1. Disclosures for Palumbo Antonio, MD
Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx
Honoraria
Scientific Advisory Board
Speakers Bureau
No relevant conflicts of interest to declare
Major Stockholder
Consultant
Employee
Research Support/P.I.
Presentation includes discussion of the off-label use of a drug or drugs

2. Improving Outcomes in Myeloma
Should alkylators be used upfront in transplant-ineligible patients?
Yes/May be
Antonio Palumbo
University of Torino, Italy, EU
25min

3. Early vs late ASCT 3

4. 402 NDMM patients < 65 years
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
NO MAINTENANCE Rd
four 28-day courses
R: 25 mg/d, days 1-21
d: 40 mg/d, days 1,8,15,22
1° R
2° R
MEL200
two courses
M: 200 mg/m2 day -2
Stem cell support day 0
R MAINTENANCE
28-day courses until relapse
R: 10 mg/day, days 1-21
Median follow-up 38 months
PFS
HR 0.55
P<
.0001
0.00
0.25
0.50
0.75
1.00 10 20 30 40 50 60 3 -
years PFS
MPR
MEL200
36%
60%
Median
Not
reached
25.88
months OS
HR 0.868
P = 0.542
0.00
0.25
0.50
0.75
1.00 10 20 30 40 50 60
Months
Months
NDMM, newly diagnosed multiple myeloma; Rd, lenalidomide plus low-dose dexamethasone; MPR, melphalan-prednisone-lenalidomide; R, lenalidomide maintenance; MEL200, melphalan 200 mg/m2
Cavallo F, et al. EHA 2012;97:1142

5. MPR vs MEL200 vs MPR-R vs MEL200-R
Progression-free survival
Overall survival 25 50 75
100 10 20 30 40 60 70
MEL200-R
MEL200
MPR-R
MPR
100 10 20 30 40 50 60 70 25 75
MEL200-R
MEL200
MPR-R
MPR
Months
Months
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance

6. Early vs late ASCT Role of CR after induction MPR vs MEL200 Random
PAD MEL100 vs VMP+VMPT
No random
1-year landmark PFS CR patients only
1-year landmark PFS CR patients only
0.00
0.25
0.50
0.75
1.00 12
HR 0.39; P=.026
MEL200
MPR 24 36 48 60
HR 0.55; P=.032
0.00
0.25
0.50
0.75
1.00
PAD MEL100
VMP+VMPT 12 24 36 48 60
Months
Months
Palumbo A, et al. Gr. Emat. Milano 19 November 2012
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; MEL100, melphalan 100 mg/m2; VMP, bortezomib-melphalan-prednisone; VMPT, VMP plus thalidomide; PAD, bortezomib-pegylated doxorubicin-dexamethasone; CR, complete response; PFS, progression-free survival

7. Progression-free survival according to quality of response
Dia
Pre
maint
+3 m
+6 m
+12 m
+18 m
MRD - CR +
Progression-free survival
100
MRD - CR + 80 60
Dia
Pre
maint
+3 m
+6 m
+12 m
+18 m
Percent survival
MRD+ CR + 40
MRD + CR + 20 10 20 30 40 50
Months
MRD, minimal residual disease; CR complete response
Palumbo A, et al. Unpublished data.

8. PLEASE Do not compare CR rates Do compare PFS rates
Progression-free survival
according to quality of response
Dia
Pre
maint
+3 m
+6 m
+12 m
+18 m
MRD - CR +
Progression-free survival
100
PLEASE
Do not compare CR rates
Do compare PFS rates
MRD - CR + 80 60
Dia
Pre
maint
+3 m
+6 m
+12 m
+18 m
Percent survival
MRD+ CR + 40
MRD + CR + 20 10 20 30 40 50
Months
MRD, minimal residual disease; CR complete response
Palumbo A, et al. Unpublished data.

9. Standard of Care for Elderly Patients9

10. which is the right T dosage?
MPT meta-analysis:
which is the right T dosage?
MP better
MPT better
Progression-free survival
Overall survival
NOTE: weights are from random effects analysis
Overall (I-squared = 61.7%,
p = 0.023)
FR < 75
NMSG
HOVON
Italy
Fr ≥ 75
Turkey
Study
0.67 (0.55– 0.80)
0.50 (0.39– 0.65)
0.89 (0.70–1.13)
0.79 (0.62–1.00)
0.62 (0.48–0.80)
0.61 (0.46–0.82)
0.59 (0.35–0.99)
HR (95% CI) 1
0.5
0.75
1.5
Overall (I-squared = 60.6%, p = 0.026)
Fr ≥ 75
0.82 (0.66–1.02)
1.12 (0.85–1.47)
1.04 (0.75–1.44)
0.61 (0.45– 0.81)
0.75 (0.57–1.00)
0.68 (0.48– 0.96)
0.87 (0.46–1.67)
MPT MP
mOS
39.3 m
32.7 m
mPFS
20.3 m
14.9 m
Fayers PM, et al. Blood. 2011;118:

11. 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
<
TTNT
46.6 mos
27.8 mos
Landmark analysis
4-year PFS
Median PFS
33%
31.5 mos
16%
17.8 mos
5-year OS
61%
51%
0.01
Median OS
Not reached
60.6 mos
4-year OS
67%
55%
54.2 mos
0.006
OS from relapse
3-year OS
47%
46%
27.3 mos
Palumbo et al. ASH 2012 (Abstract 200), oral presentation

12. 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
PFS
35.3 mos
24.8 mos
<
TTNT
46.6 mos
27.8 mos
Landmark analysis
4-year PFS
Median PFS
33%
31.5 mos
16%
17.8 mos
5-year OS
61%
51%
0.01
Median OS
Not reached
60.6 mos
4-year OS
67%
55%
54.2 mos
0.006
OS from relapse
3-year OS
47%
46%
27.3 mos
Palumbo et al. ASH 2012 (Abstract 200), oral presentation

13. Melphalan limitations?13

14. Incidence rate per 100 per year Different lenalidomide combinations
Hematologic SPMs
0,5 1
1,5 2
Melphalan only
Lenalidomide + melphalan
Lenalidomide + cyclophosphamide
Lenalidomide only
Solid SPMs
0,5 1
1,5 2
Melphalan only
Incidence Rate per 100 per year
Lenalidomide + melphalan
Lenalidomide + cyclophosphamide
Lenalidomide only

15. Cumulative incidence per 100 at 60 months
SPM and SAE
Cumulative incidence per 100 at 60 months
No Lenalidomide studies
Lenalidomide studies

16. Cumulative incidence per 100 at 60 months
SPM and SAE
Cumulative incidence per 100 at 60 months
No Lenalidomide studies
Dear opponent:
You start to have:
…some… right
Lenalidomide studies

17. Alternatives? 17

18. VCD vs VRD vs VCRD Progression free survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Proportion of patients
VDCR (N = 48)
VDC (N = 33)
VDR (N = 42)
VDC-mod (N = 17)
Censored VDCR
Censored VDC
Censored VDR
Censored VDC-mod
Time (days)
Subjects at risk: 48 45 42 40 37 35 33 28 26 25 21 20 19 17 16 10 9 7 4 3 2 41 38 36 31 29 27 18 15 14 11 8 5 1 30 23 13 12 6
VDCR (n = 48)
VDR (n = 42)
VDC (n = 33)
VDC-mod (n = 17)
Median PFS, days (range)
710 (1*–802*)
NE (1*–800*)
NE (41–825*)
NE (178*–515*)
PFS at 1 year, % 85 83 93
100
*censored observation

19. 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
MAINTENANCE V
For 4 six-week cycles
V: 1.3 mg/m2 d 1,8,15,22
For ASCT eligible:
Stem cell collection after cycle 4
Progression-free survival
Best response
100%
100
100 80 80 60 60
47%
Patients (%)
Patients (%) 40 40
29% 20
1-year rate 100% 20 6% 0% 60
120
180
240
300
360
420
480
540 PD
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.

20. Carfilzomib, Cyclophosphamide, Dexamethasone
(CCyd)
58 newly diagnosed elderly MM patients enrolled at 10 Italian centers C
Until progression/intolerance
C: 36 mg/m2 d 1,2,15,16
MAINTENANCE
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
Progression-free survival
Best response
sCR
sCR/nCR/CR
≥VGPR
≥PR 25 50 75
100
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
1-year rate 86% 13 15 24 41 46 64 63 72 76 89 94 96 20 40 60 80
100
Cycle 2
Cycle 6
Cycle 9
Patients (%)
Patients (%)
Time (months)
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.

21. Frail condition 21

22. New treatment algorithm for elderly MM
PATIENT STATUS ASSESSMENT
- Age
- ADL
- IADL
- Charlson co-morbidity score
FIT
UNFIT
FRAIL
Age <80 yr
ADL 6
IADL 8
Charlson 0
Fit >80 yr
ADL 5
IADL 6-7
Charlson 1
Unfit >80 yr
ADL ≤4
IADL ≤5
Charlson ≥2
Full-dose regimens
Dose level 0
Reduced-dose regimens
Dose level -1
Reduced-dose
Palliative approach
Dose level -2
Go-go moderate-go slow-go
ADL, Activity of Daily Living; IADL, Instrumental Activity of Daily Living; ASCT, autologous stem cell transplantation
Palumbo A. IMW 2013, oral presentation

23. Subgroup analyses OS: age >75 or <75 years
PFS: fit vs. frail 25 50 75
100 5 10 15 20 25 25 50 75
100 5 10 15 20
Patients (%)
Age < 75 years
Age > 75 years
fit
frail
p=0.27
p=0.02
OS: Age >80 or <80 years
OS: fit vs. frail
p=0.58 25 50 75
100 5 10 15 20
100 75
Patients (%) 50
Age < 80 years
Age > 80 years 25
fit
frail
p=0.001 5 10 15 20 25
Time (months)
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)

24. Dose adjustment recommendations for the treatment of frail elderly patients
Agent
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
Thalidomide
100 mg/d
50 mg/d
50 mg qod
Lenalidomide
25 mg/d
d 1-21 / 4 weeks
15 mg/d
10 mg/d
Dexamethasone
40 mg/d
d 1,8,15,22 / 4 week
20 mg/d
Melphalan
0.25 mg/kg
d 1-4 / 4-6 weeks
0.18 mg/kg
0.13 mg/kg
Prednisone
25 mg qod
12.5 mg qod
Cyclophosphamide
Palumbo et al. BLOOD, 27 OCTOBER (17):

25. Progression-free survival
Rd, len-dex
CPR, cyclophosphamide
MPR, melphalan
VP, bort-prednisone
CVP, cyclophosphamide
VMP, melphalan;
VD, bort-dex
VTD, thalidomide
VMP, melphalan VD
VTD
VMP
vs.
CVP VP Rd
CPR
MPR
0.00
0.25
0.50
0.75
1.00 5 10 15 20 25 30 35 40
Larocca A, et al. IMW 2013
Niesvizky R, et al. EHA 2010
Larocca A, et al. Gr. Emat. Milano 2012
1.0
0.8
0.6
0.4
0.2 4 8 12 16 24 28 32 36 44
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.

26. RP-MPR-RP Phase 2 Study Two drugs Three drugs Maintenance Induction
Consolidation
Maintenance
Two drugs
Three drugs
Maintenance
RP:
Pred: 50 mg/day, 3x/week
Len: 25 mg/day, d1–21
Four 28-day cycles
MPR:
Mel: 2 mg, 3x/week
Pred: 50 mg/day, 3x/week Len:10–15 mg/day, d1–21
Six 28-day cycles
RP:
Len:10 mg/day, d1–21
Pred: 25 mg/day, 3x/week
28-day cycles until PD
MPR, melphalan, prednisone, Lenalidomide; RP, Lenalidomide, prednisone; RP-MPR-RP, Lenalidomide-prednisone induction followed by melphalan-prednisone-Lenalidomide consolidation and Lenalidomide-prednisone maintenance.
Falco P, et al. Leukemia. 2013;27:

27. Conclusions FIT PATIENTS Triplets should be considered standard
Melphalan too toxic
Cyclophosphamide better tolerated
UNFIT PATIENTS
Doublet preferred 27

29. Thank you 29