Disclosures for
Palumbo Antonio, MD
Research Support/P.I.
No relevant conflicts of interest to declare
Employee
No relevant conflicts of interest to declare
Consultant
Amgen, Bristol-Myers Squibb, Celgene, Janssen,
Millenium, Onyx
Major Stockholder
No relevant conflicts of interest to declare
Speakers Bureau
No relevant conflicts of interest to declare
Honoraria
Amgen, Bristol-Myers Squibb, Celgene, Janssen,
Millenium, Onyx
Scientific Advisory Board
No relevant conflicts of interest to declare
Presentation includes discussion of the off-label use of a drug or drugs
CONTINUOUS TREATMENT vs FIXED
DURATION OF THERAPY IN NEWLY
DIAGNOSED MYELOMA PATIENTS:
PFS1, PFS2, OS ENDPOINTS
Antonio Palumbo1, Francesca Gay1, Pellegrino Musto2, Tommaso Caravita2, Alessandra
Larocca1, Davide Rossi2, Dina Ben Yehuda3, Massimo Offidani2, Francesca Donato1,
Paola Finsinger2, Paola Omedè1, Concetta Conticello2, Arnon Nagler4, Roberto Ria2,
Maide Cavalli2, Roberto Mina1, Maria Teresa Petrucci2, Izhar Hardan5, Federica Cavallo1,
Mario Boccadoro1.
1Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy; 2Italian Multiple
Myeloma Network, GIMEMA, Italy; 3Hadassah Medical Center, Jerusalem, Israel; 4Director
Division of Hematology Chaim Sheba Medical Center, Tel Hashomer, Israel; 5Hematology
Division, Meir Medical Center, Kfar-Saba, Israel
Rationale
PFS from random1
OS from random1
PFS from random2
OS from random2
PFS, progression-free survival; OS, overall survival
1. Palumbo A. et al, NEJM 2012; 366:1759-1769; 2. Palumbo A, et al, JCO 2014 ; 32: 634-40
Rationale
PFS1: from random to 1st progression
100 pts
First line
Second line
XX th lines
Death
PFS2: from random to 2nd progression
100 pts
First line
Second line
XX th lines
Death
Second PFS: from 1st progression to 2nd progression
100 pts
First line (40 pts)
60 pts
PFS, progression-free survival; OS, overall survival, th, therapy.
Second line
XX th lines
Death
Impact of time on patient stratification
First line
Time from random
4 year
Second line
54%
46%
3 year
47%
53%
2 year
34%
66%
1 year
13%
87%
0%
20%
40%
60%
% of randomized patients
80%
100%
Study design
3 phase III trials comparing CT vs FDT
VMPT-VT vs VMP1
N= 511
MPR/Mel200-R vs
MPR/Mel2002
N= 402
PATIENTS INCLUDED
N= 1218
CONTINUOUS THERAPY
N= 604
VMPT-VT1
Rd-MPR/Mel200-R2
MPR-R3
MPR-R vs MPR vs MP3
N= 459
MP
N=154
FIXED DURATION OF THERAPY
N= 614
VMP1
Rd-MPR/Mel2002
MPR3
CT, continuous therapy; FDT, Fixed duration of therapy, VMPT, bortezomib-melphalan-prednisone-thalidomide, VT, bortezomib-thalidomide maintenance, VMP,
bortezomib.melphalan,prednisone,MPR, melphalan, prednisone, lenalidomide, Mel200, melphalan 200 mg/mq followed by autologous transplant, R, lenalidomide
maintenance, MP, melphalan-prednisone.
1. GIMEMA MM-03-05 trial, Palumbo A, et al, JCO 2014 ; 32: 634-40 2. GIMEMAM RV-MM-209 trial, Gay F, Blood 2013; 122: 21 (abstr 2089 3. MM-015 trial Palumbo A,
et al N Engl J Med 2012; 366: 1759–69.
Patient characteristics
Continuous Therapy
(N=644)
Fixed Duration of Therapy
(N=614)
68
69
62-73
62-74
Male sex
51%
52%
ISS Stage
I
II
III
33%
37%
30%
33%
35%
32%
25%
25%
42%
33%
25%
42%
33%
25%
Age - median
IQR
Cytogenetic Abnormalities
Del17 or t(4:14) or t(14:16)
Protocol
GIMEMA MM-03-051
GIMEMA MM-RV-2092
MM-0153
N, number, ISS, International Staging System.
1. Palumbo A, et al, JCO 2014 ; 32: 634-40. 2. Gay F, et al Blood 2013; 122: 21 (abstr 2089). 3. Palumbo A, et al N Engl J Med 2012; 366: 1759–69.
CONTINUOUS vs FIX DURATION
Median follow-up 52 months
N= 1218
O
S
P
F
S
2
P
F
S
1
N= 687
2nd
P
F
S
PATIENTS INCLUDED
N=1218
CONTINUOUS THERAPY
N=604
CURRENTLY ON STUDY, N=145
DISCONTINUED , N=459
during induction/consolidation N= 238
during maintenance, N= 221
Progression/death, n=225
Adverse events, n= 130
Consent withdrawal/lost FU, n=52
Other reasons, n=50
SPM, n=2
FIXED DURATION OF THERAPY
N=614
CURRENTLY ON STUDY, N=90
DISCONTINUED, N=524
during induction/consolidation, N=243
during observation, N=281
Progression/death, n=355
Adverse events, n=83
Consent withdrawal/lost to FU, n=37
Other reasons, n=45
SPM, n=4
FIRST PROGRESSION, N= 280
DEATH BEFORE SECOND LINE, N=35
FIRST PROGRESSION, N=407
DEATH BEFORE SECOND LINE, N=38
SECOND PROGRESSION, N=164
DEATH BEFORE THIRD LINE, N=80
SECOND PROGRESSION , N=217
DEATH BEFORE THIRD LINE, N=99
DEATH AFTER SECOND PD/THIRD LINE,
N=87
DEATH AFTER SECOND PD/THIRD LINE,
N=121
N, number, PFS, progression-free survival; OS, overall survival, SPM, second primary malignancies.
PFS1
FDT: from random to 1st progression
614
N= 1218
First line
Second line
XX th lines
Death
CT: from random to 1st progression
604
First line
Second line
PFS, progression-free survival; FDT, fixed duration of therapy, CT, continuous therapy, th, therapy, pts, patients.
XX th lines
Death
CONTINUOUS vs FIX DURATION: PFS1
N= 1218
P
F
S
P
F
S
2
1
N= 687
2nd
P
F
S
Inductionconsolidation
Maintenance
Median PFS1
1.00
% of patients
O
S
1-year Landmark analysis
CT
32 months
FDT
16 months
0.75
0.50
CT
0.25
FDT
HR 0.47, 95% CI 0.40-0.56, P <.001
0.00
0
12
24
36
Months
CT, continuous therapy; FDT, fixed duration of therapy; PFS, progression-free survival; OS, overall survival, N°number.
48
60
PFS2
FDT: from random to 2nd progression
614
N= 1218
First line
Second line
XX th lines
Death
CT: from random to 2nd progression
First line
Second line
% of randomized pts
604
PFS, progression-free survival; FDT, fixed duration of therapy, CT, continuous therapy, th, therapy, pts, patients.
XX th lines
Death
CONTINUOUS vs FIX DURATION: PFS2
N= 1218
P
F
S
P
F
S
2
1
N= 687
2nd
P
F
S
Inductionconsolidation
Maintenance
Median PFS2
1.00
CT
55 months
FDT
40 months
0.75
% of patients
O
S
1-year Landmark analysis
CT
0.50
0.25
FDT
HR 0.61, 95% CI 0.50-0.75, P <.001
0.00
0
12
24
36
Months
CT, continuous therapy; FDT, fixed duration of therapy; PFS, progression-free survival; OS, overall survival, N°number; N, number
48
60
2nd PFS
FDT: from 1st progression to 2nd progression
614
N= 1218
First line
407
Second line
XX th lines
Death
CT: from 1st progression to 2nd progression
Randomized
First line
280
Second line
% of randomized pts
614
PFS, progression-free survival; FDT, fixed duration of therapy, CT, continuous therapy, th, therapy, pts, patients.
XX th lines
Death
CONTINUOUS vs FIX DURATION: 2nd PFS
N= 1218
P
F
S
2
Median Second PFS
P
F
S
1
N= 687
2nd
P
F
S
1.00
CT
15 months
FDT
15 months
0.75
% of patients
O
S
Subset of patients who experienced first progression
0.50
FDT
0.25
CT
HR 0.76, 95% CI 1.10-1.33, P =.313
0.00
0
12
24
36
Months
CT, continuous therapy; FDT, fixed duration of therapy; PFS, progression-free survival; N°number
48
60
OS
FDT: from random to death
614
N= 1218
First line
Second line
XX th lines
Death
CT: from random to death
Randomized
604
First line
Second line
OS, overall survival; FDT, fixed duration of therapy, CT, continuous therapy, th, therapy, pts, patients.
XX th lines
Death
CONTINUOUS vs FIX DURATION: OS
N= 1218
P
F
S
P
F
S
2
1
N= 687
Inductionconsolidation
Maintenance
4-year OS
1.00
% of patients
O
S
1-year Landmark analysis
CT
69%
FDT
60%
0.75
CT
0.50
FDT
0.25
2nd
P
F
S
HR 0.69, 95% CI 0.54-0.88, P =.003
0.00
0
12
24
36
Months
CT, continuous therapy; FDT, fixed duration of therapy; OS, overall survival; N°number; ITT, intention to treat
48
60
Conclusion
Continuous Therapy
Fixed Duration of Therapy
P value
N= 1218
1-year landmark analysis
Median PFS1
32 months
16 months
< 0.001
Median PFS2
55 months
40 months `
< 0.001
69%
60%
0.003
Continuous Therapy
Fixed Duration of Therapy
P value
15 months
15 months
0,313
4-year OS
N= 687
Median Second PFS
At relapse  higher proportion of poor prognosis patients
N, number, PFS, progression-free survival; OS, overall survival.
We Are Grateful to All Patients, Nurses and
Physicians of the Participating Centers
1. ALESSANDRIA
2. ANCONA
3. AOSTA
4. ASCOLI PICENO
5. ASTI
6. AVELLINO
7. AVIANO
8. BARI
9. BARI
10. BELLUNO
11. BENEVENTO
12. BERGAMO
13. BOLOGNA
14. BOLZANO
15. BRA
16. BRESCIA
17. BRESCIA
18. BRINDISI
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20. CAGLIARI
21. CAMPOBASSO
22. CANDIOLO
23. CATANIA
24. CATANZARO
25. CATTOLICA
26. CESENA
27. CIRIE'
28. COSENZA
29. CREMONA
30. CUNEO
31. FIRENZE
32. FOGGIA
33. FORLI’
34. FROSINONE
35. GALLARATE
36. GENOVA
37. FORLI’
38. GENOVA
Levis, Baraldi
Leoni, Offidani
Di Vito
Galieni
Favro, Ciravegna
Cantore, Volpe
Tirelli, Rupolo
Vacca, Ria
Liso
Pianezze
Di Lonardo, Vallone
Rambaldi, Galli
Baccarani,Cavo
Cortellazzo, Pescosta
Vanni, Stefani
Rossi, Crippa
Russo, Malagola
Quarta
Angelucci, Derudas
La Nasa, Ledda
Storti
Aglietta, Capaldi
Di Raimondo
Peta, Piro
Pasquini
Guardigni
Girotto, Freilone
Morabito
Lanza
Gallamini, Grasso
Bosi/Nozzoli
Capalbo
Amadori, Gentilini
Sala
Mozzana, Ciambelli
Gobbi, Canepa
Amadori, Gentilini
Gobbi, Canepa
39. GENOVA
40. GENOVA
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62. ORBASSANO
63. PADOVA
64. PALERMO
65. PARMA
66. PAVIA
67. PERUGIA
68. PESARO
69. PESCARA
70. PIACENZA
71. PINEROLO
72. PISA
73. POTENZA
74. RAVENNA
75. REGGIO CALABRIA
76. REGGIO EMILIA
Carella, Spriano
Bacigalupo, Dominietto
Girotto, Aitoro
De Blasio
Cimino
Di Renzo
Fragasso
Brugiatelli
Musolino
Corradini, Montefusco
Morra
Ciceri
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Gianni
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Sacchi
Pogliani, Rossini
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Mettivier
D’Arco, Califano
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Gabbas
Saglio, Guglielmelli
Semenzato, Zambello
Mirto, Cangialosi
Rizzoli, Giuliani
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Visani, Leopardi
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Cavanna, Lazzaro
Griso
Petrini/Benedetti
Ricciuti, Vertone
Zaccaria, Cellini
Nobile, Callea
Gugliotta, Masini
77. RIMINI
78. RIONERO VULTURE
79. RIETI
80. ROMA
81. ROMA
82. ROMA
83. ROMA
84. ROMA
85. ROMA
86. ROMA
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88. ROMA
89. ROMA
90. ROZZANO
91. S. G. ROTONDO
92. SASSARI
93. SIENA
94. TARANTO
95. TERNI
96. TORINO
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99. TREVISO
100. TRICASE
101. TRIESTE
102. UDINE
103. VENEZIA
104. VERBANIA
105. VERCELLI
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107. VICENZA
108. VITERBO
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Pasquini, Fattori
Musto
Capparella
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Majolino, De Rosa
Amadori
Avvisati
Recine
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Dore, Podda
Lauria, Gozzetti
Mazza, Casulli
Liberati
Boccadoro
Pregno, Benevolo
Tarella, Gottardi
Gherlinzoni
Pavone
De Sabbata
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Chisesi
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Santagostino
Pizzolo, Meneghini
Rodeghiero, Elice
Montanaro
Nagler
Ben Yehuda
Manor
Kornberg
Attias