debate: what is the best induction therapy for transplant-eligible patients? sequential therapy

Debate: What is the best induction therapy for transplant-eligible patients?

Sequential therapy.

1

Tomer M. MarkDepartment of Medicine, Division of Hematology /

OncologyWeill-Cornell Medical College /

New York Presbyterian Hospital, New York, NY, USA

Lymphoma & Myeloma 2013

Disclosures

2

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?

3

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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