Post-ASH 2015 Koblenz - MaxIT4uinvo.maxit4u.de/wp-content/uploads/2016/02/Neues zur Therapie des... · Post-ASH 2015 Koblenz ... Xavier Leleu, MD, PhD 6, ... MD 12, Lionel Karlin

21.01.2016

1

Post-ASH 2015Koblenz

03.02.2016 Hartmut Goldschmidt

Autologous Transplantation For Multiple Myeloma in

the Era of new Drugs: a Phase 3 Study of the

“Intergroupe Francophone du Myélome”.

Second Interim Analysis of the IFM 2009 Trial.

Michel Attal, Valerie Lauwers-Cances, Cyrille Hulin, Thierry

Facon, Denis Caillot, Martine Escoffre, Bertrand Arnulf, Margaret

Macro, Karim Belhadj, Laurent Garderet, Murielle Roussel, Claire

Mathiot, Hervé Avet-Loiseau, Nikhil Munshi, Paul Richardson,

Kenneth Anderson, Jean Luc Harousseau, and Philippe Moreau

for the IFM.

21.01.2016

2

Registration

)

RVD 1

Lenalidomide + Bortezomib + Dexamethasone25mg/d (d1 to 14) 1.3mg/m2 (d 1, 4, 8, 11) 20mg/d (d1,2,4,5,8,9,11,12)

) Randomization (stratified on ISS and FISH)

Arm AArm A Arm BArm B

RVD 2 and 3

PBSC Collection

(cyclophosphamide 3g/m2 and G-CSF)

10mcg/kg/d)

ASCT HDM 200mg/m2 RVD 4 to 8

RVD 4 and 5

Lenalidomide Maintenance

12 months (10-15 mg/d)

RVD 2 and 3

PBSC Collection

(cyclophosphamide 3g/m2 and G-CSF)

IFM 2009 : Study Design

Lenalidomide Maintenance

12 months (10-15 mg/d)

IFM 2009: Objectives.

�Primary objective:

• To compare PFS between the 2 arms.

�Secondary objectives:

• To compare RR, MRD (by FCM) between the 2

arms.

• To compare TTP between the 2 arms.

• To compare OS between the 2 arms.

• To compare toxicity between the 2 arms.

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IFM 2009: Inclusion Criteria

�De novo myeloma patients.

�Age between 18 and 65 years.

�ECOG performance status <2.

�Symptomatic myeloma with organ damage related

to myeloma.

�Measurable disease : serum M-protein > 10 g/l,

and/or urine M-protein > 200 mg/24 h, and/or

serum FLC assay: involved FLC level > 100 mg/l

provided serum FLC ratio is abnormal.

IFM 2009: Patient characteristics (1)

RVD Arm

N=350

Transplant Arm

N=350P-value

Total

N=700

Age, yr 59 60 NS 59

Sex, n (%)

-Male

-Female

208 (59)

142 (41)

214 (61)

136 (39)

NS

422 (60)

278 (40)

Type of Myeloma, n (%)

-IgG

-IgA

-Light chain

-other

209 (60)

71 (20)

57 (16)

13 (4)

223 (64)

73 (21)

46 (13)

8 (2)

NS

432 (62)

144 (21)

103 (15)

21 (3)

ISS stage, n (%)

-I

-II

-III

115 (33)

170 (49)

65 (19)

118 (34)

171 (49)

61 (17)

NS

233 (33)

341 (49

126 (18)

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IFM 2009: Patient characteristics (2)

RVD Arm

N=350

Transplant Arm

N=350p-value

Total

N=700

Evaluable FISH, n (%) 256 (73) 259 (73) NS 515 (74)

Cytogenetic risk, n (%)

-Standard risk

-High risk

212 (83)

44 (17)

213 (82)

46 (18)

NS 425 (83)

90 (17)

t(4-14), n (%)

-No

-Yes

230 (90)

26 (10)

230 (89)

28 (11)

NS

460 (89)

54 (11)

Del (17p), n (%)

-No

-Yes

241 (94)

15 (6)

242 (94)

15 (6)

NS

483 (94)

30 (6)

t (14-16), n (%)

-No

-Yes

250 (98)

6 (2)

252 (98)

6 (2)

NS

502 (98)

12 (2)

IFM 2009: Best Response

RVD arm

N=350

Transplant arm

N=350p-value

CR 49% 59%

VGPR 29% 29% 0.02

PR 20% 11%

<PR 2% 1%

At least VGPR 78% 88% 0.001

Neg MRD by FCM , n (%) 228 (65%) 280 (80%) 0.001

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IFM 2009: VGPR rate

During each Treatment Phase.

RVD arm

N=350

Transplant arm

N=350p-value

Post induction 47% 50% NS

Post transplant or at C4 55% 73% <0.0001

Post consolidation 71% 81% <0.006

Post maintenance 78% 88% <0.001

IFM 2009: PFS (9/2015)

RVD arm

N=350

Transplant arm

N=350p-value

Median follow-up, months 41 41

Progression or Death, n 204 158

Median PFS, months 34 43

4-year PFS 35% 47%

Hazard ratio (95% CI) 1 0.69 (0.56-0.84) <0.001

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IFM 2009: PFS (9/2015)

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

(%

)

350 296 228 128 24no HDT350 309 261 153 27HDT

N at risk

0 12 24 36 48

Months of follow-up

HDT

no HDT

IFM 2009: OS (9/2015)

RVR arm

N=350

Transplant

N=350

P-value

Death, n 48 54

4-year survival 83% 81%

Hazard ratio (95% CI) 1 1.2 (0.7-1.8) NS

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P NS

0

10

20

30

40

50

60

70

80

90

100

Patients

(%

)

350 338 320 244 56no HDT350 328 309 226 55HDT

N at risk

0 12 24 36 48

Months of follow-up

HDT

no HDT

IFM 2009: OS (9/2015)

IFM 2009: Cause of Death (9/2015)

RVD arm

N=48

Transplant

N=54

Myeloma, n (%) 40/48 (83%) 35/54 (65%)

Toxicity, n (%) 4/48 (8%) 9*/54 (16%)

SPM 1/48 (2%) 6/54 (11%)

Others 3/48 (6%) 4/54 (7%)

*Including 5 transplant related deaths.

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IFM 2009: Conclusions

� This second interim analysis demonstrates that transplantation :

• Is feasible: 93%

• Is associated with an acceptable Transplant Related Mortality: 1.4%.

• Is associated with an increased rate of neg MRD (80% vs 65%, p<0.01).

• Is associated with an improved 4-year PFS (47% vs 35%, p<0.001).

• Is associated with an improved 4-year TTP (49% vs 35%, p<0.001).

� A longer follow up is required to draw any conclusion concerning OS,

• Since the 4-year survival is high in both arms (81% vs 83%).

• However, transplantation is already associated with a reduced risk of

death due to myeloma.

� in the era of new drugs, Transplantation should Remain

“A Standard of Care”.

Registration

)

RVD 1

Lenalidomide + Bortezomib + Dexamethasone25mg/d (d1 to 14) 1.3mg/m2 (d 1, 4, 8, 11) 20mg/d (d1,2,4,5,8,9,11,12)

) Randomization (stratified on ISS and FISH)

Arm AArm A Arm BArm B

RVD 2 and 3

PBSC Collection

(cyclophosphamide 3g/m2 and G-CSF)

10mcg/kg/d)

ASCT HDM 200mg/m2 RVD 4 to 8

RVD 4 and 5

Lenalidomide Maintenance

Until progression (10-15 mg/d)

RVD 2 and 3

PBSC Collection

(cyclophosphamide 3g/m2 and G-CSF)

US Trial = Study Design

Lenalidomide Maintenance

Until progression (10-15 mg/d)

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Evaluation of Minimal Residual Disease (MRD) Evaluation of Minimal Residual Disease (MRD)

by Next Generation Sequencing (NGS)by Next Generation Sequencing (NGS)

is highly predictive of PFS in the IFM/DFCI 2009 trial.is highly predictive of PFS in the IFM/DFCI 2009 trial.

Herve Avet-Loiseau, MD, PhD1*, Jill Corre2*, Valerie Lauwers-Cances, MD3*, Marie-

Lorraine Chretien4*, Nelly Robillard,5*, Xavier Leleu, MD, PhD6, Cyrille Hulin, MD7*,

Catherine Gentil, Engineer8*, Bertrand Arnulf9*, Karim Belhadj, MD10*, Sabine

Brechignac, MD11*, Laurent Garderet, MD12, Lionel Karlin13*, Gerald Marit14*, Lotfi

Benboubker15*, Frederique Orsini-Piocelle, MD16*, Bruno Royer, MD17,18*, Bernard

Drenou, MD19*, Mourad Tiab, MD20*, Thierry Lamy, MD, PhD21, Margaret MACRO,

MD22*, Paul G. Richardson, MD23, Kenneth C Anderson, MD24, Malek Faham, MD,

PhD25, Thierry Facon26, Philippe Moreau27,28,29*, Michel Attal30 and Nikhil C. Munshi,

MD31

Diagnosis 1012

CR 1010

iCR 108-107

mCR 106

Sensitivity matters

80% HD trials

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What are the available tests?

Advantages/Disadvantages

Flow Cytometry: +: Feasible in 100% of the patients

Does not require diagnostic sample

-: Fresh sample (< 24-48 h)

Sensitivity 10-4-10-5

Worlwide acceptability of a common protocol

NGS (Sequenta): +: Sensitivity < 10-6

Frozen samples

Fully standardized (almost FDA-cleared)

-: Requires diagnostic sample (clone ID)

Feasibility ~ 92% (somatic hypermutations)

IFM DFCI 2009 Trial

700 patients < 66y, Newly diagnosed symptomatic MM

3 RVD

5 RVD MEL200 + ASCT

2 RVD

12 months Lenalidomide maintenance

MRD*MRD*

MRD*MRD*

MRD*MRD*

MRD*MRD*

* Primary objective = 7-color Flow, Secondary objective = Molecular

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54% Conventional CR

289 patients analyzed by NGS

Applicability of NGS: 92% (8% clone ID failure)

Median follow-up: 36 months

IFM/DFCI 2009 trial

P-value : p<0.0001

NegativeNegative

Positive

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pat

ient

s w

ithou

t pro

gres

sion

(%

)

153 153(0) 132(21) 111(21) 97(14) 77(18) 45(13) 15(13) 2(2)MRD positive322 322(0) 312(9) 292(20) 273(11) 224(30) 141(15) 67(12) 19(4)MRD neg (FCM)

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at pre-maintenance by FCM (7 colors, sensitivity 10-4)

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P-value (trend) : p<0.0001

<10-6

[10-6;10-5[

[10-5;10-4[

>=10-4

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pat

ient

s w

ithou

t pro

gres

sion

(%

)

79 79(0) 70(9) 59(11) 50(9) 38(11) 28(6) 6(9) 0(3)[10-4;10

-3[

49 49(0) 47(2) 45(2) 43(2) 34(7) 22(4) 8(6) 2(0)[10-5;10

-4[

31 31(0) 30(1) 28(2) 27(0) 22(4) 17(1) 8(2) 4(1)[10-6;10

-5[

87 87(0) 87(0) 85(2) 83(2) 74(6) 54(4) 31(3) 8(0)<10-6

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at pre-maintenance

CONCLUSION

MRD NGS is feasible in 92% of the patients

MRD NGS is highly sensitive (< 10-6)

This sensitivity is achieved in 100% of the patients

10-6 level is the most powerful cutoff for PFS

13/26 pts with t(4;14) achieved MRD negativity vs no with del(17p)

May identify patients cured from myeloma

21.01.2016

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Prospective Evaluation of MRI and PET-CTat Diagnosis and before Maintenance Therapy

in Symptomatic Patients with Multiple Myeloma Included in the IFM/DFCI 2009 Trial

P.Moreau, M.Attal, L.Karlin, L.Garderet, T.Facon, L.Benboubker, M.Macro, D.Caillot, M.Escoffre-Barbe, A.M.Stoppa, K.Laribi, C.Hulin, G.Marit, J.R.Eveillard,

F.Caillon, C.Bodet-Millin,J.M.Nguyen, B.Pégourié, V.Dorvaux, C.Chaleteix, K.Anderson, P.Richardson, H.Avet-Loiseau,

A.Gaultier, J.M.Nguyen, B.Dupas and F.Bodéré

Rationale

MRI and PET-CT are important imaging techniques to detect bone lesions in multiple myeloma at diagnosis

Both MRI and PET-CT have been described to have pronostic value for PFS and/or OS (at diagnosis, during follow-up)

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Few trials have compared prospectively

MRI and PET-CT

in the setting of recent frontline intensive therapy programs

IMAJEM (NCT01309334), 134 patients

RVDx3

RVD x 2

RVD x 5

Revlimid 1 year

Melphalan 200mg/m 2* +

ASCT

CY (3g/m2) MOBILIZATIONGoal: 5 x10 6 cells/kg

RVDx3

CY (3g/m2)MOBILIZATIONGoal: 5 x10 6 cells/kg

Randomize

Revlimid 1 year

ARM A ARM B

ASCT at relapse

PET-CT / MRI at diagnosis

PET-CT / MRI after 3 cycles

PET-CT / MRI before maintenance

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n = 134

Median age (range)Male / femaleISS1ISS2ISS3Median Calcium mM/L (range)Median LDH UI (range)Median Hb g/dL (range)Median creatinine µM/L (range)t(4;14) yes/nodel17pArm A, n (%)Arm B, n (%)

59 (37-65)83 / 51(62% / 38%)

41 (31%)74 (55%)19 (14%)

2.28 (2.04-2.95)211 (71-843)10.9 (8-14.6)78 (39-162)

6 / 1295 / 129

71 (53%)63 (47%)

Patients characteristics

• At diagnosis,MRI was positive in 127/134 (94.7%),and PET-CT in 122/134 (91%) patients,(McNemar test = 0.94, p-value = 0.33).

• MRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis.

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Secondary end-point : PROGNOSTIC IMPACT

PET-CT vs MRI

after 3 cycles of induction therapy with RVD

MRI normalisation following 3 cycles of RVD

Impact on PFS (3% normalised)

61.6%

p = 0.29

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PET-CT normalisation following 3 cycles of RVD

Impact on PFS (32% normalised)

p = 0.04

78.7%

54.8%

Conclusions

- PET-CT and MRI are equally effective to detect bone involvement in symptomatic patients at diagnosis.

- MRI is not a good imaging method during follow-up

- PET-CT after 3 cycles of RVD and pre-maintenance is a powerful prognostic marker for PFS

- PET-CT pre-maintenance is a powerful prognostic marker for OS

- PET-CT and CMF are complementary tools to evaluate minimal residual disease

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Sonneveld P, Salwender H, van der Holt B, el Jarari L, Bertsch U, Blau IW Zweegman S, Weisel K, Vellenga E, Pfreundschuh M, Broyl A, Scheid C, Wittebol S, Bos GMJ, Stevens-Kroef M, Hose D, Jauch A, Raymakers R,

Schaafsma MR, Kersten MJ, van Marwijk Kooy M, Duhrsen U, Lindemann W, Brossart P Wijermans PW, Lokhorst HM, Goldschmidt H

for the Dutch-Belgian HOVON group and the German GMMG group

(EudraCT no. 2004-000944-26)

Most recent data of November 10, 2015

Long term follow up of HOVON-65/GMMG-HD4 randomized phase III trial comparing Bortezomib vs

standard treatment in patients with Multiple Myelom a

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

In GMMG 2 nd

MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2 nd

MEL 200 + PBSCT

Thalidomidemaintenance50 mg/day for 2 years

Allogeneic Tx

Bortezomib Maintenance1.3 mg/m2 / 2 weeks for 2 years

Trial design

Bortezomib 1.3 mg/m2i.v., 2x/w

Doxorubicin 9 mg/m 2

Dexameth 40 mg

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A: VADB: PADCox LR Stratified P =0.001

N414413

F324300

A: VADB: PAD

10 Nov 2015

At risk:414413

202240

101123

4977

1830

A: VAD

B: PAD

0

25

50

75

100

Cum

ulat

ive

perc

enta

ge

months0 24 48 72 96

Randomization armProgression free survival

Primary endpoint PFS by treatment arm

PFS at 96m: 17% vs 10%HR:0.77, 95% confidence interval (CI) = 0.65-0.90; P = 0.001

A: VADB: PADCox LR Stratified P =0.22

N414413

D217204

A: VADB: PAD

10 Nov 2015

At risk:414413

327341

261278

199231

8488

A: VAD

B: PAD

0

25

50

75

100

Cum

ulat

ive

perc

enta

ge

months0 24 48 72 96

Randomization armOverall survival

OS by treatment arm

OS at 96m: 48% vs 45%HR: 0.87, 95% C.I. 0.71-1.04; P=0.22

RMST8y: 4.8 months (95% CI 0.2-9.5; P=0.04)

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PAD vs VAD response

PFSHR

P-value OSHR

P-value

Treatment arm 0.75 0.000 0.86 0.11

ISS 1.18 0.006 1.20 0.02

LDH > n 1.26 0.04 1.55 0.000

RI 1.11 0.5 1.58 0.07

double HDM 0.90 0.2 0.79 0.02

del/13q KA 1.28 0.02 1.52 < 0.001

IgA 1.60 0.000 1.70 <0.01

Multivariate Cox regression analysis

Original observation : single vs double ASCT

Rel Risk P-value

Treatment

VAD single HDT HR 1.00 Ref.

PAD single HDT HR 0.86 ns

VAD double HDT HR 0.88 ns

PAD double HDT HR 0.57 0.0005

Sonneveld P, et al. Blood. 2013;122: abstract 404. Updated data presented at ASH 2013.

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HOVON-VADHOVON-PADGMMG-VADGMMG-PAD

N213219201194

D1191239881

HOVON-VADHOVON-PADGMMG-VADGMMG-PAD

10 Nov 2015

At risk:213219201194

164179163162

137144124134

10512494

107

50463442

HOVON-VAD

HOVON-PADGMMG-VAD

GMMG-PAD

0

25

50

75

100C

umul

ativ

e pe

rcen

tage

months0 24 48 72 96

Study group + treatment armOverall survivalOS by study group and by

treatment arm

OS by study group and by treatment armHOVON: single HDM/ASCTGMMG: double HDM/ASCT

PAD + Single vs Double HDM/ASCT at 96 m: 42% vs 55%Cox all arms: HR:0.71, 95%, (CI) = 0.54-0.94; P = 0.018

NoYesCox LR P <.001

N368

45

F28439

No

Yes

20 Nov 2015

At risk:36845

18714

974

47

2

17

1

No

Yes0

25

50

75

100

Cum

ulat

ive

perc

enta

ge

months0 24 48 72 96

Renal impairment at entry (arm A:VAD)Progression free survival (censored at allo-SCT)

NoYesCox LR P =0.62

N37636

F274

25

No

Yes

20 Nov 2015

At risk:37636

21722

11112

689

26

4

No

Yes

0

25

50

75

100

Cum

ulat

ive

perc

enta

ge

months0 24 48 72 96

Renal impairment at entry (arm B:PAD)Progression free survival (censored at allo-SCT)

PFS by treatment armSubgroup with renal impairment

VAD PAD

p<0.001 p: 0.6

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NoYesCox LR P <.001

N368

45

D17838

No

Yes

20 Nov 2015

At risk:36845

30521

248

12

191

7

812

No

Yes

0

25

50

75

100

Cum

ulat

ive

perc

enta

ge

months0 24 48 72 96

Renal impairment at entry (arm A:VAD)Overall survival

NoYesCox LR P =0.68

N37636

D186

18

No

Yes

20 Nov 2015

At risk:37636

312

28

252

25

213

17

83

5

No

Yes

0

25

50

75

100

Cum

ulat

ive

perc

enta

gemonths0 24 48 72 96

Renal impairment at entry (arm B:PAD)Overall survival

OS by treatment armSubgroup with renal impairment

PADVAD

p<0.001 p: 0.6

At 96m: 12 vs 42 % At 96m: 47 vs 48 %

Conclusions

• Bortezomib based treatment improves PFS and OS in

patients with newly diagnosed MM who are transplant

candidates. This benefit is confirmed at long follow-up.

• Bortezomib plus double HDM/ASCT improves OS at 96

months from 42% to 55%

• Subgroup analysis indicates that:

• Prolonged Bortezomib treatment mostly abrogates

del(17/17p) effect on PFS and OS

• Limited benefit is observed in t(4;14) and gain(1q)

• Prolonged Bortezomib largely abrogates the negative

prognosis in patients with renal impairment

21.01.2016

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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 intensification according to local protocol (GMMG standard)

1) Revlimid ® (Lenalidomide) 25mg p.o., day 1-21; Dexamethasone 40mg p.o., day 1, 8, 15, 222) stem cell mobilization only if no useable stem cells from earlier mobilization are available 3) Revlimid ® (Lenalidomide) - maintenance 10mg/dayR-Revlimid ® (Lenalidomide), d-Dexamethasone, HD Mel - high dose chemotherapy Melphalan, Auto Tx - autologous stem cell transplantation

Relapsed Multiple Myeloma (1 st - 3rd relapse)age 18-75 years

3x Rd 1)

Cyclophosphamide + G-CSFstem cell collection 2)

3x Rd 1)

Rd 1)

until progressive disease

Randomization

Cylophosphamide + G-CSFstem cell collection 2)

HD Mel 200mg/m²+ autologous transplantation

R-maintenance 3)

until progressive disease

for patients with progressive disease HD Mel + Auto Tx recommended

(outside this trial)

ReLApsE trial282 patients

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24

Thank You for Your Attention!