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The Role of Lenalidomide in
in Myeloma
Myeloma
Patients Eligible for High Dose Therapy
S. Vincent Rajkumar
Professor of Medicine
Mayo Clinic
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center

Ideal front-line regimen
· 100% response rate
· 100% survival rate at 4 months
months
· 100% survival rate at 1 year
· Oral
· Manageable adverse-effect profile
· Excellent ability for stem-cell harvest/transplant
· Best long-term survival

Transplant Candidates
54
42
Attal M. N Engl J Med 1996; 335:97; Child J. N Engl J Med 2003; 348:1875

Consolidation: Role of Upfront Transplantation
100
Auto (n=258): 58 months
80
VBMCP: (n=252): 53 months
60
%
40
20
0
24
48
72
96
120
Fermand. Blood 1998; 92:3131; Barlogie ASH 2003

Lenalidomide/Dex in
in New
New MM
Response
All patients
Rev/Dex as
to therapy
(n=34)
1º therapy
(n=21)
Objective
91%
90%
Response
CR
18%
24%
CR +
VGPR 67%
VGPR
38%
43%
PR
35%
24%
Rajkumar et al. Blood 2005;106:4050-4053; Lacy. ASH 2006

Lenalidomide/Dex: Overall Survival
0.
92%
.810
90%
ive
.60
Al
roportionP
0.4
P
2 yr OS rate
No Transplant
Transplant
0.2
0.0
0
5
10
15
20
25
Time in Months

RD vs TD
Mayo phase II study anal
analysis
sis
2yr survival
· RD (n=34): 90%
· TD (n=50): 70%
p=0.058
Nowakowski G. IMW 2007

ECOG E4A03
R
445 pts
A
N
@ 4 months
D
Len + Dex
CR/PR
Pts eligible for
O
x4 cycles
SCT
M
proceed to SCT*
SCT
I
Z
A
Len + Low
Less
Thal +
T
dose Dex
Dex
CR/PR/St b
a l
than
Dex
ble
I
x 4 cycles
PR
x 4 cycles
O
N
Rajkumar, ASCO 2007

Treatment Schedule
Days
1
8
15
22
28
Lenalidomide 25 mg PO d1-21
A
Total Dex
dose per
Dex
Dex
Dex
Cl
Cycle =
d1-4
d9-12
d17-20
480 mg
Lenalidomide 25 mg PO days 1-21
Total Dex
B
dose per
D
D
D
D
Cycle
y
=
e
e
e
e
160 mg
x
x
x
x
d1
d8
d15
d22
Rajkumar, ASCO 2007

Patient Characteristics
Characteristics
Arm A
Arm B
(n=223)
(n=222)
ISS (%)
Stage I
30.5
31.5
Stage II
37.8
37.8
Stage
g III
23.3
23.9
Rajkumar, ASCO 2007

Initial Therapy and Early Mortality
Regimen*
RR
Early
Deaths
Dex (E1A00)
(E1A00)
41%
11%
11
Dex (+/-IFN) (IFM 4 arm)
41%
10.5%
MP (IFM)
40%
8%
Thal/Dex (E1A00)
63%
7%
Len/Dex (E4A03)
?
4.5%
MPT (IFM)
81%
3%
Len/low-dose Dex
?
1.5%
(E4A03)
*Recent Phase III trials that did not restrict entry to transplant candidates

Si
Serious adverse events
Hematologic Toxicity
Toxicity
Arm A
Arm B
P value
(N=433 Ever Reported)
(N=217)
(N=216)
Hemoglobin
7.8%
6.0%
0.12
Neutrophils
9.7%
19%
0.002
Platelets
4.1%
5.1%
0.16
Rajkumar, ASCO 2007

Serious adverse events
Non-Hematologic Toxicity
Toxicity
Arm A
Arm B
P value
(N=433 Ever Reported)
(N=217)
(N=216)
DVT/PE (AdEERS*)
23.8%
9.1%
<0.001
Infection/Pneumonia
14.7%
5.1%
<0.001
Hyperglycemia
9.7%
6%
0.05
Cardiac ischemia
2.8%
0.5%
0.05
Atrial fibrillation/flutter
2.3%
0.5%
0.09
Neuropathy
14
1. %
4%
09
0. %
9%
03
0. 1
31
Rajkumar, ASCO 2007

DVT/PE
Arm A
Arm B
Before
After
Before
After
mandatory
mandatory
mandatory
mandatory
prophylaxis
prophylaxis
prophylaxis
prophylaxis
N=132 (%)
N=91(%)
N=132 (%)
N=88 (%)
First 4 months
23
14
8
5
All time
26
21
10
8
Rajkumar, ASCO 2007

Si
Serious adverse events
Non-Hematologic Toxicity
Toxicity
Arm A
Arm B
P value
(N=433 Ever Reported)
(N=217)
(N=216)
Any non Hem toxicity (Grade >=3)
52.1%
34.3%
<0.001
Toxicity of Any Type (Grade >=4)
28.6%
18.1%
0.003
Early Deaths (< 4 months)
4.5%
1.4%
0.034
Rajkumar, ASCO 2007

One-year Survival Rate
N
Events
Survival
Probability
(95%CI)
Len-High
223
26
0.87 (0.82, 0.92)
Dex(RD)
Len-Low
222
8
09
0. 6
96 (0 94
.
, 0 99)
.
Dex(Rd)
Rajkumar, ASCO 2007

Overall Survival
Survival (months)
Rd
RD
Rajkumar, ASCO 2007

One-year Survival Rate by Age
N
Events
S
i
urv
l
va P b
ro
b
a ili
bility
(95%CI)
Age <65
Len-High Dex
104
8
0.91 (0.85, 0.97)
Len-Low Dex
108
2
0.98 (0.96, 1.00)
Age 65
Len-High Dex
119
18
0.83 (0.76, 0.90)
Len-Low Dex
114
6
0.94 (0.89, 0.99)
Rajkumar, ASCO 2007

Overall Survival
Survival (months): Age <65
Rd
RD
Rajkumar, ASCO 2007

Overall Survival
Survival (months): Age 65

Rd
RD
Rajkumar, ASCO 2007

Mortality of Combination Chemotherapy vs
Ml
Mel hl
phal
/
an P
/Prednisone
Years
01
23
4
5
6+
100
90
MP 1 yr OS = 71%
alive 80
CC 1 yr OS = 68%
still 70
60
27 randomized trials
50
ercentage 40
p
30
24.4
%
19.4
20
%
1.4% SD 1.4
timated
23.0
t
18.0
(log-rank
Allocated cct (% ± SD)
0
(g
SD)
10
Es
2P > .1; NS)
Allocated MP (% ± SD)
0
Deaths/person-years:
CCT
642/1999 392/1456 305/1044 196/724 133/506 255/1130
MP
576/1968 407/1423 294/983 194/652 130/444 215/839
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;12:3832

One-year Survival rate in
in Phase
Phase III Newly
Diagnosed MM Trials
1-yr
Study
Age
Phase
N
Regimen
Survival
Ref
rate
Rajkumar,
Rajkumar E1A00
E1A00
Median=65
III
103
Thal Dex vs
vs Dex
Dex
80%
JCO 2006
Rajkumar, MM003
Median=65
III
470
Thal Dex vs Dex
80%
ASH 06
Palumbo
Median=72
III
255
MPT vs MP
87%~
Lancet 06
Attal, IFM
<65
III
200
Auto vs Chemo
88%~
NEJM 1996
Child, MRC
<65
III
401
Auto vs Chemo
87%~
NEJM 2003
Barlogie, S9321
<=70
III
516
Auto vs Chemo
84%*
JCO 06
Attal, IFM
<60
III
399
Single vs Double Auto
90%~
NEJM 2003
Barlogie, TT II
<75**
III
668
TT2 +/-Thal
92%
NEJM 2006
E4A03 Arm A
Median=65
223
223
Len + high-dose dex
87%
ASCO 2007
E4A03 Arm B
Median=65
222
222
Len + low-dose dex
96%
ASCO 2007
*intent to treat population; **80% age <65
Rajkumar, ASCO 2007

Mayo Rev-Dex Experience
N=72
ECOG Arm B (Rd)
1
ECOG Arm A
Mayo II - 4 months
.8
l
Similar OS with
a
4t
4 mon h
ths vs t
i
ox i
c t
ity
.6
adjusted high-dose
dex
.Surviv 4
m .
m
Cu
.2
0
0
5
10
15
20
25
30
35
40
Time

Mayo Rev-Dex Experience
p
1
Si il
m ar TTP with
Rd
RD and Rd
.8
l
RD
.6
.Surviva 4
.
Cum
.2
0
0
5
10
15
20
25
30
35
40
Time

Preliminary data on stem cell harvest
harvest,
transplant
% Reporting
% reporting
% missing
% unsuccessful
successful
data
harvest/SCT
Harvest
26%
94%
3.4%
2.6%
Transplant
24%
93.3%
4.8%
1.9%

www.msmart.org
mSMART- Off St
Study
Tr
T ansplant
r
Eligible
*If no response after 2
Lenalidomide-Low Dose Dex 4 cycles*
cycles, consider
bortezomib containing
regimen.
Collect Stem Cells
High Risk
Standard Risk
Bortezomib containing regimen (eg.,
Tr
T ansplant***
ansplant
(Second transplant
transplan if
MPV, VTD, etc) to max response**
not in CR or VGPR after first)
If not in CR, consider Thal-Pred to
Observation
max response
response if
if no
no prior
prior thalidomide
**Potential allogeneic approaches
***If transplant deferred continue induction to max
considered in selected patients
response
Mayo Clin Proc 2007;82:323-341

Ideal i d
n uction regimen
Ideal
Phase III
data with Rd
· 100% response rate
?
· 100% survival rate at 4 months
98.5%
· 100%
i
surv
l
va
t
ra e t
a 1 year
96%
· Oral
Yes
· Manageable adverse-effect profile
Yes
· Excellent ability for stem-cell harvest/transplant
Yes
· Best long-term survival
?

FD
Future i
Directions
· Compare Rd to VRd (SWOG/ECOG trial)
· Trials with more intensive regimens, new
combinations: eg., CBD, CVRD, CVTD, liposomal
doxorubicin containing regimens
· Define role of SCT, especially in patients in CR or
VGPR