Immunomodulation: The
Cornerstone of the Treatment
of Multiple Myeloma
Nikhil C. Munshi, MD
Associate Professor of Medicine
Harvard Medical
Medical School
School
Asso. Director, Jerome Lipper Myeloma Center
Dana-Farber Cancer Institute
Boston VA Healthcare System
DANA-FARBER
CANCER INSTITUTE
Faculty disclosure information
Consultant: Celgene, Millennium, Novartis
Grant/Research Support: No
Speakers Bureau: Celgene, Millennium,
Novartis
Major Stock Shareholder: No
Paradigm Change
From Targeting MM Cells
to Targeting BM Microenvironment
1960s - Targeting MM Cell
2005 - Targeting MM Cell
And BM Milieu
Melphalan, Prednisone,
Thalidomide, Bortezomib,
Radiation therapy
Lenalidomide, LPD, Hsp90
inhibitors, HDAC inhibitors
Hideshima T & Anderson KC Nat Rev Cancer 2002 2:927-937
Mechanism of Action of Thalidomide/IMiD
C.
C Cytokine
C
Cytokine effect
eeffect
MM cells
IL-6
TNF
B. Effect on
IL
IL--11
A.
A Direct
D
Direct effect
Adhesion
Bone marrow
Stromal cells
ICAM
ICAM--11
Bone marrow
Vessels
V
VEGF
IL
IL--22
bFGF
NK Cells
IFN
T Cell Co
Co--
D. Anti-angiogenic effect
eeffect
ti
s
l
mu t
a i
E. Immune
Immune effect
tion
E. Immune
Raje and Anderson N Engl J Med. 1999;341
RVD in patients with
relapsed/refractory MM
MM
Non-randomized, open-label, dose-comparison study
21-Day cycle (maximum 8 cycles)
1
4
8
11
14
21
B
B
B
B
Dex
Dex
Dex
Dex
Lenalidomide daily
daily
Lenalidomide 15 mg; bortezomib 1.0 mg/m2; dexamethasone (on days 1, 2, 4, 5, 8, 9,
11, and 12) 40 mg in cycles 14, 20 mg in cycles 58
Per recent protocol amendment, starting dose of dexamethasone reduced to 20 mg in
cycles 14, with further reduction to 10 mg in cycles 58
Maintenance therapy consists of treatment with the study drugs at the dose levels
tolerated upon completion of cycle 8
RVD = lenalidomide + bortezomib + dexamethasone.
Richardson PG, et al. Blood. 2007;110 [abstract 2714].
RVD: efficacy
33 response-evaluable patients as of 15 Nov 2007
Bt
Best responses to d t
a e
nCR in 2 (6%)
PR in 16 (48%)
()
VGPR in 10 (30%)
MR in 6 (18%)
SD in 9 (27%)
(27%)
ORR (CR or nCR + PR + MR) 73%, including 55%
with CR or nCR or PR
Median duration of response in responding patients
is 7 cycles (range 416)
Median TTP, PFS, and OS have not yet been reached
Richardson PG, et al. Blood. 2007;110 [abstract 2714].
Phase I/II: VRDC EVOLUTION Study (N = 25)
Patients: 25 enrolled with previously untreated MM
Dose: RV
RVD with
with dose escalated
escalated CY 100 500mg/m2
-500mg/m days 1 and 8;
pts could undergo SCT after 4 cycles
Best Unconfirmed Response:
ORR -
100%,
sCR -
20%
CR -
36%
VGPR -
68%
Stem Cell Collection: 11 pts collected a median of 5.9x106 CD34+
cells/kg; 2 pts required a second cycle of stem cell mobilization
Safety: Gr 3 AE 24% neutropenia 24%, PN 16%,
Thrombocytopenia 12%, no DVT
Kumar S et al. ASH 2008, abstract #93
Phase II Study: Sequential Bortezomib,
Cyclophosphamide, Dex (VCD) followed by
VTD
Patients: 44 enrolled with
with previously
previously untreated MM; median age 58
yrs (38-83); 72% ISS stage II/III
Response
VCD + VTD (n=43)
· Estimated 12-mos OS and EFS
CR
26%
were 86% each after median
CR/nCR
35%
follow up
-
of 10 6
. mos
mos
VGPR
21%
PR
40%
· 22 pts proceeded to SCT; 100%
ORR
96%
had successful SC collection
Safety: 82% of pts complete 6 cycles; there were 11 Gr 3-4
events requiring
requiring dose adjustment
Bensinger W et al. ASH 2008, abstract #94
Overview of trials with lenalidomide
combinations in newly diagnosed MM
CR or nCR,
TTP or PFS,
Md
Me i
dian OS
OS,
Regimen
ORR, %
VGPR, %
%
months
months
Not reached
Not reached
RVD1
RVD
100
44
74
(> 8 mos)
(> 8 mos)
VDCR2
100
36
68
Not reached
Not reached
Not reached
Not reached
RCD3
85
NR
32
(> 2 yrs)
(> 2 yrs)
MPR4
81
24
48
29
91% @ 2 yrs
1. Richardson PG, et al. Blood 2008;112:[abstract 1742]. 2. Kumar S, et al. Blood
2008;112[abstract 93]. 3. Kumar S, et al. Blood 2008;112:[abstract 91]. 4. Palumbo
A, et al. Blood 2008;112:[abstract 2768].
RAD in relapsed MM
Day
1
2
3
4
17 18 19 20 21
28
Lenalidomide, p.o.
Doxorubicin, 24-h continuous i.v.
Dexamethasone, p.o.
Patients,
Lenalidomide,
Doxorubicin,
Dexamethasone,
Pegfilgrastim
Dose level
n
mg/day
mg/m2
mg/day
1
3
10
4
40
2
3
10
6
40
3
3
10
9
40
4
6
15
9
40
4 + G-CSF
3
15
9
40
6 mg, day 6
5+G
5 + -
G CSF
6
25
9
40
6 mg
mg, day 6
RAD = lenalidomide + doxorubicin + dexamethasone.
Knop S, et al. Blood. 2007;110 [abstract 2716].
RAD trial: efficacy
Response other than nCR or CR
100
nCR
87
CR
80
)
60
60
(%
60
tsn
40
Patie
20
25
23
0
Dose levels 14
Dose level 5
(n = 20)
+ G-CSF
(n = 30)
Cytogenetic abnormality
Patients, n/evaluable (%)
PR, n
del(13q)
17/37 (46)
12
t(4;14)
4/25 (16)
3
del(17p)
6/31 (19)
2
Knop S, et al. Blood. 2007;110 [abstract 2716].
Overview of trials with lenalidomide
combinations in relapsed/refractory MM
CR or nCR,
TTP or PFS,
Median OS,
Regimen
g
ORR, %
,%
VGPR, %
,%
%
th
mon smo th
n s
Len + Dex1
61
24
NE
11
358
Len + Dex2
Dex
60
25
NE
11
RMPT3
76
13
33
55% @ 1 yr
66% @ 1 yr
RAD4
RAD
73
15
45
45
88% @ 1 yr
RVD5
78
20
29
Not reached
Not reached
6
RCD
65
5
20
Not reported
Not reported
DVd-R7
75
29
NE
12
Not reached
1. Weber DM, et al. N Engl J Med. 2007;357:2133-42. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-32. 3. Palumbo
A, et al. Blood 2008;112:[abstract 868]. 4. Gerecke C, et al. Blood 2008;112:[abstract 2782]. 5. Anderson KC, et al. J Clin
Oncol 2008;26:[abstract 8545]. 6. Morgan GJ, et al. Br J Haematol. 2007;137:268-9. 7. Baz R, et al. Ann Oncol.
2006;17:1766-71. 8. Weber D, et al. Blood 2007;110;[abstract 412].
CALGB-100104: lenalidomide as maintenance
therapy after autologous PBSCT
Ongoing phase III, randomized, placebo-controlled trial
Patients with active MM, stable disease, or disease responsive to 4 months'
induction therapy (N = 588)
PBSCT
Re-staging
90100 days after PBSCT
Randomize
Lenalidomide
Placebo
10
/d
mg ay
/d
p.o.
10
/d
mg ay
/d
p.o.
(n = 250)
(n = 250)
Primary end-
end point: time to disease progression
progression after autologous PBSCT
Secondary end-points: CR rate, PFS, OS, feasibility of long-term lenalidomide
PBSCT = peripheral blood stem cell transplant.
www.clinicaltrials.gov.
Rationally based combination therapies
· Lenalidomide and anti CD40
-
antibody
· Lenalidomide and mTOR inhibitor
· Lenalidomide and doxil
· Lenalidomide and HuLuc63
· Lenalidomide and LBH 589
· Lenalidomide and perifosine
p
· Lenalidomide and bevacizumab
· Lenalidomide and vaccine
Phase I trial of perifosine, Len, and
Dex in
in relapsed/refractory
relapsed/refractory MM
Day
1 2 3 4
9 10 11
11 12
17 18 19 20 21
28
Perifosine 50 or 100 mg/day
Lenalidomide 15 or 25 mg/day
D
D
D
Cycles 14 only
D
Cycles 5+
D = dexamethasone 20 mg
Results
·
32 patients enrolled, median age 61 (range 3780) years
·
Median 2 (range 14) prior therapies, including Dex (94%), Thal (83%), Bort (47%)
·
ORR ( PR) 50%, VGPR 17% (VGPR 10%; nCR
nCR = 7%)
7%)
·
Median TTP for patients having PR is 31 (range 1179) weeks
·
Grade 3 or 4 adverse events include neutropenia (20%), hypophosphataemia
(17%), thrombocytopenia (13%), anaemia (10%), fatigue (79%)
Bort = bortezomib; nCR = near-complete response;
Jakubowiak A, et al.
ORR = overall response rate; PR = partial response;
Blood. 2008;112:[abstract 3691].
TTP = time to progression; VGPR = very good PR.
NPI-0052 + Lenalidomide Trigger
Synergistic/Additive Anti-MM Activity
Synergistic
Additive
MM.1S cells
MM.1R cells
CI = 1 0
. 0
00
CI < 1.00
CI = 1.00
CI < 1.00
O hr
24 hr
48 hr
Rev
NPI-0052
Dharminder Chauhan et al., 2009
NPI-0052 + Lenalidomide Trigger
Synergistic/Additive Anti-MM Activity in Patient cells
Dharminder Chauhan et al., 2009
Combination of lenalidomide and NPI-0052
Prolongs Survival
Oral NPI-0052 (X2 WK) and lenalidomide (X4 WK)
Pv
P al
va ue
u 0
-. 01
001
110
100
Control
90
Rev 5 mg + NPI 0.15 mg/kg
NPI-.150mg/kg
eic 80
Rev-2.5mg/Kg
M 70
Rev 2. 5 mg
mg + NPI 0 15
.
mg/kg
70
e
Rev 5mg/Kg
60
liv 50
Rev 2.5 +NPI-.150mg/Kg
Af 40
Rev 5+ NPI-.150mg/Kg
o 30
mg/kg
% 20
0.15
10
NPI
0 0 25 50 75 100 125 150
Survival (Days)
1- Animals in control, Rev 2.5 and 5 mg died between 30-45 days.
2- Low dose NPI-treated animals have 10-15 days more survival.
3- Animals in combination group
gp survived 4-5 month.
Dharminder Chauhan et al., 2009
IMiDs Augment anti-MM Immunity
T Cell
NK Cell
NFA
NF T
A
IL-2
IL-2
PKC
D
d
en ritic Cell
PI3K
CD28
Apoptotic
MM Cell
MM Cell
IMiDs
VEGF
IL-6
Bone Marrow Stromal Cell
LeBlanc R et al. in press Hayashi T et al. in press
IMiD3 Overcomes CTLA-
CTLA 4 Blockade
Blockade
100000
80000
60000
pmc 40000
20000
0
T-cells Imm Mat
DCs DCs
antiCD3
Immature DCs
mature DCs
T
ll
-ce s+IMiD3
IMiD
T-cells+CTLA-4-Ig
Treatment of PBMCs with Thal and IMiD
increases lysis
y
of MM cell lines
DMSO
Thal
1ug/ml
40
30
5ug/ml
20
lysis 20
15
ysis
cell 10
l
%
10
0
cell
5
30:115:17.5:1
%
0
effector:target ratio
30:1
15:1
75
7.5:1
effector:target ratio
IMiD1
DMSO
40
Thal
s
IMiD1
30
IMiD2
lysi 20
IMiD3
cell 10
%
0
30:1
15:1
7.5:1
effector:target ratio
IMiDs Enhance NK Cytotoxicity against MM Cells
Natural cytotoxicity
ADCC
DMSO
DMSO
Target: U266
Target: MM.1S
IMiD1
40%
IMiD1
40%
IMiD3
IMiD3
30%
city 30%
ity
20%
totoxi 20%
totoxic
Cy
Cy
10%
10%
0%
0%
40:1
20:1
10:1
E : T 60:1
30:1
60:1
30:1
Effector : Target
Control Ab
rhuCD40 mAb
Target: RPMI8266
Target: ARH-77
20%
40%
30%
c
city
city 15%
10%
20%
totoxi
totoxi
Cy
Cy
5%
10%
0%
0%
40 : 1
20 : 1
10 : 1
E : T 60:1
30:1
60:1
30:1
Effector : Target
Hayashi T et al. in press
Control Ab
rhuCD20 mAb
Lenalidomide Induces
Induces Increased anti
anti--CD40
CD40
induced ADCC Against Autologous MM Cells
Patient 1
Patient 2
Patient 3
60
**
50
**
25
** **
50
40
**
20
lysis
40
30
15
fic
30
*
20
10
*
10
20
*
*
10
5
Speci
10
%
0
0
0
L
L
L
on
G
o
40
de
+
on
G
40
de
+
on
G
o
40
de
4
+
c
Ig
S
c
Ig
S
c
Ig
S
med
con
SGN-
med
con
SGN-
med
con
SGN-
lenalidomi
lenalidomi
lenalidomi
Clinical Trial in MM in 2008
Lenalidomide + SGN40
Tai et al. Cancer Res 2005, 65: 7896-7901.
Lenalidomide + anti-CS-1
Immunomodulatory role of lenalidomide
on pneumococcal responses
responses
Cohort A
Lenalidomide 25 mg, days 1-21, every 28 days,
6 cycles
Pneumococcal vaccine day 0 cyc
cy le
cle 1 and
and day
Relapsed MM
15 cycle 2
patients,
lenalidomide naïve,
treated with 3 prior
therapies
p
Cohort B
Lenalidomide 25 mg, days 1-21, every 28 days,
6 cycles
Pneumococcal vaccine day 15, on cycles 2
and 4
Noonan KA, et al. Blood 2008;112:[abstract 2772].
Immunomodulatory role of lenalidomide
on pneumococcal responses:
responses: results
Cohort A:
A: 80% decrease in
in antibody titres
titres, 0%
0% of
of total
total T
cell population proliferated to CRM-197
Cohort B: 2 fold increase in antibody responses, 1.8% of
total T cell population proliferated to CRM-197
· Antibody responses more pronounced in BM ers
v
s
u PBL
· MCP-1 and MIP-1 levels decreased during trial
· IFN and IL-
IL 17 undetectable in
in PBL but were elevated
and unchanged respectively in BM samples
Noonan KA, et al. Blood 2008;112:[abstract 2772].
Randomized Study to evaluate ability of
Lenalidomide to
to Augment
Augment Vaccine
Vaccine Response
VA
V /DFCI
A
Randomized Study
Hepatitis B
Day 28
Vaccine
V
Arm I. Lenalidomide
AI
Arm I. L
lid
ena
id
om e
25 mg/day PO, Days 11
77
25 mg/day PO, Days 88
14
14
Patients with
Anti-HepB
MM
Immune
response
Arm II. Placebo
Arm II. Placebo
Days 1-7
Days 8-14
Pomalidomide in Myeloma
C
MM cells
IL-
IL 6
TNF
B
IL-1
A
BM
Bone Marrow
ICAM-1
Stromal Cells
Bone Marrow
Vessels
NFAT
PKC
IL-2
IL-2
IFN
NK Cells
VEGF
PI3K
CD28
bFGF
CD8+ T
Dendritic
Cells
D
E
Cells
Mitsiades et al. Blood 99: 4525, 2002
Hideshima et al. Blood 96: 2943, 2000
Lentzsch et al Cancer Res 62: 2300, 2002
Davies et al. Blood 98: 210, 2001
LeBlanc R et al. Blood 103: 1787, 2004
Gupta et al. Leukemia 15: 1950, 2001
Hayashi T et al. Brit J Hematol 128: 192, 2005
In Vivo Anti-Tumor Activity of Thalidomide/IMiDs
)3 B
A100
(mm 3000
80
rvival 60
u
lume 2000
S
o
40
%
rv 1000
20
om
0
0
Tu
0
25
50
75
100
125
0
7
14
21
28
Days of treatment
Days of treatment
C
50
45
40
Thalidomide
35
IMiD1
30
25
IMiD3
20
15
10
5
0
Contro
IMiD1
IMiD3 Thalidomide
l
Treatment
Lentsch et al. Leukemia 2003:17:41
Phase II trial of pomalidomide + low-
dose Dex
Dex in relapsed/refractory MM
MM
Day
1
8
15
22
28
Pomalidomide 2 mg/day
D
D
D
D
D = dexamethasone 40 mg/day
Aspirin 325 mg/day as routine thromboprophylaxis
Results
·
37 patients enrolled, median age 66 (range 4088) years
·
3 prior regimens (38%), 2 prior regimens (35%), 1 prior regimen (27%),
prior ASCT (76%)
(76%)
·
ORR ( PR) 62%, VGPR 24%
·
Adverse events in 5% of patients
grade 3 neutropenia (31%), thrombocytopenia (3%), anaemia (3%)
ASCT = autologous stem cell transplant; ORR = overall
response rate; PR = partial response; VGPR = very good PR.
Lacy MQ, et al. Blood. 2008;112:[abstract 866].
Phase II trial of Pomalidomide in
Relapsed/Refractory
py Myeloma
y
(N
( = 60)
· Dose: Pomalidomide - 2mg po daily days 1-28
Dexamethasone - 40mg po
po days 1, 8, 15
15 & 22
Aspirin - 325mg po days 1-28
Confirmed Response
Response
N=
N 60
=60
sCR
1 (2%)
CR +VGPR 25%
VGPR
14 (23%)
ORR 58%
58%
PR
20 (33%)
SD
11 (18%)
Among the first
first 37 patients, there were
were 13
13 lenalidomide
lenalidomide refractory
refractory
patients, with responses seen in 29%
One death due to pneumonia while neutropenic
Primarily fatigue Grade ¾
28%
Neutropenia
32%
No DVT
Lacy et al, ASH 2008; Abstr. 866
Nearing The Cure
Improving OS from the Time
Impact of novel agents on
of Relapse Post-ASCT with
outcome in newly diagnosed
Novel Agents (n=387)
disease (n=2981)
70
1.0
Relapsed before 1998
60
Relapsed 20002001
0.8
Relapsed 20042005
50
al
(months)
viv 0.6
S 40
v
O
Sur
30
0.4
Median 20
P < 0.001
0.2
10
Multi Agent Sequential
gq
Therapy
py
0.0
Improves Sustained CR
1971 1977
1983
1989 1995
2000
0
20
40
60
80
100
1976
1982
1988
1994
2000
2006
Is it a Cure? (n=2981)
Year of diagnosis
Kumar
100%
et al. Blood 2008;111: 2516Z
TT3 (13/162)
CR DURATION
Kumar et al. Blood 2007;110: (#3594)
80%
P=0.0008
TT2+Thal
60%
(78/201)
P=0.19
40%
TT2-Thal (67/148)
20%
P=0.0002
TT1 (78/94)
0% 0
5
10
15
20
Years from complete response
Barlogie et al. ASCO 2008, #8516
Thank you