27. April 2013

German-SpeakingMyeloma Multicenter Group

Hartmut Goldschmidt

Priv.-Doz. Serke, Professor HuhnPriv.-Doz. Martin, Professor HoelzerDr. Goldschmidt, Professor HaasHD1 1995

Dr. Cremer, Prof. Ho„Triple MMM“ 2000

Front-Line Trials of the GMMGHD1 Trial: Tandem-Transplantation 1996 – 1998 (Phase II, n=151)

HD2 Trial: Single- versus Double-Transplantation (Phase III, n=480) 1998 – 2001

HD3 Trial: Tandem-Transplantation (Germany) plus/minus Thalidomide (Phase III, GMMG n=550, HOVON n=500) 2001 – 2004

HO65/HD4 Trial: VAD vs. PAD, Transplantation, maintenance Thalidomide vs. Bortezomib (Phase III, GMMG n=399, HOVON=434) 2005-2008

MM5 Trial: VCD vs. Pad, Standard-intensification, consolidation / maintenance Lenalidomid, maintenance 2a vs. until CR (Phase III, n=504, Start II/2010; Extension n=100 Start 6/2013)

HD-1:Treatment Plan

Time

VA(I)D, until CR or plateau, max. 6 cycles

HD-cyclophosphamide + G-CSF

Melphalan200 mg/m²

cycle 1

cycle 2

PBSCT

PBSCT

Leukaphereses(CD34+-selection)

-interferon

1996-1998(n=151)

HD-1: Improvement of Remission-Status

151 140 140 95

Interferon

n=60

GMMG-HD2 Trial: Single versus Double Autologous Stem CellTransplantation for Newly Diagnosed Multiple Myeloma

• 385 pts < 65 yrs (recruited 1998-2002), 358 pts evaluable

• Treatment– 3-6 cycles of VAD-like induction– Randomization: single ASCT versus double ASCT

• Results– No significant difference for PFS between two treatment arms (P=0.36) – Only ~ 51% of pts received intended double ASCT arm

• Conclusions– Data do not support double HDT as standard frontline treatment in general– Role of double HDT in the era of new drugs is under investigation

Goldschmidt et al. IMW 2013 (Abstract P-216), poster presentation

GMMG-HD2 Trial

GMMG-HD2 Trial - Patient baselinecharacteristics

GMMG-HD2 TrialConsort Diagram

GMMG-HD2 Trial

Analysis 08/12

Intention to treat Per ProtocolITT

Progression Free Survival

GMMG-HD2 Trial

Analysis 08/12

PPIntention to treat Per Protocol

Overall Survival

Mobilisation & Leukapheresis

Randomisation

MM Stage II oder III, Age 18-65

CAD

3 x VAD

CAD

3 x AD

MEL 200 + PBSCT

MEL 200 + PBSCT

MEL 200 + PBSCT

MEL 200 + PBSCT

Thal

idom

ide

-Interferon9 Mio. U/Week

Allogeneic Tx2Gy + FludaraEBMT-study

Del13 / B2MG >3 mg/l, HLA-sib Donor

HD3/HOVON50-Studie 2001-2004

C

umul

ativ

e pe

rcen

tage

0 2 4 6

0

5

10

15

20

25

VAD

AD+thal

months At risk:

VAD 201 194 191 187 AD+thal 211 197 187 185

Logrank P=.15

VAD 201 11 AD+thal 211 19

N O

Minnema et al., Leukemia, 2004

ArmA: DVT 8 (4%)Arm B: DVT 16 (8%)Arm B + LMWH: 12 (6%)

HOVON 50/GMMG-HD3: Safety analysis

Median CD34+ yield

HOVON 50/GMMG-HD3: Interim analysis

0

2

4

6

8

10

12

VAD TAD VAD TADGMMG HOVON

GMMG HOVON

VAD (n=105)

TAD (n=93)

P-valueChi²

VAD (n=100)

TAD (n=100)

P-valueChi²

Med. total CD34+ cellscollected

10.9 9.8 0.02 9.4 7.4 0.009x 106 /kg

Breitkreutz et al., Leukemia, 2007

EFS

p = 0.012p = 0.73

Gesamtpopulation

OS

p = 0.70p = 0.42

Gesamtpopulation

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

In GMMG 2nd MEL 200 +

PBSCT

MEL 200 + PBSCT

In GMMG 2nd MEL 200 +

PBSCT

Thalidomide50 mg/day for2 yearsmaintenance

AllogeneicTx

Bortezomib1.3 mg/m2 / 2 weeksfor 2 yearsmaintenance

HOVON 65 MM / GMMG-HD4 Trial

Bortezomib 1.3 mg/m2

Doxorubicin 9 mg/m2

Dexamethasone 40 mg HDD

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

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

PFS (allo censored) OS

t HR p t HR p

Arm 0.74 .002 Arm 0.70 .013

WHO 1.22 .005 WHO 1.49 <.001

IgA 1.62 .002 IgA 1.82 .01

IgG 1.33 .041 IgG 1.71 .008

LDH 1.25 .10 LDH 1.59 .006

ISS 1.25 .001 ISS 1.47 <.001

13q- 1.43 .001 13q- 1.62 .002

SG 0.81 .039 SG 0.73 .031

Multivariate Cox regression analysis

A;cr<=176A;cr>176B;cr<=176B;cr>176Logrank

N32844

33634

D89318310

P <.001

A;cr<=176

A;cr>176B;cr<=176

B;cr>176

24 Nov 2010-11:21:42

At risk:3284433634

29128

30728

26920

28025

16310

17615

A;cr<=176

A;cr>176

B;cr<=176

B;cr>176

0

25

50

75

100

months0 12 24 36

Cum

ulat

ive

perc

enta

ge

Overall survival

C. Scheid et al., ASH 2010 / EBMT 2011

HO65/HD4: Impact of kidney function

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

„Standard für die Induktionstherapie war bislang VAD, so dass der Ersatz der ohnehin nicht sehr wirksamen Substanz Vincristin durch Bortezomib entsprechend dem GMMG/HOVON-Protokoll als neuer Standard für die Induktionstherapie anzusehen ist. Dies entspricht auch der Bewertung der deutschen Studien-gruppe GMMG.“

MDK Gutachten Prof. Heyll, August 2009

PAD (Vel/Dex) zur Erstlinienbehandlung vonPatienten mit multiplen Myelom

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

Bortezomib-based versusnon-bortezomib-based inductionprior 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) <0.0001

IFM 2005-01 1.99 (1.34, 2.96) 238 56 (24) 236 90 (38) 0.0006

PETHEMA GEM05MENOS65 2.31 (1.40, 3.83) 126 44 (35) 130 72 (55) 0.0010

Pooled (fixed effect) 2.05 (1.64, 2.56) 772 182 (24) 775 298 (39) <0.0001

Heterogeneity I2 = 0%Q = 0.25 with df = 2

GIMEMA MM-BO2005 1.75 (1.22, 2.52) 238 98 (41) 236 130 (55) 0.0025

Pooled (fixed effect) 1.96 (1.62, 2.37) 1010 280 (28) 1011 428 (42) <0.0001

Heterogeneity I2 = 0%Q = 0.82 with df = 3

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

Odds ratio and 95% CI (log scale)

0.2 0.5 1 2 5

ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index for OS

Score Definition % of overall population Outcome

0 Absence of adverse factors (neither high LDH, nor ISS 3, nor t(4;14) and /or del(17p)) 57% 3-year OS: 89%

1 Presence of only 1 adverse factor (either high LDH or ISS 3 or t(4;14) and/or del(17p)) 32% 3-year OS: 73%

2 Presence of high LDH plus ISS 3 in the absence of t(4;14) and /or del(17p) 6% 3-year OS: 68%

3 Presence of t(4;14) and/or del(17p) in addition to either ISS 3 or high LDH 5%

Median OS: 19 mos

3-year OS: 24%

Moreau et al. ASH 2012 (Abstract 598), oral presentation

ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index for OS

Score: 0

Score: 1

Score: 2

Score: 3

Moreau et al. ASH 2012 (Abstract 598), oral presentation

Scoring system

Score GIMEMA

N = 399

IFM

N = 405

Pethema

N = 381

HOVON /GMMGN = 416

Total

N = 16010 232

(58%)234

(58%)236

(62%)201

(48%)903

(56%)

1 134(34%)

128(32%)

110(29%)

143(34%)

515(32%)

2 8(2%)

23(6%)

16(4%)

21(5%)

68(4%)

3 25(6%)

20(5%)

19(5%)

51(12%)

115(7%)

24181260

1,0

,8

,6

,4

,2

0,0

3

2

1

0

2-year Overall survival (OS) according to « scoring system »in 850 patients receiving bortezomib-based induction

OS 1

0.8

0.6

0.4

0.2

06 12 18 24 months

93%86%

73%

52%

P < 0.0001

Cereblon Expression in HOVON-65/GMMG-HD4

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

symptomatic MM 1st line treatment

18-70a

3 x PAd

Lenalidomide

for 2 years

CAD + leukapheresis

3 x VCD

HDM + TPL

2. HDM + TPL (if no nCR/CR)

2 x Lenalidomide

Randomization

Lenalidomide

for 2 years

Lenalidomideif no CR

Lenalidomideif no CR

A1 B1 A2 B2

A1 + B1 A2 + B2

1) 1)

MM5-Trial

Flowsheet 31.03.20111) High Risk Patients, optional in Phase II trial

Standard intensificationaccording to local protocol(GMMG standard)

Amendment – seit 02/2012→ subkutane Applikation von Bortezomib

Moreau et al., Lancet Oncol., 2011:

- Bessere Verträglichkeit (PNP-Rate ↓)

- Vergleichbare Response-Raten

Umstellung in MM5

von i.v. zu s.c.-Applikation

- Gleiche Dosis, Injektionsvolumen ↓

GMMG-ReLApsE study

1) stem cell collection only if no useable stem cells are available from earlier mobilization2) Lenalidomide maintenance therapy 10mg/dayR-Lenalidomide, D-Dexamethasone, HD Mel-high dose Melphalan

relapsed Multiple Myeloma (1.-3. relapse)age 18-70 years

relapse ≥12 months after high dose therapy

Randomization

3x RD

Cyclophosphamide + G-CSF + stem cell collection 1)

Cyclophosphamide + G-CSF + stem cell collection 1)

RD until progression/ relapse

HD Mel 200mg/m²+ autologous transplantation

R-maintenance 2)

until progression/ relapse

3x RD

OS GMMG-HD2 vs HD3/HD4

years since first HDM

OS

Pro

babi

lity

0 1 2 3 4 5 6 7 8

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival ITT

HD2HD3/HD4

GMMG-HD2, -HD3, -HD4 – Beteiligte Kliniken und Praxen

Assoziierte Prüfzentren in hämatologischen Studien• Hinweis auf Publikation im Ärzteblatt

Schurich, B., Bertsch, U., Hügle-Dörr, B.: Deutsches Ärzteblatt, Jg. 110, Heft 5, Seite 176 -177, 01. Februar 2013

Altenkirchen / StrehlAschaffenburg/WelslauBaden-Baden / StaigerBad Honnef / ForstbauerBad Kreuznach / SchulzBad Mergentheim / HartungBerlin / KieweBerlin / Ilona BlauBerlin Seestraße/ SchmittelBochum / NückelBonn / KoBonn / VerbeekBonn-Beuel / ForstbauerBraunschweig / PiesBuchholz / SchiederCelle / MarquardCoburg / LambertiDarmstadt / KojouharoffDortmund / LathanDuisburg / Selbach, AnhufErfurt / WenigerEschweiler / StaibFrankfurt / BollingFrankf.NW-KH / WeidmannFrankfurt Maingau KH/ Böck

Frankfurt / Prof. ChowFrechen / SchulzGießen / Schließer Hamburg / Engel (HOPA)HH-Schnelsen /Müller-HagenHH-Lerchenfeld / WolffHanau / FauthHanau Klinikum / ImmenschuhHeidelberg / Karcher/FuxiusHeilbronn / KoniczekHeilbronn / Martens (SLK)Hennigsdorf/SpeidelIdar-Oberstein / RoemerKaiserslautern / ReebKarlsruhe / ProcacciantiKoblenz / Thomalla (InVO)Köln / ReiserKöln / SchmitzKöln-Holweide / SchulteKöln / MVZ WeihrauchKronach / StauchLandshut / Vehling-KaiserLebach / KremersLüneburg / GoldmannMainz / Papesch

Mannheim / HenselMarburg / BalserNeunkirchen / SchmidtNürtingen / GolfOberhausen / SteinigerOffenbach / BöckOstfildern Paracelsus / AbelePforzheim / DencaussePinneberg / LeonhardPirmasens / ScheuerSiegburg / FronhoffsSiegen / KlumpSingen / FietzSpeyer / Franz-WernerStuttgart / DenzlingerTrier / GrundheberTrier / Kirchen (Brüder-KH)Trier / RendenbachTrier / Mahlberg (Mutterh.)Troisdorf / ForstbauerViersen / ReiterWendlingen / EckertWesterstede / JanssenWolfsburg / Gabrysiak

First patient in:

26.07.2010

Last patient in:

11.10.2012

n=504 Patienten

Rekrutierung MM5

geplantregistriert

Soll: ca. 7 Pat./Monat (erste 6 Monate)

Soll: ca. 15 Pat./Monat (ab Monat 7)

MM5 – Rekrutierung (11.10.2012)

To do 2013• Fokus auf Relapse

• Extension MM 5 (LKP Goldschmidt)

• Benda-Borte-Pred. (LKP Knauf)

• Poma responseadaptiert plus Cyclo (LKP Weisel)

• MM6 Protokoll (Start 2/14)

• Tumorzell-Mob (Start multizentrisch 4/14)

GMMG - Study group meeting