Phase 2 randomised open label study of 2 modalities of
Pomalidomide plus low-dose Dexamethasone in patients
with Multiple Myeloma, refractory to both lenalidomide
and bortezomib. IFM 2009-02.
Xavier Leleu, Michel Attal, Philippe Moreau, Alain Duhamel, Jean Paul Fermand,
Catherine Traulle, Mauricette Michalet, Gerald Marit, Claire Mathiot, Marie Odile
Petillon, Margaret Macro, Murielle Roussel, Bertrand Arnulf, Brigitte Pegourie,
Brigitte Kolb, Anne Marie Stoppa, Sabine Brechiniac, Laurent Garderet, Bruno
Royer, Cyrille Hulin, Lotfi Benboubker, Olivier Decaux, Denis Caillot, Martine
Escoffre-Barbe, Jean Luc Harousseau, Herve Avet-Loiseau, Thierry Facon
Service des Maladies du Sang
Hôpital Huriez, CHRU, Lille, France
Disclosures for Xavier leleu
In compliance with ACCME policy, ASH requires the following disclosures to the
session audience:
Research Support/P.I.
Celgene; Janssen; Chugai; Roche;
Novartis; Amgen
Employee
N/A
Florida
Consultant
N/A
Orlando,
Major Stockholder
N/A
Meeting
Honoraria
Celgene; Janssen; LEO pharma;
Annual
Speakers Bureau/
ASH
Scientific Advisory Board Celgene
52nd
Background
Phase
Regimen
N
Schema
Doses
PR and
PFS / DOR / OS,
better
months (m)
Schey et al.
1
Poma
24
28/28
MTD 2 mg
54%
9.7 / - / 22.5
JCO 2004
Streetly et al.
MTD
1
Poma
20
28/28
50%
10.5 / - / 33
BJH 2008
5 mg QOD
Richardson et al.
Poma +/-
1
32
21/28
2 to 5 mg
28%
- / - / -
ASH 2009
Dex
Lacy et al.
Poma +
11.6 / 97% at 6m /
1/2
60
28/28
2 mg
63%
JCO 2009
Dex
94% at 6m
Lacy et al.
Poma +
2 mg
2
34
28/28
32%
9.1 / 4.8 / 13.9
Leuk 2010 *
Dex
4mg (N=8)
Lacy et al.
Poma +
2 mg
TTP 8 m / - /
2
35
28/28
31%
ASCO 2010 $
Dex
4mg (N=9)
86% at 6m
* Lenalidomide refractory patients
$ Refractory to both lenalidomide and bortezomib
Study Design
Arm A Cycle 21 days
Arm B Cycle 28 days
·Pomalidomide 4mg oral/d, 121
· Pomalidomide 4mg oral/d, d 128
Dexamethasone 40mg oral/w, 1, 8, 15, 22
Dexamethasone 40mg oral/w, 1, 8, 15, 22
· Aspirin/LMWH continue
· Aspirin/LMWH continue
6 pts per arm
- Simon two stage design
- 22 IFM centres
STOP #1/DMC TOLERANCE
Rule: acceptable
- 92 pts included
Simon stage 1
- N=84 evaluable
17 pts per arm
STOP #2 DMC - EFFICACY
Rule: 4 PR and better/arm
Simon stage 2
40 pts per arm
Until Progression
(relapse or refractory)
Study Objectives
Primary objectives:
· Response rate (PR and better) according to IMWG in either arm
Secondary objectives: In either arm
· Safety of pomalidomide and dexamethasone
· Time to response and Response duration of pomalidomide and
dexamethasone
· Time to disease progression and EFS to pomalidomide and dexamethasone
· Overall Survival of pomalidomide and dexamethasone
· Response with regards to cytogenetic of the BM tumor plasma cells
Key Eligibility Criteria
·
Relapsed multiple myeloma with one or more prior therapies
·
Refractory to at least 2 cycles of both lenalidomide and bortezomib
·
Measurable disease: M protein of 1.0 g/dL in serum; 0.2 g in 24 hr
urine collection sample; freelite >100mg/L (and abnormal K/L ratio)
·
ECOG performance status = 0-2
·
ANC > 1 x109/L; Platelets 75 x109/L; Hb 8 g/dL
·
Creatinine clearance 50 mL/min
·
Known Intolerance of thalidomide or lenalidomide
·
Neuropathy < Grade 2
Assessments
· Patients continue to participate to the study until Progression
· Disease response was assessed according to IWMG criteria
Efficacy assessments included monthly M-protein measurements in
serum and 24-hour urine, and bone marrow examination if CR
Assessments of M-protein were objective and performed by a
central laboratory
· Adverse events (AEs), serious AEs and laboratory values were recorded
Toxicities were graded according to NCI-CTCAE version 3.0
Patient Characteristics at diagnosis
Arm
21/28
28/28
N = 43
N = 41
Time from Diag-Screening, months (range)
61
78
(11-224)
(8.8-334)
Median b2m, mg/L (range)
3.9 (1.2-15.7)
2.7 (1.3-6.4)
Median albumin, g/L (range)
37 (25-49)
38 (28-47)
ISS Stage II / III (%)
50 / 18
46 / 11
Bone lesion, presence (%)
60
53
Measurable M component, N (%)
Serum M spike
36 (84)
33 (82)
Bence Jones
4 (9)
4 (10)
sFLC
3 (7)
3 (8)
Patient Characteristics at entry into IFM2009-02
Arm
21/28
28/28
N = 43
N = 41
Median age, years (range)
54 (39-78)
53 (36-69)
Gender ratio (M/F)
22
Neuropathy (all grades), N (%)
34 (79)
25 (61)
DVT/PE prophylaxis, N (%)
LWMH
10 (23)
8 (19.5)
VKA
7 (16)
4 (10)
Median Hb, g/dL (range)
11 (7-14)
13 (6-14)
Median PNn, x109/L (range)
2.6 (1.0-10)
2.8 (0.9-8)
Median Plat, x109/L (range)
168 (51-366)
142 (63-269)
T(4;14), N(%)
03 (7)
Del17p, N(%)
5 (12)
4 (10)
Prior line of therapy, N (range)
4 (1-8)
4 (1-8)
Thalidomide, N (%)
20 (46.5)
24 (58.5)
Revlimid, N (%)
(100)
(100)
Velcade, N (%)
(100)
(100)
DVT: Deep Veinous Thromboembolism/PE: Pulmonary Embolism; LWMH: Low Weight Molecular Heparin; VKA: Vitamin K antagonist
Response (ITT - Central lab)
Arm
21/28
28/28
N=43
N=41
Number of cycle, median
55
ORR (PR and better), N(%)
18 (42)
16 (39)
sCR
00
CR
1 (2)
0
VGPR
3 (7)
2 (5)
PR
14 (32.5)
14 (34)
Stable disease, N(%)
20 (46.5)
21 (51)
Progression, N(%)
5 (12)
1.7 (10)
Time to best response, months (range)
2 (1-9)
1.7 (1-9)
Time To Progression (TTP)
Median follow-up is 6.5 months (arm A 21/28) and 7 months (arm B 28/28)
1.00
0.75
Function
0.50
Distribution
0.25
Survival
0.00
0
50
100
150
200
250
300
350
400
Days
Median,
Arm
O/N
Range
months
21/28
19/43
7
(4- )
28/28
16/41
9.7
(4- )
O/N: observed number / total number
Overall Survival
1.00
0.75
Function
0.50
Distribution 0.25
Survival 0.00
0
50
100
150
200
250
300
350
400
Days
Arm
O/N
Median
21/28
5/43
88% at 4.3 months
28/28
6/41
85% at 5.4 months
TTP according to Presence of del17p or t(4;14)
1.00
0.75
Function
0.50
Distribution
0.25
Survival
0.00
0
50
100
150
200
250
300
350
400
Days
Arm
Del17p t(4;14) Total
Del17p or t(4;14)
O/N
Median,
Months (range)
21/28, (N)
50
5
No
17/43
9.7 (5.2- )
28/28, (N)
43
7
Yes
4/12
6.9 (2- )
Hematological Adverse Events ( grade 3)
Arm
21/28
28/28
N = 43
N = 41
Grade 3 and more,
% hematological AE out of all AE
23.5
26.5
% hematological AE out of grade 3 AE
66
76
Hb<= 8 g/dL, %
11
14
PNn<= 1 x109/L, %
34
33.5
Plat<= 50 x109/L, %
18
21
Support (at least once per patient), %
EPO
32.5
34
G-CSF
30
44
Red cell transfusion
28
34
Platelet transfusion
16
17
Non Hematological Adverse Events ( grade 3) of special
interest
Arm
21/28
28/28
N = 43
N = 41
% Grade 3 and more non hematological AE out of all AE
12
9
Neuropathy, N
0
0
DVT (with DVT prophylaxis), N
0
0
Asthénia, N
42
Cramps, N
02
Diarrhea, N
02
Hyperglycemia, N
10
Bronchitis, N
11
Pneumonia, N
11
Reduced doses of study treatment
Arm
A
B
N = 43
N = 41
Reduced dose of Pomalidomide, N (%)
21 (49)
17 (41)
3 mg
75
2 mg
24
1 mg
0
1
Dose interruption / discontinuation
12
7
Reduced dose of Dexamethasone, N (%)
21 (49)
22 (54)
20 mg
6
9
10 mg
11
Dose interruption / discontinuation
14
12
Conclusions
The association of Pomalidomide and Dexamethasone is safe and
provide responses in patients with advanced and refractory myeloma
to bortezomib and lenalidomide
Pomalidomide 4mg per day is well tolerated
Pomalidomide 4mg /day 21 days out of 28 days-cycle does not appear
inferior to pomalidomide 4mg /day continuous on 28 days-cycle
Acknowledgments
· The authors would like to thank
The patients for their participation in this trial
Celgene for their help in the design of the study and their financial
support
IFM centres and study investigators
IFM study support teams
Patient Disposition
Arm
A
B
Total Enrolled
43
41
Still on study
25 (58)
17 (41)
End of study treatment, N(%)
18
24
Reasons for withdrawal
Disease progression
12
13
Adverse event
15
Death
56
*Initial study design limited 5 patients to 6 cycles of treatment
Response (ITT - Central lab)
Arm
21/28
28/28
N=43
N=41
Number of cycle, median
55
ORR (PR and better), N(%)
18 (42)
16 (39)
sCR
00
CR
1 (2)
0
VGPR
3 (7)
2 (5)
PR
14 (32.5)
14 (34)
Stable disease, N(%)
20 (46.5)
21 (51)
Progression, N(%)
5 (12)
4 (10)
Median, days (range)
Time to first response
54.5 (25-259)
28 (24-252)
Time to best response
56 (25-259)
48 (28-252)
Duration of response
119 (28-280)
126 (28-280)
Event Free Survival
Follow-up median is 6.5 months (A) and 7n months (B)
1.00
Function 0.75
0.50
Distribution 0.25
Survival 0.00
0
50
100
150
200
250
300
350
400
Days
Arm
O/N
Median, months
Range
A
20/43
7.8
(4.5- )
B
25/41
5.4
(3.1-12.8)
Survival according to Response status
TTP
OS
1.00
1.00
0.75
0.75
Function
Function
0.50
0.50
Distribution 0.25
Distribution 0.25
Survival 0.00
Survival 0.00
0
50
100
150
200
250
300
350
400
0
50
100
150
200
250
300
350
400
Days
Days
Resp O/N
Median, days
Range
Resp
O/N
Median
Range
PR
7/34
Not Reached
(273- )
PR
2/34
Not Reached
( - )
SD
19/41
160
(118- )
SD
6/41
Not Reached
( - )
Hematological Adverse Events ( grade 3)
Arm
A
B
N = 43
N = 41
Grade 3 and more, N
122
141
% / All AE
23.5
26.5
% / All AE grade 3
66
76
Hb<= 8 g/dL, N (%)
(11)
26 (14)
PNn<= 1 x109/L, N (%)
62 (34)
62 (33.5)
Plat<= 50 x109/L, N (%)
34 (18)
39 (21)
Support (at least once per patient), N (%)
EPO
14 (32.5)
14 (34)
G-CSF
13 (30)
18 (44)
Red cell transfusion
12 (28)
14 (34)
Platelet transfusion
7 (16)
7 (17)
Non Hematological Adverse Events ( grade 3)
Arm
A
B
N = 43
N = 41
Grade 3 and more, N (% / All AE)
63 (12)
54 (9)
Neuropathy, N
0
0
DVT (with DVT prophylaxis)
0
0
Anorexia
01
Asthénia
42
Bronchitis
11
Cramps
02
Diarrhea
02
Generalized pain
11
Chest pain
11
Dyspnea
10
Fever
10
Hyperglycemia with diabetis
10
Hypokaliemia
10
Hypotension orthostatic
10
Lombalgia
01
Pneumonia
11
Caugh
10
Other
48
42