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