Transcript Content Library

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
Improving Outcomes in Myeloma
Should alkylators be used upfront in
transplant-ineligible patients?
Yes/May be
Antonio Palumbo
University of Torino, Italy, EU
25min
Early vs late ASCT
Early vs late ASCT
MPR vs MEL 200
402 NDMM patients < 65 years
MPR
six 28-day courses
M: 0.18 mg/Kg/d, days 1-4
P: 2 mg/Kg/d, days 1-4
R: 10 mg/d, days 1-21
Rd
1° R
four 28-day courses
R: 25 mg/d, days 1-21
d: 40 mg/d, days 1,8,15,22
NO MAINTENANCE
2° R
MEL200
R MAINTENANCE
two courses
M: 200 mg/m2 day -2
Stem cell support day 0
28-day courses until relapse
R: 10 mg/day, days 1-21
Median follow-up 38 months
PFS
1.00
OS
1.00
0.75
0.75
0.50
0.50
3-years OS
3-years PFS
0.25
MEL200
60%
MPR
36%
Median
Not
PFS
reached
HR 0.55
MEL200
80%
MPR
79%
0.25
HR 0.868
P = 0.542
P< .0001
25.88 months
0.00
0.00
0
10
20
30
40
50
60
0
Months
NDMM, newly diagnosed multiple myeloma; Rd, lenalidomide plus low-dose dexamethasone; MPR, melphalanprednisone-lenalidomide; R, lenalidomide maintenance; MEL200, melphalan 200 mg/m 2
10
20
30
40
50
60
Months
Cavallo F, et al. EHA 2012;97:1142
MPR vs MEL200 vs MPR-R vs MEL200-R
Progression-free survival
Overall survival
100
100
MEL200-R
75
75
MPR-R
MEL200
50
MPR
50
MEL200-R
MEL200
25
25
MPR-R
MPR
0
0
10
20
30
40
Months
50
60
0
70
0
10
20
30
40
50
60
70
Months
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance
Early vs late ASCT
Role of CR after induction
MPR vs MEL200
PAD MEL100 vs VMP+VMPT
Random
No random
1-year landmark PFS
CR patients only
1-year landmark PFS
CR patients only
1.00
1.00
PAD MEL100
0.75
MEL200
0.50
0.75
0.50
VMP+VMPT
MPR
0.25
0.25
HR 0.55; P=.032
HR 0.39; P=.026
0.00
12
0.00
24
36
Months
48
60
12
24
36
48
60
Months
Palumbo A, et al. Gr. Emat. Milano 19 November 2012
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2; MEL100, melphalan 100 mg/m 2; VMP, bortezomib-melphalan-prednisone; VMPT, VMP plus
thalidomide; PAD, bortezomib-pegylated doxorubicin-dexamethasone; CR, complete response; PFS, progression-free survival
Progression-free survival
according to quality of response
20000
15000
MRD -
10000
CR +
5000
Progression-free survival
PC/uL
500
400
100
300
MRD -
200
CR +
100
-100
Dia
Pre
maint
+3 m
maint
+6 m
maint
MRD+
CR +
+12 m
maint
+18 m
maint
20000
15000
10000
5000
PC/uL
500
Percent survival
0
80
60
40
MRD +
20
400
CR +
300
200
100
0
0
0
-100
Dia
Pre
maint
+3 m
maint
+6 m
maint
+12 m
maint
MRD, minimal residual disease; CR complete response
+18 m
maint
10
20
30
40
50
Months
Palumbo A, et al. Unpublished data.
Progression-free survival
according to quality of response
20000
15000
MRD -
10000
CR +
5000
Progression-free survival
PC/uL
500
400
100
300
MRD -
200
CR +
PLEASE
•Do not compare CR rates
•Do compare PFS rates
100
-100
Dia
Pre
maint
+3 m
maint
+6 m
maint
MRD+
CR +
+12 m
maint
+18 m
maint
20000
15000
10000
5000
PC/uL
500
Percent survival
0
80
60
40
MRD +
20
400
CR +
300
200
100
0
0
0
-100
Dia
Pre
maint
+3 m
maint
+6 m
maint
+12 m
maint
MRD, minimal residual disease; CR complete response
+18 m
maint
10
20
30
40
50
Months
Palumbo A, et al. Unpublished data.
Standard of Care
for
Elderly Patients
MPT meta-analysis:
which is the right T dosage?
Progression-free survival
Study
MPT better
Overall survival
HR (95% CI)
MP better
Study
MPT better
HR (95% CI)
MP better
FR < 75
0.50 (0.39– 0.65)
FR < 75
0.61 (0.45– 0.81)
Turkey
0.59 (0.35–0.99)
0.68 (0.48– 0.96)
Fr ≥ 75
0.61 (0.46–0.82)
Fr ≥ 75
HOVON
Italy
0.62 (0.48–0.80)
Turkey
0.87 (0.46–1.67)
HOVON
0.79 (0.62–1.00)
Italy
1.04 (0.75–1.44)
NMSG
0.89 (0.70–1.13)
NMSG
1.12 (0.85–1.47)
Overall
(I-squared = 61.7%,
p = 0.023)
0.67 (0.55– 0.80)
Overall
(I-squared = 60.6%,
p = 0.026)
0.82 (0.66–1.02)
0.5 0.75 1
0.75 (0.57–1.00)
1.5
0.5
NOTE: weights are from random effects analysis
0.75 1
1.5
NOTE: weights are from random effects analysis
MPT
MP
mOS
39.3 m
32.7 m
mPFS
20.3 m
14.9 m
Fayers PM, et al. Blood. 2011;118:1239-47
VMPT-VT versus VMP in newly
diagnosed elderly patients
• Median follow-up: 54 mos
VMPT-VT
VMP
P
PFS
35.3 mos
24.8 mos
< 0.0001
TTNT
46.6 mos
27.8 mos
< 0.0001
Landmark analysis
4-year PFS
Median PFS
33%
31.5 mos
16%
17.8 mos
5-year OS
61%
51%
Median OS
Not reached
60.6 mos
Landmark analysis
4-year OS
Median OS
67%
Not reached
55%
54.2 mos
47%
27.8 mos
46%
27.3 mos
OS from relapse
3-year OS
Median OS
0.01
0.006
Palumbo et al. ASH 2012 (Abstract 200), oral presentation
VMPT-VT versus VMP in newly
diagnosed elderly patients
Dear opponent:
•Randomized study
•Follow-up 54 mos
•Age 71 yrs
•PFS 35.3 mos
•TTNT 46.6 mos
• Median follow-up: 54 mos
VMPT-VT
VMP
P
35.3 mos
24.8 mos
< 0.0001
TTNT
46.6 mos
27.8 mos
< 0.0001
Landmark analysis
4-year PFS
Median PFS
33%
31.5 mos
16%
17.8 mos
5-year OS
61%
51%
Median OS
Not reached
60.6 mos
Landmark analysis
4-year OS
Median OS
67%
Not reached
55%
54.2 mos
47%
27.8 mos
46%
27.3 mos
PFS
OS from relapse
3-year OS
Median OS
0.01
0.006
Palumbo et al. ASH 2012 (Abstract 200), oral presentation
Melphalan limitations?
Incidence rate per 100 per year
Different lenalidomide combinations
Hematologic SPMs
Lenalidomide + melphalan
Lenalidomide + cyclophosphamide
Lenalidomide only
Melphalan only
0
0,5
1
1,5
2
Solid SPMs
Lenalidomide + melphalan
Lenalidomide + cyclophosphamide
Lenalidomide only
Melphalan only
0
0,5
1
1,5
Incidence Rate per 100 per year
2
SPM and SAE
Cumulative incidence per 100 at 60 months
No Lenalidomide studies
Multiple Myeloma
Adverse Events
Second Primary Malignancies
0
5
10
15
20
25
30
35
40
Lenalidomide studies
Multiple Myeloma
Adverse Events
Second Primary Malignancies
0
5
10
15
20
25
30
35
Cumulative incidence per 100
40
SPM and SAE
Cumulative incidence per 100 at 60 months
No Lenalidomide studies
Dear opponent:
Multiple Myeloma
Adverse Events
Second Primary Malignancies
You start to have:
0
5
10
15
20
25
30
35
40
Lenalidomide studies
Multiple Myeloma
…some… right
Adverse Events
Second Primary Malignancies
0
5
10
15
20
25
30
35
Cumulative incidence per 100
40
Alternatives?
VCD vs VRD vs VCRD
Progression free survival
1.0
Proportion of patients
0.9
0.8
0.7
0.6
0.5
0.4
Censored VDCR
Censored VDC
Censored VDR
Censored VDC-mod
VDCR (N = 48)
VDC (N = 33)
VDR (N = 42)
VDC-mod (N = 17)
0.3
0.2
0.1
0
0
30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 540 570 600 630 660 690 720 750 780 810 840
Time (days)
Subjects at risk:
48
45
42
40
42
41
38
36
31
30
33
37
29
17
Median PFS, days (range)
PFS at 1 year, %
*censored observation
27
16
35
33
28
26
25
21
20
35
31
29
27
25
20
18
16
25
23
20
19
18
16
15
14
13
12
10
8
7
19
17
16
15
14
11
9
15
14
13
12
3
2
1
10
9
10
7
4
8
7
9
7
3
5
2
3
2
1
6
4
2
VDCR (n = 48)
VDR (n = 42)
VDC (n = 33)
VDC-mod (n = 17)
710 (1*–802*)
NE (1*–800*)
NE (41–825*)
NE (178*–515*)
85
83
93
100
Bortezomib-Cyclophosphamide-Dexamethasone
• 17 newly diagnosed transplant eligible and ineligible MM patients
VCDmod
For 8 three-week cycles
V: 1.3 mg/m2 d 1,4,8,11
C: 500 mg/m2 d 1,8,15
D: 40 mg d 1,8,15
For ASCT eligible:
Stem cell collection after cycle 4
M
A
I
N
T
E
N
A
N
C
E
V
For 4 six-week cycles
V: 1.3 mg/m2 d 1,8,15,22
Best response
100
100
80
80
Patients (%)
Patients (%)
Progression-free survival
60
40
20
0
60
120
180
240
47%
40
29%
20
1-year rate 100%
0
60
300
360
420
480
540
0
100%
0%
PD
6%
VGPR
sCR
CR
≥PR
Time (days)
VCDmod, bortezomib-cyclophosphamide-dexamethasone modified schedule; PR, partial response; VGPR, very good partial response; CR, complete response;
sCR, stringent complete response; PD, progressive disease; V, bortezomib.
Kumar S, et al. Blood 2012.
Carfilzomib, Cyclophosphamide, Dexamethasone
(CCyd)
• 58 newly diagnosed elderly MM patients enrolled at 10 Italian centers
CCyd
Cycles 1-9
C: 20 mg/m2 d 1,2 followed by 36 mg/m2
d 8,9,15,16,22 (cycle 1); 36 mg/m2 d
1,2,8,9,15,16,22 (cycle 2-9);
Cy: 300 mg/m2 d 1,8,15
d: 40 mg d 1,8,15,22
M
A
I
N
T
E
N
A
N
C
E
C
Until progression/intolerance
C: 36 mg/m2 d 1,2,15,16
Progression-free survival
Best response
100
100
75
80
Patients (%)
Patients (%)
sCR
50
25
0
0.0
2.5
5.0
7.5
10.0
12.5
Time (months)
15.0
17.5
20.0
≥VGPR
96
76
72
60
64
46
41
40
24
15
13
≥PR
94
89
63
20
1-year rate 86%
sCR/nCR/CR
0
Cycle 2
Cycle 6
Cycle 9
CCyd, cyclophosphamide-cyclophosphamide-dexamethasone; C, carfilzomib; PR, partial response; VGPR, very good partial
response; CR, complete response; sCR, stringent complete response; nCR, near complete response.
Frail condition
New treatment algorithm for elderly MM
PATIENT STATUS ASSESSMENT
- Age
- ADL
- IADL
- Charlson co-morbidity score
FIT
UNFIT
FRAIL
Age <80 yr
Fit >80 yr
Unfit >80 yr
ADL 6
ADL 5
ADL ≤4
IADL 8
IADL 6-7
IADL ≤5
Charlson 0
Charlson 1
Charlson ≥2
Go-go
Full-dose regimens
Dose level 0
moderate-go
Reduced-dose regimens
Dose level -1
slow-go
Reduced-dose
Palliative approach
Dose level -2
ADL, Activity of Daily Living; IADL, Instrumental Activity of Daily Living; ASCT, autologous stem cell transplantation
Palumbo A. IMW 2013, oral presentation
Subgroup analyses
Patients (%)
OS: age >75 or <75 years
PFS: fit vs. frail
100
100
75
75
50
50
25
25
Age < 75 years
Age > 75 years
fit
frail
p=0.27
0
5
10
15
20
0
25
5
Patients (%)
OS: Age >80 or <80 years
10
15
20
100
75
75
50
50
25
Age < 80 years
Age > 80 years
fit
frail
p=0.58
0
p=0.001
0
0
5
10
25
OS: fit vs. frail
100
25
p=0.02
0
0
15
Time (months)
20
25
0
5
10
15
20
Time (months)
*Frail defined as: ADL <4 or IADL <5 or Charlson >2 or unfit patient >80 yr (Unfit defined as: ADL 5 or IADL 6-7 or Charlson 1 or fit patient >80 y)
25
Dose adjustment recommendations for
the treatment of frail elderly patients
Dose level 0
Dose level – 1
Dose level – 2
Bortezomib
1.3 mg/m2 twice / week
d 1,4,8,11 / 3 wks
1.3 mg/m2 once / week
d 1,8,15,22 / 5 weeks
1.0 mg/m2 once / week
d 1,8,15,22 / 5 weeks
Thalidomide
100 mg/d
50 mg/d
50 mg qod
Lenalidomide
25 mg/d
d 1-21 / 4 weeks
15 mg/d
d 1-21 / 4 weeks
10 mg/d
d 1-21 / 4 weeks
40 mg/d
d 1,8,15,22 / 4 week
20 mg/d
d 1,8,15,22 / 4 week
10 mg/d
d 1,8,15,22 / 4 week
Melphalan
0.25 mg/kg
d 1-4 / 4-6 weeks
0.18 mg/kg
d 1-4 / 4-6 weeks
0.13 mg/kg
d 1-4 / 4-6 weeks
Prednisone
50 mg qod
25 mg qod
12.5 mg qod
100 mg/d
d 1-21 / 4 weeks
50 mg/d
d 1-21 / 4 weeks
50 mg qod
d 1-21 / 4 weeks
Agent
Dexamethasone
Cyclophosphamid
e
Palumbo et al. BLOOD, 27 OCTOBER 2011 118 (17):4519-4529
Progression-free survival
Rd, len-dex
CPR, cyclophosphamide
MPR, melphalan
Rd
vs.
CPR
VP, bort-prednisone
CVP, cyclophosphamide
VMP, melphalan;
vs. MPR
CVP
1.00
1.00
0.75
0.75
vs.
VMP vs.
VD, bort-dex
VTD, thalidomide
VMP, melphalan
VP
VD
vs. VTD vs. VMP
1.0
0.8
0.6
0.50
0.50
0.4
0.25
0.25
0.2
0.00
0.00
0
5
10
15
20
25
30
Larocca A, et al. IMW 2013
35
40
0
0
5
10
15
20
25
Larocca A, et al. Gr. Emat. Milano 2012
0
4
8
12 16 20 24 28 32 36 40 44
Niesvizky R, et al. EHA 2010
Rd, lenalidomide-dexamethasone; CPR, cyclophosphamide-prednisone-lenalidomide; MPR, melphalan-prednisone-lenalidomide; CVP, cyclophosphamide-bortezomib-prednisone;
VMP, bortezomib-melphalan-prednisone; VP, bortezomib-prednisone; VD, bortezomib-dexamethasone; VTD, bortezomib-thalidomide-dexamethasone.
RP-MPR-RP Phase 2 Study
Induction
Consolidation
Maintenance
Two drugs
Three drugs
Maintenance
RP:
Pred: 50 mg/day,
3x/week
Len: 25 mg/day, d1–21
MPR:
Mel: 2 mg, 3x/week
Pred: 50 mg/day, 3x/week
Len:10–15 mg/day, d1–21
RP:
Len:10 mg/day, d1–21
Pred: 25 mg/day, 3x/week
Four 28-day cycles
Six 28-day cycles
28-day cycles until PD
MPR, melphalan, prednisone, Lenalidomide; RP, Lenalidomide, prednisone;
RP-MPR-RP, Lenalidomide-prednisone induction followed by melphalan-prednisoneLenalidomide consolidation and Lenalidomide-prednisone maintenance.
Falco P, et al. Leukemia. 2013;27:695-701
Conclusions
FIT PATIENTS
•Triplets should be considered standard
•Melphalan too toxic
•Cyclophosphamide better tolerated
UNFIT PATIENTS
•Doublet preferred
Thank you