Autologous transplantation in thearea of new drugs

Pieter SonneveldUniversity Rotterdam

Hartmut GoldschmidtDepartment of Medicine V,

University Heidelberg &

National Center for Tumor Diseases (NCT)

Best wishes

CC

HDT

P < 0.02

Courtesy of M. Attal 2006

IFM 90 : Survival Pat. Age ≤ 60 years

Maximal Response

Prospective Study Comparison P Value

IFM90 CR/VGPR vs. PR vs. other

Heidelberg Cohort OS: MM patients autografted between 1992 and 2009

Kaplan-Meier Plot done as B. Barlogie publishedHeidelberg –Data unpublished

Heidelberg Cohort OS: MM patients autografted between 1992 and 2009

Kaplan-Meier Plot done as B. Barlogie publishedHeidelberg –Data unpublished

LenalidomideIMF 2005-02,

CALGB

ThalidomideIMF 99/02

VRDVTD

Vel-Dex (VD)Vel-Cyclo-Dex (VCD)Vel-ADM-Dex (PAD)

Mel 200 Mel 200

Len-DexRAD

BortezomibHovon/GMMG

DSMM XIPETHEMA/GEM

VTDVRD

BortezomibLen 25

VTDVRD

BortezomibLen 25

MaintenanceConsolidationInduction

Improving the response quality / Increasing CR rate after SCT

Einsele 2012

Mobilisation & Leukapherese

Randomisation

MM St. II oder III, Alter 18-65

CAD

3 x VAD

CAD

3 x PAD

MEL 200 + PBSCT MEL 200 + PBSCT

Thalidomid50 mg pro Tag

Allogene Transplantation

MEL 200 + PBSCT MEL 200 + PBSCT

Bor

tezo

mib

1,3

mg/

m²

2 m

al p

ro W

oche

B2MG >3 mg/l / ungünstige Prognosegemäß FISH,HLA-sib donor

Bortezomib 1,3 mg/m² alle 2 Wo

(MM: Multiples Myelom; B2MG: Beta-2-Mikroglobulin; FISH: Fluoreszenz-in situ-Hybridisierung; HLA-sib donor: HLA-identischer Familienspender; MEL 200: Melphalan 200mg/m²; PBSCT: autologe periphere Blutstammzell-Transplantation)Ungünstige Prognose gemäß FISH: t(4:14) / del17p13 o. del13q14 (ohne t(11;14))

GMMG-HD4 / HOVON-65 Studie

A: VADB: PADCox LR Stratified

N373371

F225197

P =0.005

A: VADB: PAD

10 Nov 2010-15:13:13

At risk:373371

258295

176218

97

112

2636

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48

Cum

ulat

ive

perc

enta

ge

PFS with censoring at allo-SCT

HR = 0.75 (0.62-0.91), P=0.004

Progression-free survival with censoringat allo-SCT: primary endpoint

Analysis of HOVON/GMMG trial (German centres)PFS OS

Neben et al. Blood 2012;119(4):940-8.

Impact of intensive therapy in high-riskdisease

Bortezomib-based versusnon-bortezomib-based induction

prior to ASCT in multiple myeloma:meta-analysis of phase 3 trials

Pieter Sonneveld,1 Hartmut Goldschmidt,2 Laura Rosiñol,3 Joan Bladé,3Juan José Lahuerta,4 Michele Cavo,5 Paola Tacchetti,5 Elena Zamagni,5

Michel Attal,6 Henk M. Lokhorst,7 Avinash Desai,8 Andrew Cakana,9 Kevin Liu,10 Helgi van de Velde,11 Dixie-Lee Esseltine,12

Philippe Moreau13

1Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands; 2University Hospital of Heidelberg, Heidelberg, Germany; 3Hematology Department, Hospital Clinic de Barcelona, IDIBAPS,

Barcelona, Spain; 4Servicio de Hematología, Hospital Universitario 12 de Octubre, Madrid, Spain; 5Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Bologna, Italy; 6Department of

Hematology, Hopital Purpan, Toulouse, France; 7Utrecht Medical Center, Utrecht, the Netherlands; 8Janssen Global Services, Raritan, NJ, USA; 9Janssen Research & Development, High Wycombe, UK; 10Janssen Research & Development, Raritan, NJ, USA; 11Janssen Research & Development, Beerse, Belgium; 12Millennium: The Takeda Oncology Company, Cambridge, MA, USA; 13University Hospital,

Nantes, France

1. Harousseau JL, et al. J Clin Oncol 2010;28:4621-9. 3. Rosiñol L, et al. Blood 2012;120:1589-96.2. Sonneveld P, et al. J Clin Oncol 2012;30:2946-55. 4. Cavo M, et al. Lancet 2010;376:2075-85.

• Bortezomib-based regimens compared to non-bortezomib-based previous standards of care as induction therapy prior to ASCT ina total of 4 multicenter, cooperative group phase 3 studies1–4

Study 1º endpoint Bortezomib-based regimen Non-bortezomib-based regimen

IFM 2005-01 Post-induction CR+nCR rate

Bortezomib-dexamethasone(N=240)

Vincristine-doxorubicin-dexamethasone (VAD, N=242)

HOVON-65/ GMMG-HD4

PFS Bortezomib-doxorubicin-dexamethasone (PAD, N=413)

VAD(N=414)

PETHEMA GEM05MENOS65*

Post-induction and post-ASCT CR rate

Bortezomib-thalidomide-dexamethasone (VTD, N=130)

Thalidomide-dexamethasone(TD, N=127)

GIMEMAMM-BO2005

Post-induction CR+nCR rate

VTD(N=241)

TD(N=239)

*Study included a third induction arm, comprising VBMCP/VBAD followed by bortezomib

Background

OR for post-transplant CR+nCR rate similar across studies

• With inclusion of study-level data from GIMEMA MM-BO2005, the pooled OR remained similar (1.96) to that for the integrated analysis

Non-bortezomib-basedBortezomib-based

Study Odds ratio (95% CI) N CR/nCR (%) N CR/nCR (%) P-value

HOVON-65/GMMG-HD4 2.02 (1.46, 2.79) 408 82 (20) 409 136 (33)

OS significantly improved in bortezomib-based group in integrated analysis

• Median follow-up ~37 months• Median OS not reached in either group

– 3-year OS rates: 79.7% vs 74.7%– HR 0.81, p=0.402

• HRs for OS consistent across studies in the integrated analysisNon-bortezomib-basedBortezomib-based

Median MedianStudy Hazard ratio (95% CI) Event/N (months) Event/N (months) P-value

HOVON-65/GMMG-HD4 0.82 (0.63, 1.05) 130/416 NE 109/417 NE 0.1195

IFM 2005-01 0.88 (0.58, 1.35) 45/242 NE 40/240 NE 0.5606

PETHEMA GEM05MENOS65 0.80 (0.48, 1.34) 32/127 NE 26/130 55.5 0.3932

Pooled (fixed effect) 0.81 (0.66, 0.99) 207/785 NE 175/787 NE 0.0402

Heterogeneity I2 = 0%Q = 0.15 with df = 2

Favor bortezomib-based treatment Favor non-bortezomib-based treatment

Hazardratio and 95% CI (log scale)

0.2 0.5 1 2 3

Michele Cavo1,5, Pieter Sonneveld2, Philippe Moreau3, Joan Bladè4, Hartmut Goldschmidt2, Jesús F San Miguel4, Michel Attal3, Hervé Avet-Loiseau3, Wolgang Igor Blau2, ThierryFacon3, Norma Gutierrez4, Jean-Luc Harousseau3, Bronno van der Holt2, Juan Jose Lahuerta4, Henk Lokhorst2, Gerald Marit2, Maria Luisa Martin4, Giulia Marzocchi1,5, Antonio Palumbo1, Francesca Patriarca1, Maria Teresa Petrucci1, Laura Rosiñol4, Hans Salwender2 and Carolina Terragna1,5

Impact of Bortezomib Incorporated Into AutotransplantationOn Outcomes of Myeloma Patients with High-Risk Cytogenetics:

An Integrated Analysis of 1894 Patients Enrolled in Four European Phase 3 Studies

1GIMEMA MM-BO2005 study, 2HOVON-65/GMMG-HD4 study, 3IFM 2005-01 study, 4PETHEMA GEM05MENOS65 study5Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy

VD ± DCEP ASCT1 ± ASCT2 ± Len cons. Len maint.

VAD ± DCEP ASCT1 ± ASCT2 ± Len cons. Len maint.

PAD ASCT1 ± ASCT2 Bort maint.

VAD ASCT1 ± ASCT2 Thal maint.

IFM 2005-01 HOVON-65/GMMG-HD4

VTD ASCT1 ± ASCT2 ± VTD cons. Dex maint.

TD ASCT1 ± ASCT2 ± TD cons. Dex maint.

VTD ASCT1 VT

CHT/B ASCT1 Thal

TD ASCT1 IFN

GIMEMA MM-BO2005 PETHEMA GEM05MENOS65

2169 enrolled patientsHarousseau JL et al. J Clin Oncol 28:4621-4629, 2010Cavo M et al. Lancet 376:2075-2085, 2010

Sonneveld P. J Clin Oncol 30:2946-2955, 2012Rosinol L et al. Blood 120:1589-1596, 2012

Study Design

611 540 441 272 135 43534 441 364 206 101 36

Number at risk

0 12 24 36 48 60Months

Del(17p) and t(4;14) negative*0

2550

7510

0

B-based ASCT(s)Non-B-based ASCT(s)

B-based ASCT(s)

Non-B-based ASCT(s)

P=0.0101

50

41

HR 0.79 (0.67-0.95) p=0.010

172 144 112 59 28 9150 112 71 33 15 5

Number at risk

0 12 24 36 48 60Months

Del(17p) and/or t(4;14) positive*

025

5075

100

B-based ASCT(s)Non-B-based ASCT(s)

B-based ASCT(s)

Non-B-based ASCT(s)P=0.0002

35

23

HR 0.58 (0.44-0.76) p=0.000

* Regardless of presence or absence of del(13q)

PFS according to B-based and non-B-based ASCT(s) within subgroups with or without cytogenetic abnormalities

Arm A=Placebo(N=307)

until relapse

Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line

Arm B=Lenalidomide

(N=307)10-15 mg/d until

relapsePrimary end-point: PFS.Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….

Phase III randomized, placebo-controlled trialN= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008

ASCT = autologous stem cell transplant. IFM = Intergroupe Francophone du Myelome.

Consolidation:Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Randomization: stratified according to Beta-2m, del13, VGPR

IFM 2005-02: Study design

Inclusion

3 x PAd2)

Lenalidomide7)

for 2 years

CAD4) + leukapheresis

3 x VCD3)

HDM + TPL5)

2. HDM + TPL5) (if no CR)

2 x Rd6)

Randomization8)

Lenalidomide7)

for 2 years

Lenalidomide7)if no CR

Lenalidomide7)if no CR

A1 B1 A2 B2

A1 + B1 A2 + B2

1) 1)

GMMG-HD5

1) Risk assessm. within first 4 weeks; high risk patients may go off protocol with participation in an experimental phase II trial (e.g. allogeneic transplantation)2) PAd = Bortezomib (PS-341) 1,3mg/m² d1,4,8,11; Adriamycin 9mg/m², d1-4; Dexamethasone 20mg, d1-4, d9-12, d17-203) VCD = Bortezomib (PS-341) 1,3mg/m² d1,4,8,11; Cyclophosphamid 900mg/m², d1, Dexamethasone 40mg, d1-2, d4-5, d8-9, d11-124) CAD = Cyclophosphamide 1g/m² d1; Adriamycin 15mg/m², d1-4; Dexamethasone 40mg, d1-4; 5) HDM + TPL = High Dose Melphalan 200mg/m² and autologous stem cell transplantation6) Rd = Lenalidomide 25mg/d, d1-21; Dexamethasone 20 mg/die d1, 8, 15, 22;7) Lenalidomide 10mg/d, increase to 15mg/d after 3 months8) randomization to one of four treatment strategies A1, B1, A2, B2: A1= PAd induction, lenalidomide maintenance for 2 years; B1= PAd induction, lenalidomide maintenance if

no CR; A2= VCD induction, lenalidomide maintenance for 2 years; B2 = VCD induction, lenalidomide maintenance if no CRFlowsheet 31.08.09

MRD negative (n=94) MRD positive (n=53)

Median: 71 months

0 20 40 60 80 100 120 140

0

20

40

60

80

100

P=0.009

0 25 50 75 100 125

0

20

40

60

80

100

P

Broyl A, et al. Blood. 2013;121:624-7.

48

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36

Prog

ress

ion

free

sur

viva

l

Months

p = 0.009

> median< median

42 31 13 430 19 4 0

A

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36

Prog

ress

ion

free

sur

viva

l

Months

p = 0.18

> median< median

38 19 3 239 33 10 4

C

48

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36

Ove

rall

surv

ival

Months

p = 0.81

> median< median

42 35 15 847 43 25 10

D

48

–2

60

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36

Ove

rall

surv

ival

Months

p = 0.13

> median< median

48 38 18 940 31 16 6

B

48

11

60

A-B: thal-treated, C-D: bort-treated

Cereblon Expression in HOVON-65/GMMG-HD4

VTD consolidation: long-term follow up

SMR

SMR

No SMR

No SMR

Probability of PFS Probability of OS

Ladetto et al. ASH 2011 (Abstract 827), oral presentation

SMR: Standard molecular remission (MRD negativity on two consecutive samples by RQ-PCR)

• Impact of MRD detection by RQ-PCR on late recurrences and OS• Median follow-up: 65 months; n=39

5 yr OS 100% vs 74%, p=0.0125-yr PFS 82% vs 44%, p=0.009

• No patient with full molecular remission or SMR has died• Dynamic increase in molecular tumor burden predicts late disease

relapses before clinical recurrence

0.0

0.2

0.4

0.6

0.8

1.0

Overall survival of patientswith autologous stem cell transplantations in Heidelberg (since 9.6.1992)

Years from 1st autologous stem cell transplantation

Overall survival

0.0 3.5 5.0 10.0 15.0

until 1999

2000 to 2006

from 2007

Multiple Myeloma – Heidelberg Center20 Years ABSCT (n = 1486 pts.)

Unpublished data