1

Highlights from EHA

Mieloma MultiploMichele Cavo

Istituto di Ematologia “L. e A. Seràgnoli”Alma Mater Studiorum

Università degli studi di Bologna

Firenze, 22-23 Settembre 2017

7Myeloma XI – TE pathway

CTD

CRD

CVD

No CVDASCT

Lenalidomide

Observation

Induction 1 Induction 2 Maintenance

R1:1

R1:1

R1:1

Max.

response

PD SD

MR PR

VGPR

CR

Patients were ineligible for the CVD randomisation if they had achieved a CR or VGPR to induction (went straight to ASCT if eligible or maintenance if not) or had PD or SD to induction

(all primary refractory received CVD). Patients were ineligible for the maintenance randomisation if they failed to respond to lenalidomide as their induction IMiD or failed to respond to all

trial induction treatment, had PD or had previous or concurrent active malignancies. Dose adjustments for renal impairment and following AEs were permitted.

This analysis compares toxicity and response to KCRD vs

triplets pre and post - ASCT

KCRD

15Response to initial induction

Lenalidomide led to deeper responses than thalidomide

100

90

80

70

60

50

40

30

20

10

0 CTD

(n=1021)

CRD

(n=1021)

79.5%

KCRD (n=526)

Pe

rce

nta

ge

of

pati

en

ts

VGPR

CR w/o BM

CR

52.8%

60.8%

16Response to initial induction

Quadruplet KCRD led to deeper responses than either triplet

100

90

80

70

60

50

40

30

20

10

0 CTD

(n=1021)

CRD

(n=1021)

KCRD

(n=526)

Pe

rce

nta

ge

of

pati

en

ts

VGPR

CR w/o BM

CR

52.8%

60.8%

79.5%

13Myeloma XI – trial outline, TE pathway

• Primary endpoints: PFS and OS for each randomisation

• Median follow up 36.3 months

CTDn=1021

CRDn=1021

ASCTn=1231

Induction 1

R

Maintenance

Lenalidomide

R

Observation

Patients with a suboptimal response to Induction 1 (<VGPR) were eligible for Induction 2. Patients with PR/MR were randomised to CVD (cyclophosphamide, bortezomib and dexamethasone) or no

further therapy prior to ASCT. Patients with NC/PD all received CVD. Patients were ineligible for the CVD randomisation if they had achieved a CR or VGPR to induction (went straight to ASCT) or had

PD or SD to induction. Patients were ineligible for the maintenance randomisation if they failed to respond to lenalidomide as their induction IMiD or failed to respond to all trial induction treatment, had PD or had

previous or concurrent active malignancies. Dose adjustments for renal impairment and following AEs were permitted.

14Maintenance randomisation

Significant improvement in PFS from 28 to 50 months, HR 0.47

02 0

4 0

6 0

8 0

10

0

12 24 36 48 60

Time from maintenance randomisation (m)

PF

S

(%)

720

Number at risk

Median PFS [95%CI]Obs. (n=377) 28, [24, 32]

Len. (n=451) 50, [44, Inf.)Len

HR: 0.47 95%CI [0.37, 0.59]

Logrank P < 0.0001

Est. [95%CI]

Obs. (%)

Len. (%)

76.0 [ 71.5, 80.7] 53.5 [ 48.0, 59.7] 38.5 [ 32.5, 45.5] 22.2 [ 16.0, 30.9] 15.0 [ 8.3, 27.3]

88.9 [ 85.8, 92.2] 71.5 [ 66.5, 76.9] 63.3 [ 57.6, 69.5] 53.8 [ 46.7, 61.9] 49.5 [ 41.2, 59.4]

Obs

GH Jackson et al ASH 2016 (abstract no. 1143)

Obs. 377 237 121 52 16 1

Len. 451 285 163 92 30 2

15Maintenance randomisation

Overall 185/377118/451 0.47 (0.37, 0.60)

0.10 0.15 0.20 0.50

HR

1.00

Significant improvement in PFS from 28 to 50 months, HR 0.47

FavoursLen

Favours

ObsSubgroup

Gender

Level

Male

No treat.

n/N

113/235

Len.

n/N

91/294

HR [ 95%CI ]

0.56 (0.42, 0.74)

P. (het)

0.0241

Female 72/142 27/157 0.30 (0.19, 0.47)

Age <=65 years 149/306 90/364 0.47 (0.36, 0.61) 0.906

>65 years 36/71 28/87 0.44 (0.26, 0.74)

ISS Stage I 62/137 37/149 0.42 (0.28, 0.64) 0.3322

Stage II 69/148 49/168 0.57 (0.39, 0.82)

Stage III 45/71 25/97 0.35 (0.22, 0.58)

t(4,14) Present 14/17 11/29 0.44 (0.19, 0.98) 0.8415

Absent 70/138 35/149 0.37 (0.24, 0.55)

del(17p) Present 8/9 9/17 0.41 (0.14, 1.25) 0.9872

Absent 76/146 37/161 0.37 (0.25, 0.55)

1q gain Present 26/44 24/69 0.46 (0.26, 0.83) 0.3116

Absent 58/111 22/109 0.30 (0.18, 0.50)

Cytogenetic Risk SR 46/97 17/86 0.31 (0.18, 0.55) 0.8505

HiR 23/41 13/66 0.29 (0.15, 0.59)

UHiR 15/17 16/26 0.36 (0.14, 0.92)

16Maintenance randomisation

Lenalidomide improved PFS irrespective of cytogenetic risk

Standard risk

02

04

06

08

01

00

Time from maintenance randomisation (m)

PF

S

(%)

0 12 24 36 48 60 72

Median PFS [95%CI] Obs.

(n=97) 28, [21, 48]

Len. (n=86) NR, [50, Inf.)

HR: 0.31 95%CI [0.18, 0.55]Logrank P < 0.0001

Est. [95%CI]

Obs. (%)

Len. (%)

79.6 [ 71.7, 88.5] 55.2 [ 45.0, 67.6] 45.4 [ 34.7, 59.3] 30.9 [ 18.5, 51.8]

97.2 [ 93.4, 100.0] 81.2 [ 71.6, 92.1] 76.0 [ 65.1, 88.8] 66.0 [ 52.8, 82.6]

Number at risk

Obs. 97

Len. 86

69

62

34

38

15

25

6

12

0

0

High risk

02

04

06

08

01

00

Time from maintenance randomisation (m)

PF

S

(%)

0 12 24 36 48 60 72

Median PFS [95%CI] Obs.

(n=41) 24, [11, 41]

Len. (n=66) 45, [45, Inf.)

HR: 0.29 95%CI [0.15, 0.59]Logrank P = 4e-04

Est. [95%CI]

Obs. (%)

Len. (%)

63.5 [ 49.4, 81.5] 51.9 [ 37.0, 72.9] 25.4 [ 12.0, 53.8] 12.7 [ 3.7, 43.7]

87.8 [ 79.7, 96.7] 78.6 [ 68.0, 90.9] 73.0 [ 59.5, 89.7] 48.7 [ 21.3, 100.0]

Number at risk

Obs. 41

Len. 66

21

44

13

21

4

13

2

1

0

0

Ultra-‐high risk

02

04

06

08

01

00

Time from maintenance randomisation (m)

PF

S

(%)

0 12 24 36 48 60 72

Median PFS [95%CI] Obs.

(n=17) 7, [6, Inf.]

Len. (n=26) 19, [11, 30]

HR: 0.36 95%CI [0.14, 0.92]

Logrank P = 0.0852

Est. [95%CI]

Obs. (%)

Len. (%)

41.2 [ 23.3, 72.7] 21.2 [ 8.1, 55.4] 10.6 [ 2.0, 57.2] 41.2 [ 23.3, 72.7]

65.1 [ 48.1, 88.0] 30.7 [ 15.3, 61.5] 18.4 [ 6.8, 49.9] 65.1 [ 48.1, 88.0]

Number at risk

Obs. 17

Len. 26

7

14

2

5

1

3

0

0

• High risk (HiR) - presence of any one of t(4;14), t(14;16), t(14;20), del(17p), or gain(1q).

• Ultra-high risk (UHiR) - presence of more than one lesion.

• Standard risk (SR) - absence of any of the above lesions.

Len

Obs

Len

Obs

Len

Obs

18Interaction between induction and maintenance

The best outcomes are associated with lenalidomide induction and

maintenance

CTD/Obs = CTD induction, randomised to observation. CTD/Len = CTD induction, randomised to lenalidomide maintenance. CRD/Obs = CRDinduction, randomised to observation. CRD/Len = CRD induction, randomised to lenalidomide maintenance.

02 0

4 0

PF

S

(%)

60

8 0

10

0

36 48 60

Time from randomisation (m)

0 12 24 72

Median PFS [95%CI] CTD/Obs

(n=187) 41, [37, 51]

CTD/Len (n=221) 58, [49, Inf.)

CRD/Obs (n=190) 34, [32, 42]

CRD/Len (n=230) NR, [56, Inf.)

CRD - Len

Logrank P < 0.0001

MethodsMM patients enrolled in the RV-MM-COOP-0556

(EMN02/HO95 MM; NCT01208766)

• Newly diagnosed ≤ 65 years

• MRD assessement in patients achieving suspected CR before lenalidomide maintenance

4 VCDCTX + PBSC

harvest

HDM1-2

4 VMP No cons

2 VRD

Lenalidomidemaintenance

Pre Maint +24 Maint

+12 Maint

+6 Maint

+18 Maint

EVERY 6 MONTHS UNTIL CLINICAL RELAPSE

CR: complete response, N: number of patients ; V, bortezomib; C, cyclophosphamide; D, dexamethasone; CTX: cyclophosphamide 2-3g/mq, PBSC: peripheral stem cell collection, HDM: high dose melphalan 200mg/mq, R, lenalidomide; M, melphalan; P, prednisone; Cons: consolidation, Maint: maintenanc;

R1 R2

N: 1499

N: 706

N: 506

N: 459

N: 444

Cavo M et al. ASH 2016; Abstract 673. Sonneveld P. et al. ASH 2016; Abstract 292

0

20

40

60

80

100

52%

44%

MRD positive

Sub-analysis on MRD positive patients at pre-maintenance who had a second MRD evaluation >1 year of

Lenalidomide

Pre maintenance

LEN maintenance

% o

f patien

ts 6-12 months

Results

MRD status at pre-maintenance

MRD positive

MRD negative

24%

76%

0

20

40

60

80

100

52%

44%

4%

MRD positive

Results

MRD status during maintenance

Sub-analysis on MRD positive patients at pre-maintenance who had a second MRD evaluation >1 year of

Lenalidomide

Pre maintenance

LEN maintenance

6-12 months

18-24 months

% o

f patien

ts

MRD negative

Results

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50Months

Pro

gre

ssio

n-f

ree

su

rviv

al

239 222 192 131 53 13

77 68 52 33 14 4MRD PositiveMRD Negative

Numbers at risk

3-yr PFS

52%

77%

N = 316 MRD negative MRD positive

Median PFS NR 38 months

HR (95% CI)

P value

0.33 (0.20 – 0.53)

.001

Progression free Survival: Median Follow-Up from MRD enrollement of 33 Months

Study Design

Multicenter, randomized, open-label, active-controlled, phase 3 study

ISS, International Staging System; DVd, daratumumab, bortezomib, and dexamethasone; IV, intravenous; V, bortezomib; SC, subcutaneously; d, dexamethasone; PO, orally;

Vd, bortezomib and dexamethasone; D, daratumumab; Obs, observation; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall

response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. 20

• Cycles 1-8: repeat every 21 days

• Cycles 9+: repeat every 28 days

Primary endpoint

• PFS

Secondary endpoints

• TTP

• OS

• ORR, VGPR, CR

• MRD

• Time to response

• Duration of response

Exploratory

• Time to next therapy

Key eligibility

criteria

• RRMM

• ≥1 prior line of

therapy

• Prior bortezomib

exposure but not

refractory1:1

R

A

N

D

O

M

I

Z

E

Stratification factors

• ISS (I, II, and III)

• Number of prior lines

(1 vs 2 or 3 vs >3)

• Prior bortezomib

(no vs yes)

Premedication for the DVd treatment group consisted

of dexamethasone 20 mg, acetaminophen,

and an antihistamine

MRD evaluation

• Assessed at suspected

CR and at 6 and 12

months following the first

treatment dose for patients

who maintain CR

DVd (n = 251)Daratumumab (16 mg/kg IV)

Every week: Cycles 1-3

Every 3 weeks: Cycles 4-8

V: 1.3 mg/m2 SC on Days 1, 4, 8, and 11

of Cycles 1-8

d: 20 mg PO-IV on Days 1, 2, 4, 5, 8, 9,

11, and 12 of Cycles 1-8

Vd (n = 247)V: 1.3 mg/m2 SC on Days 1, 4, 8, and 11

of Cycles 1-8

d: 20 mg PO-IV on Days 1, 2, 4, 5, 8, 9,

11, and 12 of Cycles 1-8

D

onlyEvery 4

weeks:

Cycles 9+

Obs

only

≥CR

19%

≥CR

9%

Note: Primary

analysis based on

median follow-up

of 7.4 months1

Updated Efficacy: ITT

• 69% reduction in risk of progression for DVd versus Vd

• 9.6-month improvement in median PFS for DVd versus Vd

• Responses continue to deepen

HR, hazard ratio; CI, confidence interval; PR, partial response; sCR, stringent complete response.1. Palumbo A, et al. N Engl J Med. 2016;375(8):754-766.aP <0.0001 for DVd versus Vd. 21

Duration of response: 18.9 months for DVd versus 7.6 months for Vd

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

0 3 6 9 12 15 18 30

Months

21 24 27

Median: 16.7 mo

DVd

VdHR: 0.31

(95% CI, 0.24-0.39; P <0.0001)

100

No. at risk

Vd

DVd247

251

182

215

129

198

74

161

39

138

27

124

11

79

5

30

1

8

0

1

0

0

Median: 7.1 mo

P <0.0001

ORR = 84%

ORR = 63%≥CR

29%a

≥CR

10%

≥VGPR

62%a

≥VGPR

29%

Updated Updated

DVd (n = 240) Vd (n = 234)

Primary Primary

Updated Efficacy: 1 Prior Line

• 81% reduction in risk of progression/death for DVd versus Vd

• Deeper responses with longer follow-up

aKaplan-Meier estimate.bP <0.0001 for DVd versus Vd.

1. Palumbo A, et al. N Engl J Med. 2016;375(8):754-766. 22

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

100

0 3 6 9 12 15 18 30

Months

21 24

Vd

DVd

27

18-month PFSa

68%

12%

Median: 7.9 mo

Median: not reached

HR, 0.19

(95% CI, 0.12-0.29; P <0.0001)

No. at risk

Vd

DVd113

122

91

109

69

104

43

99

22

89

17

85

8

55

5

21

1

4

0

1

0

0

Updated Updated

Note: Primary

analysis based on

median follow-up

of 7.4 months1

≥CR

26%≥CR

15%

P = 0.0014

ORR = 91%

ORR = 74%

≥CR

40%b≥CR

15%

≥VGPR

76%b

≥VGPR

42%

DVd (n = 119) Vd (n = 109)

Primary Primary

CASTOR: PFS by Cytogenetic Risk Statusa

Adding DARA to standard of care prolongs PFS regardless of cytogenetic risk

aITT/biomarker-risk-evaluable analysis set: patients in the ITT population with both RNA and DNA results available.

No. at risk

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

100

0 3 6 9 12 15 18 30

Months

21 24

Vd standard risk

DVd standard risk

Vd standard risk

DVd standard risk

Vd high risk

DVd high risk

27

135

123

51

44

106

110

32

38

79

101

23

34

44

83

13

26

25

74

4

21

16

63

2

20

5

36

1

11

0

0

0

0

3

15

0

2

1

5

0

1

0

1

0

0

DVd high risk

Vd high risk

23

DVd

n = 44

Vd

n = 51

mPFS, mo 11.2 7.2

HR (95% CI)

P value

High

risk

0.45 (0.25-0.80)

0.0053

DVd

n = 123

Vd

n = 135

Standard risk

0.26 (0.18-0.37)

<0.0001

19.6 7.0mPFS, mo

HR (95% CI)

P value

POLLUX: Study Design

Cycles: 28 days

DRd (n = 286)

Daratumumab 16 mg/kg IV

• Qw in Cycles 1-2, q2w in Cycles 3-6, then q4w until PD

R 25 mg PO

• Days 1-21 of each cycle until PD

d 40 mg PO

• 40 mg weekly until PD

Rd (n = 283)

R 25 mg PO

• Days 1-21 of each cycle until PD

d 40 mg PO

• 40 mg weekly until PD

Primary endpoint

• PFS

Secondary endpoints

• TTP

• OS

• ORR, VGPR, CR

• MRD

• Time to response

• Duration of response

aOn daratumumab dosing days, dexamethasone was administered 20 mg premed on Day 1 and 20 mg on Day 2.

RRMM, relapsed and/or refractory multiple myeloma; ISS, international staging system; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, once weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; R, lenalidomide;

PO, oral; d, dexamethasone; Rd, lenalidomide/dexamethasone; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual

disease.

Key eligibility criteria

• RRMM

• ≥1 prior line of therapy

• Prior lenalidomide exposure, but

not refractory

• Creatinine clearance ≥30 mL/min

Multicenter, randomized (1:1), open-label, active-controlled phase 3 study

Stratification factors

• No. prior lines of therapy

• ISS stage at study entry

• Prior lenalidomide

R

A

N

D

O

M

I

Z

E

1:1

Pre-medication for the DRd treatment group consisted of dexamethasone 20 mga, acetaminophen, and an

antihistamine

Statistical analyses

• Primary analysis: ~177 PFS events

24

Updated Efficacy

25

Note: PFS: ITT population; ORR: response-evaluable population.*Kaplan-Meier estimate; aP <0.0001 for DRd vs Rd.

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

100

0 3 6 9 12 18 21 27

283

286

249

266

206

249

181

237

159

227

132

194

5

15

0

1Rd

DRd

No. at risk Months

24

0

0

15

48

82

76%

49%

18-month

PFS*

Rd

DRd

Median: 17.5

months

HR: 0.37 (95% CI, 0.28-0.50; P <0.0001)

Ove

rall

respo

nse

ra

te, %

15

32

32

25

2312

23

8

0

10

20

30

40

50

60

70

80

90

100

DRd (n = 281) Rd (n = 276)

sCR

CR

VGPR

PR

ORR = 93%

ORR = 76%

P <0.0001

≥VGPR: 78%a

≥CR: 46%a

≥VGPR: 45%

≥CR: 20%

Median follow-up: 17.3 (range, 0-24.5) months

Responses continue to deepen in the DRd group with longer follow-up

Median:

not reached

POLLUX: PFS by Cytogenetic Risk Statusa

mPFS, median PFS; NR, not reached.aITT/biomarker-risk-evaluable analysis set: patients in the ITT population with both RNA and DNA results available.

DRd

n = 28

Rd

n = 37

mPFS, mo 22.6 10.2

HR (95% CI)

P value

High

risk

0.53 (0.25-1.13)

0.0921

DRd

n = 133

Rd

n = 113

Standard risk

0.30 (0.20-0.47)

<0.0001

NR 18.5mPFS, mo

HR (95% CI)

P value

Patients at risk

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

100

0 3 6 9 12 15 18 33

Months

21 24

Rd standard risk

DRd standard risk

Rd standard risk

DRd standard risk

Rd high risk

DRd high risk

27

113

133

37

28

104

128

32

22

92

120

21

21

77

116

18

19

72

111

15

19

63

106

15

18

56

102

13

16

0

0

0

0

47

99

10

14

36

76

10

13

10

19

4

4

30

0

2

0

2

DRd high risk

Rd high risk

Adding DARA to Rd prolongs PFS regardless of cytogenetic risk

26

18

10

442

1

0

5

10

15

20

25

30

35

10-4 10-5 10-6

MR

D n

eg

ative

, %

Sensitivity threshold

DVd Vd

Proportion of MRD-negative Patients at 10–4, 10–5, and 10–6 Thresholds

Daratumumab in combination with standard of care significantly improved MRD-negative

rates at all thresholds

*** P <0.0001

** P <0.005

* P <0.05

***

3.6X

***

4.2X

***

4.0X

***

4.5X

**

5.0X

*

4.0X32

25

12

9

6

3

0

5

10

15

20

25

30

35

10-4 10-5 10-6

MR

D n

eg

ative

, %

Sensitivity threshold

DRd Rd

–4 –5 –6 –4 –5 –6

CASTORPOLLUX

P values calculated using likelihood-ratio chi-square test.

PFS According to MRD Status at 10–5

Lower risk of progression in MRD-negative patients

PFS benefit in MRD-positive patients who received daratumumab-containing regimens

versus standard of care

CASTORPOLLUX

Pa

tie

nts

pro

gre

ssio

n fre

e a

nd

aliv

e (

%)

0

20

40

60

80

100

0 3 6 9 12 15 18 24

Vd MRD negative

DVd MRD negative

Vd MRD positive

DVd MRD positive

Patients at risk

Months

21

6

26

241

225

6

26

176

189

6

26

123

172

5

26

68

134

3

15

20

76

2

7

7

26

0

1

0

4

0

0

0

1

0

0

0

0

Pa

tie

nts

pro

gre

ssio

n fre

e a

nd

aliv

e (

%)

0

20

40

60

80

100

0 3 6 9 12 15 21 27

Rd MRD negative

DRd MRD negative

Rd MRD positive

DRd MRD positive

Patients at risk

Months

24

16

71

267

215

16

71

233

195

16

71

190

178

15

70

166

167

15

66

144

161

12

57

120

137

0

6

5

9

0

0

0

1

0

0

0

0

18

10

28

38

54

Rd MRD–

DRd MRD–

DRd MRD+

Rd MRD+

Vd MRD–

DVd MRD–

DVd MRD+

Vd MRD+

POLLUX: MRD in Patients of High Cytogenetic Risk Status (10–5)

PFSMRD-negative rates

No. at risk

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

100

0 3 6 9 12 15 18 33

Months

21 24

Rd MRD positive

DRd MRD negative

Rd MRD negative

DRd MRD negative

Rd MRD positive

DRd MRD positive

27

0

6

37

22

0

6

32

16

0

6

21

15

0

6

18

13

0

6

15

13

0

6

15

12

0

6

13

10

0

0

0

0

0

6

10

8

0

6

10

7

0

4

4

0

DRd MRD positive

0

2

0

0

30

aPercentage of patients within a given risk group and treatment arm.

In POLLUX, high-risk patients treated with DARA who were MRD negative remained progression free

21

00

5

10

15

20

25

30

35

High risk

MR

D-n

egative p

atients

per

risk g

roup,

%a

DRd

n = 28

Rd

n = 37

P = 0.0009

29

CASTOR: MRD in Patients of High Cytogenetic Risk Status (10–5)

In CASTOR, high-risk patients treated with DARA who were MRD negative remained progression

free

aPercentage of patients within a given risk group and treatment arm.

No. at risk

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

100

0 3 6 9 12 15 18 27

Months

21 24

Vd MRD positive

DVd MRD negative

Vd MRD negative

DVd MRD negative

Vd MRD positive

DVd MRD positive

0

6

51

38

0

6

32

32

0

6

23

28

0

6

13

20

0

6

4

15

0

6

2

14

0

3

1

8

0

0

0

0

0

0

0

2

0

0

0

1

DVd MRD positive

14

00

2

4

6

8

10

12

14

16

High risk

MR

D-n

egative p

atients

per

risk g

roup,

%a

DVd

n = 44

Vd

n = 51

P = 0.0018

MRD-negative rates PFS

30

Background

Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival

Venetoclax is a selective, orally available small molecule BCL-2 inhibitor1 and bortezomib can indirectly inhibit MCL-12

When combined, venetoclax can enhance the activity of bortezomib in MM cell lines and xenograft models2

1. Roberts AW et al. N Eng J Med 2015; 374:311-22

2. Punnoose E et al. Mol Cancer Ther 2016;15(5):1132-44 31

Dosing and Enrollment

Patients received 50–1200 mg venetoclax per designated dose escalation cohorts

Enrollment by Dose Cohort

Dose

(mg)50 100 200 300 400 500 600 800 1000 1200

Total

DESE

Total

DE + SE

n 3 6 5 7 6 7 5 3 3 9 54 12 66

Day 1 2 4 5 8 9 11 12 1 8 15 22

Cycles 1–8

Designated

Cohort Dose

Cycles 9–11

Designated

Cohort Dose

Cycles 12+

Days 1–35 at

Monotherapy

Dexamethasone and bortezomib (1.3 mg/m2 SC)

Dexamethasone (20 mg, PO)

Dosing cycle – 21 days for cycles 1–8 and 35 days for cycles 9+

DE, dose escalation cohorts; SE, safety expansion cohort (800 mg)

32As of 19Aug2016

Objective Responses in All Patients and Those Non-

Refractory and Refractory to PIs and IMiDs

33

All patients

(N=66)

Non-refractory

(n=37)

Non-refractory

(n=22)

Refractory

(n=28)

Refractory

(n=42)

Prior proteasome inhibitors (PIs) Prior immunomodulatory drugs (IMiDs)

24%

23%

15%

5%

ORR=67%

24%

38%

22%

8%

ORR=92%

ORR=32%

4%4%

25%

ORR=82%

14%

27%

27%

ORR=57%

14%

31%

19%

7%

Perc

enta

ge o

f patients

As of 19Aug2016

BCL2 Gene Expression and Clinical Response

BCL2 quantitation using ddPCR performed on CD138-selected bone marrow mononuclear cells collected at baseline. BATTing was used to estimate a threshold of BCL2 to provide optimum selection of patients likely to have a response.

B C L 2 H ig h

(n = 1 8 )

B C L 2 L o w

(n = 2 7 )

0

2 0

4 0

6 0

8 0

1 0 0

Pe

rc

en

tag

e o

f P

ati

en

ts

s C R /C R V G P R P R

28%

33%

33%

37%

O R R 9 4 %

O R R 5 9 %

15%

7%

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0

0

2 5

5 0

7 5

1 0 0

M o n th s s in c e f irs t d o s e

P a tie n ts a t r is k 1 8 1 8 1 6 1 4 9 5 3 3 3 2 2 2 2

P a tie n ts a t ris k 2 7 2 2 1 8 1 0 8 6 4 2 2 2 2 2 2 2 2

T im e to P ro g re s s io n

B C L 2 H ig h

B C L 2 L ow

34As of 19Aug2016