debate: what is the best induction therapy for transplant-eligible patients? sequential therapy
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Debate: What is the best induction therapy for transplant-eligible patients? Sequential therapy. Tomer M. Mark Department of Medicine, Division of Hematology / Oncology Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Lymphoma & Myeloma 2013. Disclosures. - PowerPoint PPT PresentationTRANSCRIPT
Debate: What is the best induction therapy for transplant-eligible patients?
Sequential therapy.
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Tomer M. MarkDepartment of Medicine, Division of Hematology /
OncologyWeill-Cornell Medical College /
New York Presbyterian Hospital, New York, NY, USA
Lymphoma & Myeloma 2013
Disclosures
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Research Funding: Celgene Inc.; Onyx Inc.
Speakers Bureau: Celgene Corp; Millenium Inc.; Onyx Inc.
Membership on an entity's advisory committees: Celgene Corp., Millenium Inc.
Off-label usage of bortezomib, lenalidomide, and carfilzomib are discussed.
How do we best treat a chronic malignancy?
• Cure versus control: improved survival is the goal
• Regimen tolerability• Regimen cost• Do we burn bridges by using combination
therapy?• Do patients benefit more from deeper
response or longer duration of therapy?
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Stewart et al, 2009.
Not for debate: combination therapy gives deeper responses
What do we “know” ?
• Therapy has become better• Survival now approaches a decade• Although growing, therapy options are limited• Myeloma is not curable• More chemo is more toxic than less chemo• Deeper response to therapy does not always
translate into longer survival– We need to look at long-term follow up to see this.
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How do you maximize a limited arsenal?
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Lenalidomide
Bortezomib
Corticosteroids
Alkylators
Carfilzomib
Thalidomide
Goals of induction: quick reversal of symptoms & obtain disease control to lead to extended survival
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Induction Consolidation Maintenance Relapse Salvage
PFS
OS
Dx Death
Possible Treatment Scenarios:a) combination therapy adds to OS; salvage is just as effective
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Combination Induction
+/-ASCT Maintenance Salvage 1 Salvage 2 Salvage 3
Sequential Induction
+/-ASCT Maintenance Salvage 1 Salvage 2 Salvage 3
PFS
OS
Dx
Dx Death
Death
Possible Treatment Scenarios:b) combination therapy prolongs PFS but not OS due to less efficacious salvage
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Combination Induction
+/-ASCT Maintenance Salvage 1 2 3
Sequential Induction
+/-ASCT Maintenance Salvage 1 Salvage 2 Salvage 3
PFS
OS
Dx
Dx Death
Death
Which scenario fits the MM model better?
Tum
or V
olum
e →
Time →
Ineffective treatment
High-Dose Therapy
Alkylators
Dexamethasone
Goal of newertherapy options
Ultimate goal: Cure
Limit ofdetection
Natural History of MM:
Asymptomatic
20
50
100
Refractory Relapse MGUS* or
SmolderingMyeloma
Active Myeloma
Plateau Remission
Symptomatic
Relapse
Therapy
~60,000~20,000 New cases
in U.S.2
~11,000 Annual
deaths in U.S.2
Prevalence in the U.S.
M P
rote
in (g
/l)
*Monoclonal gammopathy of uncertain significance
Therapy Therapy
Response is not everything…• In TT-2, OS not increased in thal
arm, but CR frequency was higher1
– SUS-CR at 3 yrs predicted increased OS
– Achievement, then LOSS of CR predicted worse OS.
– Loss of CR correlates with negative prognostic factors (high ISS, IgA)
• Benefit of CR may be limited to high-GEP risk group.2
• Pts with MGUS or SMM may not benefit from getting to CR.3
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1. Barlogie B. et al. Cancer. 2008.113;2:355-3592. Haessler J. et al. Clin Cancer Res. 2007.13:7073-70793. Pineda-Roman M. et al. Br J Haematol. 2007.136:393-399.
Update of IFM 2005/01: Bortezomib/Dexamethasone (VD) vs. VAD Induction in Newly Diagnosed MM
• VAD: Vincristine 0.4 mg/m2 + doxorubicin 9 mg/m2 Days 1–4 continuous infusion; Dexamethasone 40 mg Days 1–4 (Cycles 1–4) and Days 9–12, 17–20 (Cycles 1–2)
• VD: Bortezomib 1.3 mg/m2 Days 1, 4, 8, 11; Dexamethasone 40 mg Days 1–4(Cycles 1–4) and Days 9–12 (Cycles 1–2)
• DCEP: Dexamethasone 40 mg Days 1–2; Cyclophosphamide 15 mg/m2, etoposide400 mg/m2, and cisplatin 10 mg/m2 Days 1–4 continuous infusion
Untreated MM patients ≤ 65 years
N = 482
VAD 28-day/cycle
VAD 28-day/cycle
VD21-day/cycle
DCEP Two 28-day
cycles
DCEP Two 28-day
cycles
Melphalan 200 mg/m2
+ ASCTa
4 cycles
VD21-day/cycle
aSecond ASCT or reduced-intensity conditioning allogeneic transplantation if < VGPR.DCEP = dexamethasone, cyclophosphamide, etoposide, cisplatin; IFM = Intergroupe Francophone du Myelome.Harousseau JL et al. J Clin Oncol. 2010. 28;30:4621-4629.
Best Response by Phase VD(n = 223; %)
VAD(n = 218; %)
p Value
≥ nCR rate
Induction
Post-ASCT I
Post-ASCT 2
15
35
39
7
18
32
.003
< .0001
< .0001
≥ VGPR rate
Induction
Post-ASCT I
Post-ASCT 2
39
54
68
16
37
47
< .0001
< .0003
< .0001
VD vs. VAD as Induction Therapy: Efficacy
Harousseau JL et al. J Clin Oncol. 2010. 28;30:4621-4629.
CRs and PFS does not translate into OS!
• Median PFS: 29.7m VAD vs. 36m BD
• Median OS: NR. At 32m: 81% VAD vs. 83% BD alive
Harousseau JL et al. J Clin Oncol. 2010. 28;30:4621-4629.
VTD vs. Thalidomide/Dexamethasone (TD) → Double ASCT in Newly Diagnosed MM
Cavo M. et al. Lancet. 2010. 476: 2075-2085
Primary end point: CR/nCR after 3 cycles of induction
≤ 65 years
N = 474
RANDOMIZE
Bort: 1.3 mg/m2 Days 1, 4, 8, 11Thal: 200 mg Days 1–63Dex: 320 mg/cycle
Thal: 200 mg Days 1–63Dex: 320 mg/cycle
PBSC collectioncyclophosphamide
TransplantationMel200 x 2
Bort: 1.3 mg/m2 Days 1, 8, 15, 22Thal: 100 mg/day, Days 1–70 Dex: 320 mg/cycle
Thal: 100 mg/day, Days 1–70Dex: 320 mg/cycle
VTD CONSOLIDATION
TD
3 x 21-day cycles
2 x 35-day cycles
VTD vs. TD Induction → ASCT: EfficacyEfficacy VTD
(n = 236; %)TD
(n = 238; %) p Value
Induction
ORR
≥ nCR
≥ VGPR
93
31
62
79
11
28
< .0001
< .0001
< .0001
Double ASCT≥ nCR
≥ VGPR
55
82
41
64
.01
.0004
Consolidation≥ nCR
≥ VGPR
62
85
45
68
.0009
.0005PFS 36 months 68 56 .0057OS 36 months 86 84 .3Grade 3/4 AE 56% 33%Grade 3/4 PN 10% 2%
Cavo M. et al. Lancet. 2010. 476: 2075-2085
Thal-Dex vs. MP in elderly NDMM
• TD vs. MP in 268 pts ≥ 65 with NDMM• Thal 200 daily, dex 40mg days 1-4 & 15-18
(odd cycles only) of 28-day cycles. • Mel 0.25mg/kg and prednisolone 2mg/kg on
days 1-4 of a 28-42 day cycle.
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Ludwig H et al. Blood 2009;113:3435-3442
TD vs. MP
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EfficacyTD
(n = 134; %)
MP(n = 134;
%) p Value
Induction
ORR
≥ CR
≥ VGPR
68
2
26
50
2
13
.002
1.0
.006
PFS median 16.7 m 20.7 m .10
OS median 41.5 m 49.4 m .024
Grade 3/4 PN 7% 1%
All Grade PN 72% 33%
Ludwig H et al. Blood 2009;113:3435-3442
VTD vs. CVTD in NDMM
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RANDOMIZE
Bort: 1.3 mg/m2 Days 1, 4, 8, 11Thal: 100 mg Days 1–21Dex: 40 mg Days 1-4, 9-12
Bort: 1.3 mg/m2 Days 1, 4, 8, 11Thal: 100 mg Days 1–21Dex: 40 mg Days 1-4, 9-12CTX: 400mg/m2 IV on Days 1,8
PBSC collection TransplantationMel200 x 1 or 2
VTD
CVTD
4 x 21-day cycles
Pts not eligible for ASCT or in CR post-induction received 4 more cycles, with Dex 20.
Ludwig H et al. JCO 2013;31:247-255
VTD vs. CVTD
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Efficacy VTD(n = 49; %)
VTDC(n = 48; %)
Induction
ORR
≥ nCR
≥ VGPR
100
51
69
96
44
69
ASCT
ORR
≥ nCR
≥ VGPR
100
85
86
100
77
82
PFS Median months 25.1 23.5
OS @ 36 months 80 79.7
Grade 3/4 AE 47% 59%
Grade 3/4 PN 10% 8%
Ludwig H et al. JCO 2013;31:247-255
Ld vs. CRD vs. CyBorD: retrospective comparison of 3 phase 2 studies
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RDN=34
CRDN=53
CyBorDN = 65 P- value
CR+nCR 35 15 41 < 0.0001
VGPR 12 32 26 .0003
ORR 94 85 90 .33
PFS 3.2 yrs 2.3 yrs 2.7 yrs .11
OS – 3 yrs 88 79 88 .23
Grade 4 Toxicity 6 25 8 .02
PN 21 15 59 <0.0001
Khan M. et al. Br J of Haematol. 2011. 156:326-333.
No phase 3 studies for 2 vs. 3-drug lenalidomide combinations
We are left to compare phase 2 + retrospective data
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Phase 2: 2 vs. 3 drug regimensCyBORD3
N=33BiRD1
N=72VRD2
N=66Rd4
N = 72
CR 39 45.8 29 13.9nCR NA NA 11 NAVGPR 22 27.8 27 19.4PR 27 16.7 33 45.8MR 1 5.6 NA NARefractory 1 0 0 2.8ORR 88 90.3 100 79.1PFS NR 48.3m 75% at
18m27.5m
OS NR 89.7 at 3yr 97 at 18m
73 at 3yrs
1. Niesvizky et al. Blood. 2008. 111;3:1101-1109.2. Richardson et al. Blood. 2010. 116;5:679-686.
61 73 74
3. Reeder et al. Leukemia. 2009. 23:1337-414. Gay et al. Am J Jematol. 2010. 85;9:669-669.
33.3
Possible Treatment Scenarios:b) combination therapy prolongs PFS but not OS due to less efficacious salvage
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Combination Induction
+/-ASCT Maintenance Salvage 1 2 3
Sequential Induction
+/-ASCT Maintenance Salvage 1 Salvage 2 Salvage 3
PFS
OS
Dx
Dx Death
Death
Conclusions
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CombinationTx
SequentialTx
Options Remain for Salvage
Equivalent OS
Longer treatment duration
Higher tolerability
Longer PFS
Quicker Response
Deeper Response
• There is no clear evidence that combination therapy improves OS compared to a sequential approach.
• There IS clear evidence that combination therapy is more toxic.
Thank you
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