Microsoft PowerPoint - 04_1ASH_IMF_Corp_final

Emerging Therapies
for
Transplantation-Ineligible
Patients With Myeloma
Antonio Palumbo, MD
University of Torino, Torino, I, EU

Faculty Disclosure
Antonio Palumbo, MD, has disclosed that he has
received honoraria from Amgen, Celgene, Janssen-
Cilag, and Merck and has served on the advisory boards
for Celgene and Janssen-Cilag.

Case Study

Case 1: Newly Diagnosed Myeloma
·69-year-old man with ISS stage III myeloma
·Extensive bone lesions; hemoglobin 9.8
·Cytogenetic and FISH normal
·Induction therapy: 6 courses of MP + bortezomib
·Immunofixation negative CR

Which Is the Next Action?
1. Stop treatment
2. Continue with
other 3 cycles of MPV
3. Continue with
lenalidomide maintenance
4. Continue with
other 3 cycles of MPV +
lenalidomide maintenance

Case 2: Newly Diagnosed Myeloma
·69-year-old man with ISS stage III myeloma
·Extensive bone lesions; hemoglobin 9.8
·Cytogenetic and FISH normal
·Induction therapy: 6 courses of MP + bortezomib
·Reduction of M-protein 56% PR

Which Is the Next Action?
1. Stop treatment
2. Continue with
other 3 cycles of MPV
3. Continue with
lenalidomide maintenance
4. Continue with
other 3 cycles of MPV +
lenalidomide maintenance

Case 3: Newly Diagnosed Myeloma
·69-year-old man with ISS stage III myeloma
·Extensive bone lesions; hemoglobin 9.8
·Cytogenetic and FISH show t(4;14), del 17
·Induction therapy: 6 courses of MP + bortezomib
·Reduction of M-protein 56% PR

Which Is the Next Action?
1. Stop treatment
2. Continue with
other 3 cycles of MPV
3. Continue with
lenalidomide maintenance
4. Continue with
other 3 cycles of MPV +
lenalidomide maintenance

Treatment strategies

Sensitive vs Resistant Disease
Diagnosis
1° Relapse
2° Relapse
3° Relapse
30 months
15 months
7 months
3 months
c
Combination regimen
Single
Single
Single
agent
agent
agent
Sensitive disease
Resistant disease
c
Low-risk SAE
High-risk SAE

Combination Therapy vs Single Agent
Progression
2nd-line
3rd-line
Combination therapy
treatment
treatment
Progression
2nd-line
3rd-line
4th-line
Single agent
treatment
treatment
treatment
· Combination could improve PFS only
quality of life
· Combination could improve OS
evidence needed

Clinical Impact of VTD Consolidation
in VGPR Patients After ASCT
Responses after ASCT
Responses after VTD
VGPR 85%
VGPR 49%
CR 15%
CR 49%
15%
49%
49%
85%
VGPR
CR
Ladetto M, et al. J Clin Oncol. 2010;28:2077-2084.

Clinical Impact of Minimal Residual Disease
PFS in PCR-negative patients
1
PCR NEG
0.9
0.8
0.7
0.6
0.5
0.4
PCR POS
0.3
0.2
P < .05
0.1
0
0
20406080
months
Ladetto M, et al. ASH 2009. Abstract 960.

Complete Response
are all the same?
Tumor gene
Response Criteria
copy number
Diagnosis
25,000 - 500,000
PR
5,000 100,000
VGPR
1,500 20,000
Immunofixation-negative CR 1,000 10,000
Immunophenotypic CR*
10 100
Molecular CR^
5 20
*Paiva et al Blood 2009: 114;4369-72; ^Ladetto et al. J Clin Oncol . 2010;28(12):2077-84

Treatment strategy
Continuous therapy
Prolongs PFS
burden
mouruT
Combinational therapy
Increases CR rate
Time

CR predicts long term outcome
Analysis of 1175 elderly patients
PFS
OS
100
100
CR
75
75
CR
VGPR
PR
50
50
VGPR
PR
25
25
0
0
0
10
20
30
40
50
60
70
0
1020
3040
50607080
months
months
Gay F et al. Haematologica 2010; 95[suppl.2]:236, abs. 0570.

Outcome and continuous treatment
Lenalidomide maintenance
001.
75
Revlimid
0.
500.
25
Placebo
0.
00
P < 10-7
0.
0
6
12
18
24
30
36
Placebo
Revlimid
McCarthy et al. ASCO 2010
Attal et al. ASCO 2010
Palumbo et al. EHA 2010
Bortezomib maintenance
1.00
1,0
PFS
0.75
0,8
VT
0,6
VMPT VT
0.50
0,4
VP
0.25
0,2
VT: median not reached
VMP
VP: 23 months
HR: 1.7; p=0.05
P = 0.006
0.00
0,0
0
5
10
15
20
25
30
35
010
20
30
40
50
60
Palumbo et al. ASH 2009
Mateos et al. ASH 2009

Dose-intensity in elderly patients
efficacy-toxicity ratio
Combinational
Single agent
Discontinuation %
65 - 75 years
17
10
> 75 years
34
16
Dose intensity %
65 - 75 years
88
97
> 75 years
56
97
Palumbo et al. Haematologica 2010; 95[suppl.2]:234, abs. 0566

Standard of Care
for
Elderly Patients

Meta-Analysis: MPT vs MP
Overall survival
Study
HR (95% CI)
Progression-free survival
Study
HR (95% CI)
MPT better
MP better
MPT better 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)
Fr>=75
0.68 (0.48, 0.96)
Fr>=75
0.61 (0.46, 0.82)
HOVON
0.75 (0.57, 1.00)
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)
NOTE: Weights are from random effects analysis
NOTE: Weights are from random effects analysis
.5
.75
1 1.251.5
.5
.75
1
1.25 1.5
MPT: melphalan-prednisone-thalidomide; MP: melphalan-prednisone
Waage A, et al. EHA 2010. Abstract 0567.

LMWH vs Warfarin vs Aspirin
for Lenalidomide and Thalidomide
Standard Risk of VTE
Lenalidomide
Thalidomide
LMWH
WAR
ASA
01
23
45
67
8
Patients (%)
High Risk of VTE
· Previous VTE, infection, immobilization, CVC, doxorubicin
· LMWH is suggested
ASA: Acetylsalicylic acid; LMWH: low molecular weight heparin; VTE: venous thromboembolism;
CVC: central venous catheter
Palumbo A, et al. EHA 2009. Abstract 0214.

VMP (Bortezomib/Melphalan/Prednisone)
Current Standard of Care
~52% reduced risk of progression
~36% reduced risk of death
100
100
90
VMP
VMP
90
MP
80
80
ent
MP
ent
Ev
Ev
70
70
60
Without
Without 60
50
50
Patients
40
Subjects
of
40
of
ge
30
ge
ta
ta 30
en
en
20
Median follow-up 25.9 months
Perc
Perc 20
Median OS not reached
Median TTP
10
VMP: 3-year OS rate = 72%
VMP: 24.0 months (83 events)
10
MP: 16.6 months (146 events)
MP: 3-year OS rate = 59%
0
HR=0.483, P < .000001
HR = 0.644, P = .0032
0
03
6
9
12
15
18
21
24
27
0 2 4 6 8 10 1214 161820 2224 262830 3234 36 38 40
Time (Months)
Time (Months)
San Miguel JF, et al. ASH 2008. Abstract 650.

Bortezomib: Once Weekly
VMP
VMP
VMP
(VISTA)
twice-weekly
once-weekly
CR
30%
27%
23%
2-year PFS
48%
56%
58%
Sensory PN
Any grade
44%
44%
22%
Grade 3/4
13%
14%
2%
Discontinuation due to
na
16%
4%
PN
Total planned dose
67.6 mg/m2
67.6 mg/m2
46.8 mg/m2
Total delivered dose
na
40.1 mg/m2
39.4 mg/m2
Bringhen S, et al. Blood. 2010 Aug 31. [Epub ahead of print]

New treatment options

Bortezomib-Melphalan-Prednisone-Thalidomide
VMPT-VT vs VMP
· 511 patients (older than 65 years) randomized from 61 Italian centers
· Patients: Symptomatic multiple myeloma/end-organ damage with
measurable disease
· 65 yrs or < 65 yrs and not transplant-eligible; creatinine < 2.5 mg/dL
VMP
R
Cycles 1-9
A
Bortezomib 1.3 mg/m2 IV Days 1,8,15,22*
NO MAINTENANCE
N
Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4
D
O
9 x 5-week cycles in both arms
Until relapse
M
VMPT
I
MAINTENANCE
Cycles 1-9
Z
Bortezomib 1.3 mg/m2 IV
Bortezomib 1.3 mg/m2 IV Days 1,8,15,22*
Days 1,15
Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4
E
Thalidomide 50 mg/day
Thalidomide 50 mg/day continuously
continuously
*66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of bortezomib
Palumbo A, et al. J Clin Oncol. 2010;Oct 12:[E-pub ahead of print].
26

Bortezomib-Melphalan-Prednisone-Thalidomide
Response Rate
VMP (N=253)
VMPT VT (N=250)
P Value
CR
24%
38%
.0008
VGPR
50%
59%
.03
PR
81%
89%
.01
40
40
38
VMP
VMPT VT
35
35
31
30
30
30
26
24
25
25
21
20
patients
17
patients 20
of 15
of 15
%
%
10
10
6
5
5
1
1
0
0
CR
VGPR PR
SD
PD
CR
VGPR
PR
SD
PD
Palumbo A, et al. J Clin Oncol. 2010;Oct 12:[E-pub ahead of print].
27

Bortezomib-Melphalan-Prednisone-Thalidomide
Time to first response and time to CR
VMP
VMPT VT
100
PR: VMPTVT
80
PR: VMP
60
patients
CR: VMPTVT
of% 40
CR: VMP
20
0
0
5
10
15
20
25
30
Months
Palumbo et al. JCO. 2010; [Epub ahead of print]
28

Bortezomib-Melphalan-Prednisone-Thalidomide
Median follow-up: 26.5 months
Time to next therapy
Progression-free survival
VMP: TTNT @ 3 years = 60%
VMP: PFS @ 3 years = 41%
VMPT VT: TTNT @ 3 years = 72%
VMPT VT: PFS @ 3 years = 56%
1.00
1.00
0.75
VMPTVT
0.75
VMPT VT
patients 0.50
0.50
of
VMP
%
0.25
0.25
VMP
P = .006
P = .006
0.00
0.00
0
10
203040
50
60
010
20
30
40
50
60
Months
Palumbo, et al. JCO. 2010; [Epub ahead of print]
29

Bortezomib-Thalidomide Maintenance
Phase III PETHEMA/GEM Study
Time-to-event data
Survival from first randomization:
median follow-up: 32 months
VMP
VTP
P
Median
34
25
.10
Survival from second randomization:
PFS
months
months
median follow-up: 22 months
3-year OS 74%
65%
.30
VT
VP
P
Median
32
24
.10
PFS
months
months
2-year OS 86%
81%
.7
Mateos MV, et al. Lancet Oncol. 2010;11:934-941.

Melphalan-Prednisone-Lenalidomide
N = 459, 82 centers in Europe, Australia, and Israel
Open-Label
Double-Blind Treatment Phase
Extension Phase
Cycles (28-day) 1-9
Cycles 10+
MPR-R
Continuous lenalidomide
M: 0.18 mg/kg Days 1-4
treatment
P: 2 mg/kg Days 1-4
10 mg/day
R: 10 mg/day po Days 1-21
days 1-21
TION
MPR
Lenalidomide
M: 0.18 mg/kg Days 1-4
Disease
(25 mg/day)
P: 2 mg/kg Days 1-4
Placebo
Progression
±
R: 10 mg/day po Days 1-21
Dexamethasone
MP
M: 0.18 mg/kg Days 1-4
RANDOMIZA
P: 2 mg/kg Days 1-4
Placebo
PBO: Days 1-21
Stratified by age ( 75 vs > 75 years) and stage (ISS I/II vs III)
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System.
Palumbo A, et al. EHA 2010. Abstract 0566.

Melphalan-Prednisone-Lenalidomide
Response Rate
MPR-R
MPR
MP
Best overall responsea
P Value
N = 152
N = 153 N = 154 (MPR-R vs MP)
ORR ( PR), %
77
68
50
< .001
CRb,%
16
11
4
< .001
VGPRc,%
32
33
12
< .001
PR, %
45
35
38
--
SD, %
18
26
46
--
Median time to first response,
2
2
3
< .001
months
a As measured using EBMT criteria (Bladé J, et al. Br J Haematol. 1998;102:1115-1123)
b Immunofixation negative with or without bone marrow confirmation
c VGPR: > 90% reduction in M-protein
ORR, overall response rate; CR, complete response; VGPR, very good partial response; PR, partial response;
SD, stable disease
Palumbo A, et al. EHA 2010. Abstract 0566.

Melphalan-Prednisone-Lenalidomide
Progression-Free Survival
58% Reduced Risk of Progression
65-75 Years of Age
2-Year PFS
Median PFS
2-
2 Year
-
PFS Median PFS
100
100
MPR-R
55%
Not reached
R
55%
Not
MPR-
MPR R
61%
Not reached
-R
61%
Not
MPR
27%
14.7 months
MPR
27%
14.7
75
75
MP
16%
13.0 months
MP
16%
13.0
MP
10%
12.4 months
MP
10%
12.4
HR 0.315
HR 0.423
Log rankP < .001
50
(%)
Log rank P < .001
(%) 50
Patients
Patients
25
25
HR 0.675
Log rankP = .031
0
0
0
5
10
15
20
25
30
35
40
0
5
10
15
20
25
30
35
40
Time (Months)
Time (Months)
MPR-R: melphalan-prednisone-lenalidomide lenalidomide continuous treatment;
MPR-R: melphalan-prednisone-lenalidomide; MP: melphalan-prednisone
Palumbo A, et al. EHA 2010. Abstract 0566.

Melphalan-Prednisone-Lenalidomide
Treatment Initial 9 Cycles
MPRa
MP
Discontinuation rateb, %
65-75 years of age
17
10
> 75 years of age
34
16
Cumulative dose intensityc, %
65-75 years of age
88
97
> 75 years of age
56
97
a MPR includes MPR-R and MPR for the initial 9 cycles.
b Discontinuation due to AEs or withdrawal of consent
c Cumulative dose intensity of melphalan and lenalidomide/placebo
Palumbo A, et al. EHA 2010. Abstract 0566.

Melphalan-Prednisone-Lenalidomide
Landmark Analysis
69% Reduced Risk of Progression
MPR
Lenalidomide Continuous Therapy
100
MPR-R
75
MPR
(%)
HR 0.314
50
Log rank P < .001
Patients
25
0 0
5
10
15
20
25
30
Time (Months)
MPR-R: melphalan-prednisone-lenalidomide lenalidomide continuous treatment;
MPR-R: melphalan-prednisone-lenalidomide
Palumbo A, et al. EHA 2010. Abstract 0566.

Lenalidomide-Prednisone
Melphalan-Prednisone-Lenalidomide
Cycles (28-day) 1-4
Cycles (28-day) 5-10
RP
MPR
R: 25 mg/d, days 1-21
M: 2 mg 3 times/week
P: 50 mg 3 times/week
P: 50 mg 3 times/week
R: 10 mg/d, days 1-21
M, melphalan; P, prednisone; R, lenalidomide;
Falco P. et al. SIES 2010 (abstract 102

Melphalan-prednisone-lenalidomide
(melphalan 0.18 0.13 mg/kg)
MPR2
MPR1
RP
0.18 mg/kg
0.13 mg/kg
MM015
Age
75(65-88)
75 (65-86)
71 (65-87)
GR 4 Adverse events %
Neutropenia
611
36
Thrombocytopenia
0
0
13
G-CSF Administration
14
26
66
Response Rates
VGPR
18
33
32
M, melphalan; P, prednisone; R, lenalidomide;
1Falco P. et al. SIES 2010 (abstract 102)
2 Palumbo A. et al. EHA 2010 (abstract 0566)

Age-Adjusted Therapy
INCIDENCE:
2002
8.9/100.000
Full-dose
Autologous
chemotherapy
transplant
65-74 years
25-64 years
36%
31%
33%
75-101 years
Reduced-dose
chemotherapy
Regione Piemonte, Assessorato Sanità 2006

Are all the elderly the same?

Age-Adjusted Doses
Further Dose
65-75 Years
> 75 Years
Redcution
Dexamethasone
40 mg
20 mg
10 mg
weekly
Melphalan
0.25 mg/kg
0.18 mg/kg
0.13 mg/kg
Days 1-4
Thalidomide
200 mg
100 mg
50 mg
per day
Lenalidomide*
25 mg
15 mg
10 mg
Days 1-21
1.3 mg/m2
1.3 mg/m2
1.0 mg/m2
Bortezomib
biweekly
weekly
weekly
If a grade 3-4 AE occurs: 1. discontinue therapy; 2. wait for grade 1
AE; 3. restart at a lower dose
*Lenalidomide plus melphalan starting dose 10 mg/d
Recommendations by A. Palumbo.

Therapeutic Algorithm
Level of Evidence 1b (> 1 Randomized Trial)
MPT
>
MP
5 randomized trials
MPV
>
MP
1 randomized trial
MPR
MPR-R
MP
1 randomized trial
>
MP
>
MPR
VMPT-VT
MP
1 randomized trial
>
VMP
1 randomized
>

Meta-Analysis: MPT vs MP
Progression-free survival - All
Overall survival - All
trt = MP
1.0
trt = MP
1.0
trt = MPT
trt = MPT
Median 39.3 months
0.8
(35.6-39.0)
0.8
0.6
Median 20.
Median 4
20. months
n
4 months
0.6
(1(8
1 .8-
8. 21.6)
8-21.6)
ortio
P<.001
Median 32.7 months
P<.001
0.4
(30.4-36.5)
0.4
prop
proportion
P=.085
0.2
Median 14.9 months
survival
Median 14.9 months
0.2
(14.0-16.6)
(14.0-16.6)
survival
0.0
0.0
0
12
24
36
48
0
12
24
36
48
months
months
Number at risk
Number at risk
trt = MP 868
493
206
69
24
trt = MP 868
654
465
265
122
trt = MPT 813
521
299
145
60
trt = MPT 814
621
480
289
143
MPT: melphalan-prednisone-thalidomide; MP: melphalan-prednisone
Waage A, et al. EHA 2010. Abstract 0567.

Peripheral Neuropathy
Bortezomib: once weekly vs twice weekly
Progression-free survival
Overall survival
Bringhen S, et al. Blood. 2010 Aug 31. [Epub ahead of print]