of pegylated doxorubicin (PLD) and
bortezomib
PLD + Bortezomib
IMiD exposed
n=123
PLD + Bortezomib
IMiD naïve
n=180
OR (CR + PR)
48
47
CR
4
5
PR
44
42
nCR
9
9
CR + VGPR*
31
27
319
310
Time to progression, %
Duration of response (CR + PR),
days
*According to IMWG criteria.
Sonneveld P, et al, ASCO 2007, Abstract 8023.
Factors predictive of outcome in patients treated
with bortezomib, melphalan, prednisone, and
thalidomide (VMPT)
Response: PR rate
Age: 65 years
1
≥ PR
0.75
0.50
< PR
0.25
<65 years
Proportion of Patients
Proportion of Patients
1
0.75
≥65 years
0.50
0.25
P=0.02
P=0.19
0
0
0
2.5
5.0
7.5 10.0 12.5 15.0 17.5
Months
Palumbo AP, et al, ASCO 2007, Abstract 8048.
0
2.5
5.0
7.5 10.0 12.5 15.0 17.5
Months
Factors predictive of outcome in patients treated
with bortezomib, melphalan, prednisone, and
thalidomide (VMPT)
2-microglobulin
Deletion (13)
1
1
0.75
Del (13)
0.50
No Deletion
0.25
Proportion of Patients
Proportion of Patients
2m <3.5 mg/dL
0.75
0.50
0.25
2m >3.5
mg/dL
P=0.98
P=0.06
0
0
0
2.5
5.0
7.5 10.0 12.5 15.0 17.5
Months
Palumbo AP, et al, ASCO 2007, Abstract 8048.
0
2.5
5.0
7.5 10.0 12.5 15.0 17.5
Months
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Novel Agents
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Tanespimycin + bortezomib in
relapsed/refractory MM
• Tanespimycin (17-AAG/KOS 953) disrupts
heat shock protein 90 (hsp90), a
molecular chaperone that transports
proteins critical for MM growth, survival,
and drug resistance
– Phase I dose escalation study in 49 patients
• 7th dose level reached so far
– Combination treatment was well tolerated
– Combination treatment resulted in inhibition of
hsp90 and proteasome activity
Richardson PG, et al, ASCO 2007, Abstract 3532.
Phase I evaluation of carfilzomib
(PR-171) in hematologic malignancies
• Carfilzomib is a novel irreversible proteasome inhibitor
– Promotes >80% proteasome inhibition in the blood
• Dose-limiting toxicities
– Myelosuppression: cyclic reversible thrombocytopenia and
neutropenia
– A “first dose effect” has occurred at doses ≥20 mg/m2 and
heralds rapid decline in M-protein
• Objective responses have been observed at doses of
carfilzomib ranging from 11 mg/m2 to 27 mg/m2
–
–
–
–
Rapid onset of response (<1 month)
Responses are durable (4 to >9.5 months)
Responses noted in bortezomib and IMiD failures
Stable disease for >1 year
Stewart KA, et al, ASCO 2007, Abstract 8003.
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Novel Agents
Discussion
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Moderator:
Richard Lutes, MD
Multiple Myeloma Update from the
American Society of Clinical Oncology
(ASCO) 43rd Annual Meeting
Final Thoughts
Featuring:
Nikhil Munshi, MD
Dana-Farber Cancer Institute
Boston, MA
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN
Moderator:
Richard Lutes, MD