Post on 04-Jan-2016
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Welcome and IntroductionWelcome and IntroductionWelcome and IntroductionWelcome and Introduction
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Moderator:Moderator:
Richard Lutes, MDRichard Lutes, MD
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Upfront TherapyUpfront TherapyUpfront TherapyUpfront Therapy
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)
Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)
Rajkumar SV, et al, ASCO 2007, Abstract LBA8025.
25201510500
0.2
0.6
1
Overall survival (mo)
Pro
bab
ility 0.8
0.4
Log-rank P=0.0001
Rd
RD
AB
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.
1-year survival rate 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)
Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)
Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)
Toxicity, %
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
Rajkumar SV, et al, ASCO 2007, Abstract LBA8025.
Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)
Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)
Melphalan-prednisone-thalidomide (MPT) vs melphalan-prednisone (MP) in patients aged ≥75 years (IFM 01-01 trial)
Melphalan-prednisone-thalidomide (MPT) vs melphalan-prednisone (MP) in patients aged ≥75 years (IFM 01-01 trial)
Best response at 12 months, %
MPn=100
MPTn=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)
Melphalan-prednisone-thalidomide (MPT) vs melphalan-prednisone (MP) in patients aged ≥75 years (IFM 01-01 trial)
hulin c, et al, ASCO 2007, Abstract 8001.
0
0.25
0.75
1
0.50
Time from randomization (mo)50403020100 60
Log-rank P=0.05Median follow-up time = 24 months
MPTMedian OS = 45.3 mo[33.3 – Unreached] Y/N=39/100
MP PlaceboMedian OS = 27.7 mo[24.6 – 34.9] Y/N=54/100
Pro
po
rtio
n
Overall survival by treatment (n=200)
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Upfront TherapyUpfront Therapy
DiscussionDiscussion
Upfront TherapyUpfront Therapy
DiscussionDiscussion
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Moderator:Moderator:
Richard Lutes, MDRichard Lutes, MD
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
TransplantationTransplantationTransplantationTransplantation
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
TTIII plus bortezomibTTIII plus bortezomib
Barlogie B, et al, ASCO 2007, Abstract 8020.
36241200
20
60
100
Months from Start of Induction
80
40
PR
nCR
CR
Pe
rce
nt
of
pa
tien
ts (
%)
TTIII plus bortezomibTTIII plus bortezomib
Barlogie B, et al, ASCO 2007, Abstract 8020.
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
Alternating bortezomib and dexamethasone as induction regimen in younger MM patientsAlternating bortezomib and dexamethasone as induction regimen in younger MM patients
Rosinol L, et al, ASCO 2007, Abstract 8024.
End of Induction Treatment (n=40)
Best Response Ever Achieved(n=40)
ORR: 77.5%ORR: 82.5%
17%
42%10%
12%
3%
8%
8%17%
42%10%
12%
3%
8%
8%
MR PR VGPR CR Non-evaluable Progression Stable
17%
39%8%
13%
3%
17%
3%17%
39%8%
13%
3%
17%
3%
Alternating bortezomib and dexamethasone as induction regimen in younger MM patientsAlternating bortezomib and dexamethasone as induction regimen in younger MM patients
Rosinol L, et al, ASCO 2007, Abstract 8024.
Liver
Gastrointestinal
Peripheral Neuropathy
Thrombocytopenia
Percent
Neutropenia
SkinGrade 1
Grade 2
Grade 3
0 604020 10080
Fatigue
Characteristics of patients relapsing after autologous stem cell transplantCharacteristics of patients relapsing after autologous stem cell transplant
Characteristics, %Early relapse
n=94Late 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
Stage III 72.4 63.8 NS
>1 induction regimen 18 8 0.007
Abnormal karyotype 34 14.8 <0.0001
Circulating PC at collection 51.1 36.4 0.01
Mahmood ST, et al, ASCO 2007, Abstract 8022.
Mel-based autotransplants for MMMel-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
• 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 conditioningReduced 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%)
• 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
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
TransplantationTransplantation
DiscussionDiscussion
TransplantationTransplantation
DiscussionDiscussion
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Moderator:Moderator:
Richard Lutes, MDRichard Lutes, MD
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Treating Relapsed/Refractory DiseaseTreating Relapsed/Refractory DiseaseTreating Relapsed/Refractory DiseaseTreating Relapsed/Refractory Disease
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Pegylated doxorubicin (PLD) and bortezomib vs bortezomib alonePegylated doxorubicin (PLD) and bortezomib vs bortezomib alone
Response rates, %
Bortezomibn=310
PLD + bortezomib
n=303 P value
Total (CR + nCR + PR)
44 52 0.05
CR + nCR 13 17
PR 31 35
CR + VGPR* 20 30 0.007
*According to IMWG 2006 criteria.Harousseau JL, et al, ASCO 2007, Abstract 8002.
Pegylated doxorubicin (PLD) and bortezomib vs bortezomib alonePegylated doxorubicin (PLD) and bortezomib vs bortezomib alone
Harousseau JL, et al, ASCO 2007, Abstract 8002.
PLD +Bortezomib Bortezomib
CensoredDied
82%18%
75%25%
HR (95% CI) 1.41 (1.002, 1.97)P<0.05
50040030020010000
20
60
100
Time (d)
Pe
rce
nt
of
Su
bje
cts
Aliv
e (
%)
80
40
700600
PLD + Bortezomib
Bortezomib
Overall survivalMedian follow-up time: 14 mo
Effect of prior thalidomide treatment on efficacy of pegylated doxorubicin (PLD) and bortezomib
Effect of prior thalidomide treatment on efficacy of pegylated doxorubicin (PLD) and bortezomib
Time to progression
PLD + bortezomib (vs bortezomib)IMiD exposed
PLD + bortezomib (vs bortezomib)
IMiD naiveHeterogeneity
test*
Median, d 270 (vs 205) 295 (vs 189)
Hazard ratio (95% CI)
Log-rank P value)
1.62 (1.08, 2.41)P=0.018
2.01 (1.42, 2.84)P<0.0001
P=0.446
*Treatment by subgroup (IMiD exposed, IMiD naïve) interaction test from the Cox model.Sonneveld P, et al, ASCO 2007, Abstract 8023.
Effect of prior thalidomide treatment on efficacy of pegylated doxorubicin (PLD) and bortezomib
Effect of prior thalidomide treatment on efficacy of pegylated doxorubicin (PLD) and bortezomib
*According to IMWG criteria.Sonneveld P, et al, ASCO 2007, Abstract 8023.
PLD + Bortezomib IMiD exposed
n=123
PLD + BortezomibIMiD naïve
n=180
Time to progression, %
OR (CR + PR) 48 47
CR 4 5
PR 44 42
nCR 9 9
CR + VGPR* 31 27
Duration of response (CR + PR), days
319 310
Factors predictive of outcome in patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)
Factors predictive of outcome in patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)
Palumbo AP, et al, ASCO 2007, Abstract 8048.
1
Months
0
0.75
0.50
P=0.02
≥ PR
< PR
Age: 65 yearsResponse: PR rate
0.25
7.55.02.50 17.515.012.510.0
Pro
po
rtio
n o
f P
atie
nts
1
Months
0
0.75
0.50
P=0.19
<65 years
≥65 years
0.25
7.55.02.50 17.515.012.510.0
Pro
po
rtio
n o
f P
atie
nts
Factors predictive of outcome in patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)
Factors predictive of outcome in patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)
Palumbo AP, et al, ASCO 2007, Abstract 8048.
1
Months
0
0.75
0.50
P=0.98
Del (13)
No Deletion
2-microglobulinDeletion (13)
0.25
7.55.02.50 17.515.012.510.0
Pro
po
rtio
n o
f P
atie
nts
1
Months
0
0.75
0.50
P=0.06
2m <3.5 mg/dL
2m >3.5 mg/dL0.25
7.55.02.50 17.515.012.510.0
Pro
po
rtio
n o
f P
atie
nts
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Novel AgentsNovel AgentsNovel AgentsNovel Agents
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Tanespimycin + bortezomib in relapsed/refractory MMTanespimycin + 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
• 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 malignanciesPhase 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
• 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
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Novel AgentsNovel Agents
DiscussionDiscussion
Novel AgentsNovel Agents
DiscussionDiscussion
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Moderator:Moderator:
Richard Lutes, MDRichard Lutes, MD
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting
Final ThoughtsFinal ThoughtsFinal ThoughtsFinal Thoughts
Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute
Boston, MABoston, MA
S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN
Featuring:Featuring:
Moderator:Moderator:
Richard Lutes, MDRichard Lutes, MD