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, Bertrand Arnulf, Catherine Traulle,
Mauricette Michalet, Gerald Marit, Claire Mathiot, Marie Odile Petillon, Margaret
Macro, Murielle Roussel, Brigitte Pegourie, Brigitte Kolb, Anne Marie Stoppa,
Sabine Brechignac, Laurent Garderet, Bruno Royer, Cyrille Hulin, Lotfi Benboubker,
Olivier Decaux, Martine Escoffre-Barbe, Denis Caillot, Jean Paul Fermand, Herve
Avet-Loiseau, Thierry Facon
Service des Maladies du Sang
Hôpital Huriez, CHRU, Lille, France
Disclosures for Xavier leleu
Research Support/P.I.
Celgene; Janssen; Chugai; Roche;
Novartis; Amgen
Employee
N/A
Consultant
N/A
Major Stockholder
N/A
Honoraria
Celgene; Janssen; LEO pharma;
Speakers Bureau/
Scientific Advisory Board Celgene; Janssen
1
Historical Control 9 months OS in RRMM
Patients refractory to bortezomib and
· Relapsed or
· Refractory to or
· Ineligible to receive, an IMiD:
%
100
80
60
40
20
0 0 12
24
36
48
60
Months
Median PFS: 5 months (range, 4-6)
Median OS: 9 months
Kumar et al. Leukemia. 2011
Previous phase 2 studies in relapsed refractory MM
Median Prior
Pomalidomide
ORR
Study
Phase
N
Treatment
Population
Therapies
schedule
( PR)
(Range)
Richards
Pom: 4 mg vs.
Len- and Bort-
13 vs.
2
221a
21/28
5 (2-13)
on1
Pom 4 mg + Dex
refractory
34%
Pom: 2 mg
Len-
Lacy2
2
34
28/28
4
32%
Dex: 40 mg/week
refractory
Pom: 2 mg and 4
25%
Len- and Bort-
Lacy3
2
70
28/28
mg
6 (2-8+)
and
refractory
Dex: 40 mg/week
29%
Richardson P, et al. ASH 2011.
Lacy MQ, et al. Leukemia. 2010;24:1934-1939.
Lacy MQ et al. Blood. 2011;118(11):2970-5.
2
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
- N=84 randomized
6 pts per arm
Key inclusion criteria
Primary objective
DMC TOLERANCE
· Relapsed MM
Response rate (PR and
Rule: no difference
· Resistant or Refractory to both
better) according to
lenalidomide and bortezomib
IMWG in either arm
17 pts per arm
· Measurable disease (central lab)
DMC - EFFICACY
·ANC > 1 x109/L; Platelets 75
Rule: 4 PR /arm
x109/L; Hb 8 g/dL
· Creatinine clearance 50 mL/min
40 pts per arm
Until Progression
(relapse or refractory)
Patient Characteristics at study entry
Characteristics
21/28
28/28
(N=43)
(N=41)
Median time from diagnosis to
5.1 (0.9 - 18.7) 6.5 (0.8 - 23.1)
randomization, years (range)
<=3 years, %
30
10
Median age, years (range)
60 (45-81)
60 (42-83)
Age 65 years, %
26
37
FISH cytogenetics, %
n=33
n=32
Deletion 17p
21
33
Translocation (4;14)
7
17
Median serum creatinine, (µmol/l)
80
87
>115 µmol/L, %
14
10
3
Prior Therapy
21/28
28/28
(N=43)
(N=41)
Median number of lines
5
5
(min-max)
(1-13)
(2-10)
Patients > 6 lines of therapy, %
42
46
Refractory to*, %
Lenalidomide
84
95
Bortezomib
79
83
Both, lenalidomide and bortezomib
74
78
Last prior therapy
70
68
*refractory to as per IMWG criteria
Treatment
21/28
28/28
(N=43)
(N=41)
Pomalidomide
Median numbers of cycles, n
8
6
Median treatment duration, months
7.2
5.2
Relative dose intensity, %
88
88
Dexamethasone
Relative dose intensity, %
80
81
4
Response on ITT as per IRC
· The median follow-up was 11.3 months, (similar in the 2 arms)
· Central lab
21/28
28/28
Response rate
Total
N=43
N=41
ORR (PR), n (%)
15 (35)
14 (34)
29 (34.5)
CR, n
1
2
3
VGPR, n
1
1
2
PR, n
13
11
24
Stable disease, n (%)
19 (44)
21 (51)
40 (48)
Progressive disease, n (%)
5 (12)
3 (7)
8 (9.5)
Not evaluable, n
4
3
7
Median time to First response (95%CI), months
2.7 (0.9 - 6.5)
1.1 (1.0 - 1.8)
1.8 (1.0 - 5.1)
Median Duration of response (95%CI), months
10.5 (3.5;12.6)
7.2 (3.6;12.6)
8.1 (5.6;12.6)
one year in responders, %
47.5
36
37.5
Time to events
Time to Progression
Overall Survival
Median 9.1 months
Median 13.4 months
(95%CI: 5.8;10.0)
(95%CI: 9.8;-)
5
Response by Prior Therapy
PR
21/28
28/28
Total
All patients, %
35
34
34.5
Patients 6 lines of therapy, %
33
0
21
Refractory to*, %
Lenalidomide
36
36
36
Bortezomib
32
26.5
29
Both, lenalidomide and bortezomib
34
28
31
Last prior therapy
33
31
32
Del17p and/or t(4;14)
25
31
30
*refractory to as per IMWG criteria
PFS in Refractory patients
Double Refractory (A+B)
Refractory to Lenalidomide as last
Median 3.8 months
line (A+B) Median 5.7 months
Median PFS in the entire study was 5,7 months
6
PFS - Subgroups analysis
Responders
Adverse Cytogenetic
Elderly patients
Median 11.3 for Responders
Median 2.8 for adv. Cytog.
Median 4.0 for elderly patients
vs. 3.8 months for SD
vs. 9.9 months for others
vs. 6.8 months for 65
Adverse Events
AEs, %
21/28
28/28
Total
Serious AEs
33
41.5
37
Any grade 3 and 4 AEs
91
83
87
Blood and lymphatic system disorders
72
71
71
Anemia
33
32
32
Neutropenia
63
56
59.5
Thrombocytopenia
28
24
26
General disorders and administration site
23
27
25
conditions
Asthenia
14
5
9.5
Musculoskeletal and connective tissue
21
17
19
disorders
Bone pain
14
7
11
Renal and urinary disorders
12
5
8
Renal failure
957
Discontinued due to drug related-AE, n=2
7
Conclusions
The combination of Pomalidomide and Dexamethasone is safe and
effective in MM patients resistant and refractory to bortezomib and
lenalidomide
The combination of Pomalidomide and Dexamethasone is effective
regardless of subgroups and refractoriness to prior therapy
Pomalidomide 4mg 21/28 days +Dexamethasone appeared superior to
pomalidomide 4mg 28/28 +Dexamethasone considering DOR and
treatment duration, in view of a similar safety profile
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
8