Emerging treatment strategies in
Multip
Multi le
p My
pyeloma
Antonio Palumbo, MD
Diii
Division f
o Hemat l
o ogy
University of Torino
Torino, Italy
OS From Time of Diagnosis in 6-yr Intervals
Based on Date of Diagnosis
1.0
197176
197782
0.8
198388
198994
199400
0.6
200106
Survival
0.4
02
0.2
0.0
0
20
40
60
80
100
120
140
Tim
Ti e
m
Kumar SK, et al. Blood. 2008;111:2516-2520.
Younger Patients
Patients
Novel agents as induction therapy for
patients eligible
eligible for a transplant
Conventional
Thalidomide
Bortezomib
Lenalidomide
VAD
Thal + Dex
Vel + Dex
RD
ID
TAD vs VAD
PAD
VTD
RVD
Rd
CY + Dex
CTD
VCD
Stem cell harvest
High-
g dose mel
e ph
p al
a an
a
Stem cell infusion
IFM2005/01 Study: Bortezomib-Dex vs
Vincristine-Doxorubicin-Dex (VAD
(
)
()
Primary analysis: post-induction response in VAD vs Bortezomib-Dex
Rando
ad miz
o
at
ation
o
stratified by 2-microglobulin level (>3mg/L vs 3mg/L) and presence
of chromosome 13 abnormalities (by FISH analysis)
A1
A2
B1
B2
VAD x 4
VAD x 4
Induction
Bortezomib-
Bortezomib-
Dex x 4
Dex x 4
DCEP x 2
Consolidation
DCEP x 2
Melphalan
Melphalan
Melphalan
Melphalan
200mg/m2
200mg/m2
Transplant 1
200mg/m2
200mg/m2
+ ASCT
+ ASCT
+ ASCT
+ ASCT
Second ASCT or RIC allo if <VGPR
Harousseau et al. ASH 2007 (abstract 450); ASCO 2008 (abstract 8505)
Bortezomib-Dex vs VAD: Responses
Evaluable patients
p
(Intention-to-Treat
(
p(
(ITT
(
)
ITT
() Analysis
y
)
sis
VAD
Bortezomib-Dex
n=219
n=223
Response after induction
CR + nCR
nCR
7%
15%
VGPR
16%
39%
PR
65%
82%
Response after first ASCT
CR + nCR
22%
40%
VGPR
44%
61%
Response after second ASCT
VGPR
47%
68%
Harousseau et al. ASH 2008
Bortezomib-Thalidomide-Dex (VTD) vs
Thalidomide-Dex (TD
(
)
() (GIMEMA
(
study)
y)
y
Randomization
Induction
Induction
· Bortezomib-Thal-Dex
· Thal-Dex
PBSC collection
· CTX
Transplantation
p
· MEL 200
· MEL 200
Consolidation
Consolidation
· Bortezomib-Thal-Dex
· Thal-Dex
Maintenance
· Dex
Cavo et al. Blood 2007;110: (Abstract 73)
Response Rates
VTD (%)
(%)
TD (%)
P
Response after induction (n=399)
CR
21
6
<0 001
.
CR/nCR
33
12
< 0.001
VGPR
61
30
< 0 001
.
PR
92
78.5
<0.001
Progression
0
4.5
0.002
Responses after ASCT (n=250)
CR
41
20
<0.001
CR/nCR
54
29
< 0.001
VGPR
75
53
< 0.001
Superiority of VTD over TD maintained across all sub-group analyses according to standard prognostic factors,
including 2-m, albumin, stage (ISS), Hb, PLTs, bone marrow PC, M protein isotype, LDH, CRP
Cavo et al. ASH 2008 (abstract 158); Cavo et al. ASH 2008 (abstract 1662)
Lenalidomide + Standard- (LD)
(
or Low-Dose
(Ld
(
)
() Dexamethasone in Newly Diag
Dia nosed MM
ECOG-E4A03: Phase III, Randomized Study
Courses repeat q 28 days 1 yr in absence of
If PD within 4 mo
PD or unacceptable
unaccep
toxicity
Arm I (LD). Lenalidomide 25 mg/d,
Arm III. Salvage therapy
days 121
Thalidomide 200 mg/d po,
Standard-dose dexamethasone
days 128
40 mg/d po, days 14, 912, 1720
Standard-dose dexamethasone
Newly
(n=223)
40 mg/d po, days 14, 912, 1720
diagnosed,
untreated MM
Arm II (Ld). Lenalidomide 25 mg/d,
Arm IV. Salvage therapy
(N=445)
days 121
Thalidomide 200 mg/d po,
Lower-dose dexamethasone
days 128
40 mg/d po, days 1, 8, 15
15, 22
22
Lower-dose dexamethasone
(n=222)
40 mg/d po, days 1, 8, 15, 22
1o endpoint: RR at 4 mo; 2o endpoints: safety in arms I, II; RR in arms III, IV
Induction trial: not intended to test efficacy of long-term Len/Dex
Rajkumar SV et al. Presented at: 50th ASH Annual Meeting; December 69, 2008; San Francisco, CA
E4A03: Grade 3 Non-hematologic AEs
at 4 and
aand 36 Months
Toxicity (grade 3) within first 4
P Value
LD, %
Ld, %
(Fisher's
cycles
(n=223)
(n=220)
Exact)
Any nonhematologic toxicity
53
31
<.001
Early deaths (<4 mo), all patients
5
0.5
.003
Toxicity (grade 3) at 36 mo median
P Value
(Fisher's
follow-up*
LD, %
Ld, %
Exact)
DVT/PE
26
12
<.001
Infection/pneumonia
16
9
.043
Ah
Any nonh
t
ema l
o
i
og c toxicitity
66
8
<.001
Toxicity of any type (grade 4)
21
14
<.001
*Data Monitoring Committee (DMC) closed study at median follow-up of 12.5 mo, and
immediate crossover to Ld was mandated. At median follow-up of 36 mo, 404 patients (91%)
are off study (197 were off study by 4 mo; 253 were off study by 6 mo)
Rajkumar SV et al. Presented at: 50th ASH Annual Meeting; December 69, 2008; San Francisco, CA
E4A03: Response at 4 and 36 Months
RC
Response Category
LD, %
Ld, %
P Vl
Value
Within first 4 cycles
PR
79
68
.008
VGPR
42
24
<.008
Best overall response at 36
mo*
PR
81
70
.009
VGPR
51
40
.040
CR (IF-
(IF )
17
14
428
.
PFS probability at 36 mo*
39
43
.08 (log-rank)
.04 (Pepe-
Fleming)
TTP probability at 36 mo*
45
42
NS
Stem cell harvest (n=167)
97.6% successful
2.4% unsuccessful
*DMC closed study at median follow-up of 12.5 mo, and immediate crossover to Ld was mandated. At median follow-up of
36 mo, 404 patients (91%) are off study (197 were off study by 4 mo; 253 were off study by 6 mo)
Rajkumar SV et al. Presented at: 50th ASH Annual Meeting; December 69, 2008; San Francisco, CA
E4A03: 1- and 3-yr OS
1-yr OS
3-yr OS
96%
100
100
Ld
Ld
80
80
87%
75%
ability
ability
LD
3-yr
yr OS rate
60
LD
60
Prob
Prob
40
40
rvival
rvival
20
20
Su
P=.46 log-rank;
Su
P<.001
P=.01 Pepe-Fleming
0
0
0
6
12
18
24
0
6
12
18
24
30
36
Time (mo)
Time (mo)
Numbers at Risk
Numbers at Risk
LD
223
179
103
37
0
LD
223
208
195
184
173
123
78
Ld
221
192
103
37
0
Ld
222
217
212
201
192
146
83
At median follow-up of 12.5 mo, DMC closed the study, and immediate crossover to Ld was
mandated
Rajkumar SV et al. Presented at: 50th ASH Annual Meeting; December 69, 2008; San Francisco, CA
ECOG-E4A03: landmark analysis
431 patients
alive after
4 cycles
Off
Of therapy
Primary therapy
after 4 cycles
4 cycles
(n = 176)
(n = 255)
No transplant
Tr
T ansplant
Rd
RD
(n = 91)
(n = 85)
(n = 142)
(n = 113)
1
Median age 68 years
Median age 57 years
Median age 57 years
Median age 65 years
Rajkumar SV, et al. J Clin Oncol. 2008;26 [abstract 8504];
updated data presented at ASCO 2008.
Len + Dex is a highly active
pre-
pre transplant induction regimen
regimen
Overall survival: transplant after induction therapy
with 4 cycles
y
of RD or Rd
100
RD
Rd
80
3-Year OS rate 92%
(%) 60
ients 40
Pat 20
0 0 6 12 18 24 30 36
Time (months)
Number at risk
RD 50
50
49
48
47
35
20
Rd 40
40
40
38
37
32
21
Rajkumar SV, et al. Presented at ASH/ASCO symposium, ASH 2008.
Prolonged induction with Len + Dex
could be
be an
an alternative to early ASCT
Overall survival: continued treatment with RD or Rd
beyond the 4 cycles
yy
of induction treatment
100
Rd
80
RD
(%) 60
3-Year OS rate: 79%
ients 40
Pat 20
0 0 6 12 18 24 30 36
Time (months)
Number at risk
RD 108
108
103
97
90
67
44
Rd 140
140
139 133
128
95
51
Rajkumar SV, et al. Presented at ASH/ASCO symposium, ASH 2008.
Efficacy of SCT with Len + Dex not
affected by slight reduction in cell
ht
harves
h
t
G-CSF only1
G-CSF only2
G-CSF only3
CY + G-CSF4
RD i d
n uction
RD i d
n uction
RD i d
n uction
BiRD i d
n uction
Dex
VAD
Lenalidomide therapy
Thal + Dex
Len + Dex
Other induction therapies
12
p < 0.001
p < 0.0025
9
Successful
Successful
8
n = 40
10
harvest
harvest
7
in 97.6% of
in 100% of
ion) 8
llion) 6
n = 18
6
167 patients
18 patients
(mi
(mill
5
6
/kg
4
+
count
34 4
+
3
Range:
D
4
DC
2
4.021.5 × 106
2
CD3 1
CD34+ cells/kg
0
0
Total CD34+ cells collected
1. Kumar S, et al. Leukemia. 2007;21:2035-42. 2. Paripati H, et al. Leukemia. 2008;22:1282-4. 3. Rajkumar SV,
et al. Presented at ASH/ASCO symposium, ASH 2008. 4. Niesvizky R, et al. Blood. 2008;111:1101-9.
Phase I/II trial of RVD in newly diagnosed MM:
trial design and resp
res
gponse
Non-randomized, open-label, dose-comparison study
21-Day cycle (maximum 8 cycles)
1
2
4
5
8 9
11 12
14
21
B
B
B
B
Dex
Dex
Dex
Dex
Lenalidomide daily
After a median follow-up of
EBMT response
Patients, %
8 months, median time to
CR
26
progression, progression-free
survival, and overall survival
CR or nCR
44
were not reached
VGPR
74
The most common adverse
PR
100
events included
included haematological
n = 66 response-evaluable patients; response rates
events and hyperglycaemia
independent of del(13q), t(4;14).
Richardson P, et al. Blood. 2008;112:[abstract 92];
RVD = lenalidomide, bortezomib, dexamethasone.
updated data presented at ASH 2008.
EVOLUTION: a phase I study of
RVD + cyclophosphamide (RVCD)
(RVCD)
Non-randomized, open-label, dose-comparison study
Day 1
4
8
11
14 15
21 8 cycles
Lenalidomide 15 mg/day
B
B
B
B
D
D
D
C
C
B = bortezomib 1.3 mg/m2
EBMT response
Patients, %
D = dexamethasone 40 mg
sCR
20
C = cyclophosphamide 100500 mg/m2
CR or nCR
36
VGPR
68
PR
100
25 patients, median age 61 years
Kumar S, et al. Blood. 2008;112:[abstract 93].
MPR vs MEL200
study design
Diagnosis
4 RD cycles
PBSC
harvest
random
A: 6 MPR cycles
B: 1-2 MEL200 cycles
Len
Len
no
no
MEL200
Ct
Conven i
ti
l
ona h
c emoth
therapy
Therapeutic Algorithm
Level of Evidence 1b (> 1 Randomized Trial)
Diagnosis
< 65 years
VD
VAD
>
VA
1 randomized trial
>
1 randomized
VTD
VAD
>
1 randomized trial
Rd
RD
1 randomized trial
Consolidation vs
maintenance
Thalidomide maintenance studies
N
Duration of treatment
CR (%)
PFS (%)
OS (%)
57 vs 44 (8-year)
TT2
Double ASCT;
6.0 vs 4.1 years
P=0.09
Barlogie
65 vs 43
Significant diff.
668 Randomization to thal
(median)
Blood 2008;
throughout or not; until
P<0
P
001
.
in patients with
112:31153121
disease progression
P=0.001
cytogenetic
abnormalities
Double ASCT;
ASCT;
IFM 99-02
Pamidronate + thal vs
Attal
VGPR:
52 vs 37 vs 36
87 vs 74 vs 77
pamidronate vs no
67 vs 57 vs 55
(3-year)
(4-year)
Blood 2006;
597 maintenance;
108:3289
P=0.03
P<0.009
P<0.04
3294
until disease
3294
until
progression
Single ASCT;
Spencer
42 vs 23
Prednisolone + thal vs
86 vs 75 (3-year)
JCO 2009;
243
Not available
(3-
(3 year)
prednisolone; 12
27:178893
months
P<0.001
P=0.004
PAD Induction, MEL-100, Len/Prednisone
Consolidation, and Len Maintenance in Elderly
Patients With Newly
N
Newly Diagnosed MM
PADMEL-100LPL
PBSC Mobilization
MEL-100
PAD
LP
L
(Cyclophosphamide + G-CSF)
ASCT
4 cycles
2 cycles
2 cycles
4 cycles
PAD = bortezomib + pegylated doxorubicin + dexamethasone; MEL-100 = melphalan100 mg/m2;
LP = lenalidomide + prednisone; L= lenalidomide
21-day cycle
PAD
1
4
8
11
21
B
B
B
B
PLD
2
2
B = bortezomib 1.3 mg/m2; PLD = pegylated doxorubicin 30 mg/m ;
Dex*
Dex = dexamethasone 40 mg/d *Dex days 14, 811, 1518 on cycle 1
28-day cycle
LP: Consolidation
1
21
28
Lenalidomide 25 mg/d
Prednisone 50 mg/every other day
28-day cycle
L: Maintenance
1
21
28
Lenalidomide 10 mg/d
Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA
Role of Maintenance
After Autologous Transplant
PAD
P
MEL100
LP
LP--L
L
INDUCTION
CONSOLIDAT
CONSOLIDA ION
MAINTENANCE
* Per protocol
Palumbo A, et al. J Clin Oncol. 2008;26(18S): Abstract 8518; updated results presented at: 44th ASCO Annual
Meeting; May 30 June 3, 2008; Chicago, Illinois.
CLINICAL IMPACT OF VTD CONSOLIDATION
Response at study entry
(evaluable 39 pts.
(p
)
23%
64%
CR
nCR
VGPR
13%
Response after VTD consolidation
STATUS CHANGES DURING
(evaluable 27 pts.)
CONSOLIDAT
CONSOLIDA ION:
T
4%
15%
11 VGPR CR
CR
nCR
3 VGPR nCR
VGPR
15%
PD
4 nCR CR
66%
1PR PD
MOLECULAR RESULTS
Treatment phase
evaluable pts
PCR-neg pts
After ASCT
40
2(5%) (one transient)
After VTD 2 courses
33
5(15%) (one transient)
After VTD
VTD 4 courses
courses
29
6(21%) (all true MR)
·median follow-up from enrollment: 24 months
·6 patients achieved a true molecular remission
(t
(at least two pcr
ti
-nega ve
l
samp es)
·Seven relapses among PCR+ pts vs no relapses among MR pts
(at 24
24 18(x3)
,
, 12
12 and 6 months
months from enrollment)
·No molecular relapses among patients with true "MR"
ASCT vs mini ALLO
Treatment Assignment *
Induction
(VAD - based regimens)
PBSC mobilization
(cy
(yclophos
p
phamide
p
)
Autografting
(melphalan, 200 mg/sqm)
Autografting
Low dose
dose TBI (2Gy) and
and Allografting
*Based on presence/absence of an HLA matched sibling
Outcome according to presence of HLA-identical siblings (n=162),
Median follow up from diagnosis: 45 months, range 21-90
Overall survival
Event
Ev
free survival
rv
1
1
p=0.01
p=0.02
0,5
0,
0,5
0,5
0,
0
0
0
1
23
45
012345
67
8
678
012345678
01
23
456
7
8
012345678
Years after di
i
agnos s
Years after
ft
diagnosis
HLA-Id sibling:
YES n=80
NO n=82
B. Bruno et al NEJM 2007