Induction Therapies in Transplant Eligible Patients

Tomer M. MarkDepartment of Medicine, Division of Hematology / Oncology

Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA

Disclosures

Company Role(s):

Celgene Speakers Bureau, Research Funding, Advisory Board

Millennium Speakers Bureau, Advisory Board

Onyx Speakers Bureau, Research Funding

Treatment Paradigm for MM

Induction•Transplant eligible?•Comorbidities?•Lifestyle / Social Factors?•How long to treat?

Transplant

•Delayed vs. upfront?•One or two?

Maintenance

What induction therapy should be used?

What is More Important?

– Predicted response to induction– Patient factors

• Comorbidities• Age• Degree of symptoms due to MM

EFS

p = .0007

p = 7 x 10-5

IFM99 Double ASCTIFM90

CR + VGPR: 440

0 22 44 66 880

25

50

75

100

≥ 90% (n = 51)

≥ 50% (n = 81)

< 50% (n = 46)

0 250 1,5007501,0001,250500 1,7502,0002,2500.00

Su

rviv

al

Dis

trib

uti

on

Fu

ncti

on

(%

)

1.00

0.75

0.50

0.25 PR: 290

OS

CR + VGPR: 440

0 250 1,5007501,0001,250500 1,7502,0002,2500.00

Su

rviv

al

Dis

trib

uti

on

Fu

ncti

on

(%

)1.00

0.75

0.50

0.25 PR: 290

Deeper Responses are Better: Impact of CR + VGPR on Outcome

EFS = event-free survival.Moreau et al, 2008; Attal et al, 1996, 2006.

p = 7 x 10-5

Impact of CR From PETHEMA Group

Martinez-Lopez et al, 2011.

Importance of Immunophenotypic Remission

Paiva, B. et al. J Clin Oncol; 29:1627-1633 2011

Does Consolidation With ASCT Improve Outcomes?

Significance of Depth of Response

Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

Significance of Continued Response to HDT

“Upgraders” do better

Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

Improvement for PR to nCR or CR post transplant

increases OS

Impact of Response To Induction Therapy

Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

Initial Response to Induction Conventional Chemotherapy does not Impact Transplant

benefit

• Singhal et al, 2002. Survival post C-VAMP induction ASCT had no correlation with C-VAMP response.

• Kumar et al, 2004. 50 patients with primary refractory MM (mostly VAD) compared to 100 with chemosensitive disease pre-ASCT. 20% vs. 35% CR post transplant (P = 0.06). 1-year PFS 70% vs. 83% (P=0.65).

• Alexanian et al, 1995. MM resistant to VAD or high-dose dex quadrupled OS compared to matched controls.

Initial Response to Induction Chemotherapy does not Impact

Transplant benefit

Important factors on MV analysis: PCLI >1, CR, abnormal cytogenetics, serum M-protein, circulating PC at harvest.

Kumar et al. Bone Marrow Transplantation. 2004. 34: 161-167.

Initial Response to Induction Chemotherapy does not

Impact Transplant benefit

Is this still true in the era of novel agents?

Impact of Response Failure To Induction with IMiDs

• N = 286• PFS from Day 0 of

transplantation• Plateau (232),

Refractory (29), Relapse (25)

• Thal/Dex (189), Len/Dex (97)

• Medians: 22.1 m (plateau), 15.1 (refractory), 12.0 (relapse) on induction therapy

Gertz, M. A. et al. Blood 2010;115:2348-2353

Impact of Response Failure To Induction with IMiDs

• Overall survival from Day 0 of transplant

• Med OS 73.5 (plateau), 32.7 (refractory), 23.8m (relapse on tx)

Gertz, M. A. et al. Blood 2010;115:2348-2353

Factors that impact transplant success with IMiD induction

Variable Univariable P Multivariable P Plateau vs. relapse-refractory

< 0.001 0.04

Albumin 0.58

Sex 0.78

B2 Microglobulin 0.016 0.30

Bone marrow plasma cells <0.001 0.33

Age 0.92

Abnormal Cytogenetics <0.001 0.02

CTX mobilization 0.036 0.30

Labeling Index <0.001 <0.001

Gertz, M. A. et al. Blood 2010;115:2348-2353

Stewart et al, 2009.

Not for debate: combination therapy gives deeper responses

The Ideal Induction Regimen

• Deep response• Quick response (?)

– May not be necessary for asymptomatic MM

• Tolerable• CyBorD vs. VRD vs. BiRD• CRD – molecular remissions

More is not always better:VTD vs. CVTD

EfficacyVTD

(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

PFSMedian 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

VTD vs. TD Induction → ASCT: Efficacy

EfficacyVTD

(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

.0005

PFS 36 months 68 56 .0057

OS 36 months 86 84 .3

Grade 3/4 AE 56% 33%

Grade 3/4 PN 10% 2%Cavo M. et al. Lancet. 2010. 476: 2075-2085

CyBORD3

N=35BCD + BDT4

N=65BiRD1

N=72VRD2

N=65

CR 39 28 38.9 26

nCR NA 18 13.9 18

VGPR 22 30 20.8 30

PR 27 NA 16.7 25

MR 1 NA 5.6 NA

Refractory 1 NA 0 0

Overall 88 100 90.3 100

1. Niesvizky et al Blood, 111, 1101-1109; 2008.2. Richardson et al. ASH 2008, Abstract 92

61 76 73 74

3. Reeder et al, Leukemia 2009, 23:1337-414. Bensinger et al. ASH 2008, Abstract 94

Popular Induction Regimens

Responses Deepen With Length of Therapy

CR/VGPRPR

Nu

mb

er

of

resp

on

ders

20

40

60

80

100 MM-009/MM-010 Phase III

46% of CR/VGPR achievers started with a PR and achieved a CR/VGPR with further treatment cycles

Mayo Phase II BiRd Phase II

C1C2C3C4C5C6C7C8C9 C11 C13 C15 C17 C19 C21 C23 C25

Richardson, P. G. et al. Blood 2007;110:3557-3560

Responses

continue to

deepen as more therapy is given

Long term APEX data

CyBORD3

N=35BCD + BDT4

N=65

BiRD1

N=72VRD2

N=65CRD5

N = 53CRD6

N = 45CCyTd7N = 64

CR 39 28 38.9 26 42 51 9

nCR NA 18 13.9 18 20 16 NA

VGPR 22 30 20.8 30 19 21 57

PR 27 NA 16.7 25 17 9 24

MR 1 NA 5.6 NA 0 NA NA

≥VGPR 61 76 73 74 81 88 63

Overall 88 100 90.3 100 98 98 91

1. Niesvizky et al Blood, 111, 1101-1109; 2008.2. Richardson et al. ASH 2008, Abstract 92

3. Reeder et al, Leukemia 2009, 23:1337-414. Bensinger et al. ASH 2008, Abstract 94

Popular Induction Regimens vs. Carfil Combos

5. Jakubowiak et al Blood 120, 1801-1809; 20126. Korde et al ASH 2013, Abstract 538.7. Mikhael et al ASK 2013, Abstract 3179

MRD with Carilfzomib Induction Combination

• Jakubowiak: 23/26 patients in nCR/CR were MRD negative– Patients with sCR and

MRD negative: 3 yr OS 100%, PFS 89%

• Korde/Landgren: 27/27 pts in nCR/CR were MRD negative– Overall 18-month PFS:

91%Paiva, B. et al. J Clin Oncol; 29:1627-1633 2011

• What is More Important? – Choice of Agent for Induction

• 3 drugs in combination appear effective• Carfilzomib may enhance initial response

rates, yet: – We don’t know whether the use of transplant

abrogates initial differences in response– We don’t know long-term use consequences– We don’t know implications for subsequent

therapies (ie PFS2)

– Response attained in Induction• MRD will likely trump all

What induction therapy should be used?

Conclusions• Combinations of novel agents lead to deeper

responses pre-transplant• Deeper responses pre-transplant tend to translate

to better responses post transplant– ASCT is supplementary to induction, not a substitute.– ASCT is a tool to achieve high CR and prolonged PFS

• Lack of difference in OS is a reflection on efficacy of salvage tx.

• Lack of difference in responses over time indicate that many good induction therapies exist and the choice should be tailored to the patient.

• Further study of MRD is needed to correlate initial responses with utility or predicted benefit of stem cell transplant.