Transcript Document

A PROSPECTIVE RANDOMIZED PHASE I/II STUDY OF LENALIDOMIDE, MELPHALAN, PREDNISONE
AND THALIDOMIDE (RMPT) FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS
Federica Cavallo MD (1),Alessandra Larocca MD (1), Maria Teresa Petrucci MD (2), Vincenzo Federico MD (2), Antonietta Pia Falcone MD (3), Grazia
Sanpaolo MD (3), Letizia Canepa MD (4), Monica Crugnola MD (5), Mario Boccadoro MD (1) and Antonio Palumbo MD (1).
(1) Divisione di Ematologia dell'Università di Torino – A.O.U. San Giovanni Battista, Torino; (2) Dipartimento di Biotecnologie e Ematologia, Università La Sapienza, Roma;
(3) U.O. Ematologia e Trapianto, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo; (4) Clinica Ematologica, Università di Genova, Ospedale S. Martino,
Genova; (5) Università degli Studi di Parma, Cattedra e U.O. Ematologia e Trapianti Midollo, Parma.
BACKGROUND AND RATIONALE
•
TREATMENT SCHEDULE
Grade 3-4 Adverse Events
Different in vitro activity of Thalidomide and Lenalidomide
–
–
Lenalidomide: more anti-proliferative activity in human cell lines 1,2
Thalidomide: more anti-angiogenic activity in human models 3
–
Both Thalidomide and Lenalidomide interfere with key events in the
angiogenic process and they can be differentiated qualitatively 3
MAINTENANCE: 28-day cycles until progression
1. 00
Grade 3
Grade 4
G-CSF
Anemia
1
21
Proportion of patients
•
PFS ACCORDING TO
PRIOR LINE OF TREATMENT
HEMATOLOGIC TOXICITY
28
Both drugs are administered orally
Lenalidomide 10 mg/day
Neutropenia
50
G-CSF
Thalidomide and Lenalidomide showed synergistic activity with MP
•
Different toxicity profile of Thalidomide and Lenalidomide
1.
2.
3.
Gandhi A, et al. Haematologica. 2006; 91(suppl 1): abstract 745.
Hideshima T, et al. Blood. 2000; 96: 2943-2950.
Zhang LH, et al. Proc Amer Assoc Cancer Res. 2006;47: abstract 1761.
RATIONALE
(upfront)
MivPT2
(relapsed/refractory) (relapsed/refractory)
Hemoglobin g/dL (median)
Creatinine clearance mL/min (median)
Calcium mmol/L (median)
No.
patients
229
CR
221
21%
VGPR
35%
21%
PR
16%
36%
33%
30
17%
27%
23%
24
0%
12%
29%
1Palumbo et al, ASH2008 (abstract 652)
2Palumbo et al, Eur J Haematol 2006: 76: 273–277
3 Palumbo et al,Blood 2007: 109(7):2767-72
STR
ATA:
Prior lines of treatment
1 line
2 lines
Grade 3-4
Infective
45
Thrombosis
52%
52
0
% of patients
34%
4
40
23%
0. 0
14%
RMPT: median follow-up 11,4 months
PFS@12 months = 51,5%
12%
15
42%
2%
SD
17%
5
0%
CR-
0. 50
0. 00
VGPR
PR
RMPT100
MR
45
40
40
35
35
2. 5
Legend:
5. 0
7. 5
10. 0
12. 5
Months
15. 0
17. 5
20. 0
Lenalidomide
25
Thalidomide
q 28 days for 6 cycles
15
15
10
10
5
Low doses aspirin (100 mg/die) as prophylaxis for venous thrombosis.
(n=22)
5%
5%
Pr oduct - Li m
i t
Est i m
at e C
ur ve
CR/nCR VGPR
PR
SD
PD
22. 5
t al 50=0
Ce n s o r e d
t al 50=0
t al 50=1
Ce n s o r e d
t al 50=1
0. 50
0. 25
C
ensor ed O
bser vat i ons
0. 0
2. 5
5. 0
7. 5
10. 0
12. 5
15. 0
17. 5
20. 0
22. 5
PFS
vgpr =0
Censor ed
Months
vgpr =0
vgpr =1
Censor ed vgpr =1
CONCLUSIONS
• RMPT seems superior to MPT at
relapse
46%
0. 75
36%
23%
23%
18%
5
• Better response rate were observed in
patients treated with Thalidomide 100
mg
0. 50
• RMPT has different toxicity profile
respect Bortezomib based regimen
0. 25
0. 00
0%
0
0
20. 0
1. 00
20
18%
20
17. 5
22. 5
RMPT: median follow-up 11,4 months
OS@12 months = 72%
30
25
15. 0
PFS
SD-PD
50
27%
12. 5
0. 00
(n=22)
23%
10. 0
0. 75
0. 0
PD
45%
7. 5
0. 75
0. 25
RESPONSE RATE AND THALIDOMIDE DOSE
RMPT50
5. 0
1. 00
12%
0
PR
2. 5
PFS ACCORDING TO RESPONSE
10
5
30
Prednisone
C
ensor ed l i nea2=1
Months
PF S
S T RA T A :
29%
25
20
20%
10
Thalidomide
(mg/day) po
50
100
Melphalan
l i nea2=1
0. 00
OVERALL SURVIVAL
28
C
ensor ed l i nea2=0
50
*Palumbo et al Eur J Haemat 2006, 76:273
21
22. 5
% Patients
Proportion of patients
3
20. 0
1. 00
30
20
15
30
PROGRESSION FREE SURVIVAL
Historical control
35
25
20
20%
20
35
30
10
23%
23
40
45
2
17. 5
0. 25
18%
18
45
40
50
1
15. 0
0. 50
STRATA:
n=22
n=22
Months
l i nea2=0
MivPT (N=24)*
41%
CR/nCR VGPR
Lenalidomide
(mg/day) po
10
10
12. 5
Fatigue
41%
41
0
Prednisone
(mg/Kg) po
2
2
10. 0
1. 00
59%
59
Prior treatments
Stem cell transplantation
Conventional chemotherapy
Thalidomide-based regimen
Bortezomib-based regimen
• Efficacy: RMPT is superior to MPT or
MPR regimen?
Melphalan
(mg/Kg) po
0.18
0.18
7. 5
PFS THALIDOMIDE 50 mg versus 100 mg
Cardiac
RMPT (N=44)
TREATMENT SCHEDULE
5. 0
PFS
3.9
ß2-microglobulin mg/L (median)
AIMS
• Are different Thalidomide doses
important?
2. 5
0. 75
RMPT in Advanced MM
MivPT in Advanced MM
• Safety: RMPT is better tolerated than
Bortezomib/Thalidomide containing
regimen?
0. 0
Proportion of patients
(upfront)
VMPT3
Grade 1-2
44
69 (47-80)
10.6
70
2.35
Proportion of patients
VMPT1
0. 00
NON-HEMATOLOGIC TOXICITY
Grade 1-2 and 3-4 Adverse Events
No. of patients
Median age (range)
VMP1
0. 25
% Patients
PATIENT CHARACTERISTICS
0. 50
Proportion of patients
•
0. 75
0. 0
2. 5
5. 0
7. 5
10. 0
12. 5
15. 0
17. 5
over al l
Months
CR/nCR VGPR
PR
SD
PD
Legend:
Pr oduct - Li m
i t
Est i m
at e C
ur ve
C
ensor ed O
bser vat i ons
20. 0
22. 5
• No grade 3-4 thromboembolic events
were reported