Novel combination therapies for the
treatment of relapsed/refractory Multiple
Myeloma:
Current Phase I/II combinations
Paul Richardson, Jacob Laubach, Robert Schlossman, Irene Ghobrial,
Constantine Mitsiades
Mitsiades, Teru
Teru Hideshima, Dharminder Chauhan, Noopur
Noopur
Raje, Nikhil Munshi, Kenneth C. Anderson
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute;
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
Pa
P thogenesis
a
of Multiple Myeloma
My
Hideshima T, et al. Nature Reviews Cancer 7, 585-598 (August 2007)
Rationale for Combination Therapy
in Multiple Myeloma
IMiDs, Bortezomib
Dex
Bortezomib
Alkylators
Anthracyclines
Mitochondria
NF-B
Cytochrome-c
Smac
Caspase-8
Caspase 9
Caspase-
Caspase 3
PARP
Tumor cell death
Tumor cell death
From Richardson PG , Mitsiades CS, Hideshima T, Anderson KC: Expert Review of
Rationally Based Combination Therapies
·
Bortezomib and Hsp 90
·
Lenalidomide and mTOR
inhibitor
inhibitor
·
Bortezomib and doxil
·
Lenalidomide and Anti-CD40
antibody
·
Bortezomib and NPI-0052
·
Lenalidomide and
and doxil
·
Bortezomib and perifosine
·
Lenalidomide and HuLuc63
·
Bortezomib and LBH 589
·
Lenalidomide and LBH 589
·
Bortezomib and Smac
peptides
·
Lenalidomide and perifosine
·
Bortezomib and Bcl 2
·
Lenalidomdide and
inhibitor
Bevacizumab
·
Bortezomib and p38 MAPK
·
Lenalidomide and Vaccine
inhibitor
·
Bortezomib and HuLuc63
Lenalidomide and Bortezomib
Rationale: Preclinical Combination of
Lenalidomide (Len)
(Len) + Bortezomib
Bortezomib (Bz)
(Bz)
50
Bz-Resistant Patient Cells
40
Len
)
100
0 M
(% 30
80
5 M
lDeath
(%)
20
60
Ce
40
10
Growth
20
0
0
010
20
Bz, nM
Mitsiades et al. Blood. 2002; Hideshima et al. 2003
Lenalidomide plus bortezomib
ib: study design
Phase I multicenter dose-escalation study
Relapse and/or refractory MM (N=38)
Bortezomib
Bortezomib 10o
1.0 r13m
or 1.3 g/m2
mg/m on days 1, 4, 8, 11
11
Lenalidomide 5, 10, 15, or 20 mg on days 1-14 of 21-day cycle
Dexamethasone (40 mg on day and day after each lenalidomide
dose) in patients with PD
PD
NCI CTCAE for toxicity assessment
DLT
DL G 3 non-hematological toxicity,
toxicity G4 neutropenia for
for 5 days
and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion
despite transfusion
Response assessed by modified EBMT criteria
PD, progressive disease;
Richardson PG, et al. Blood. 2006;108:a
DLT, dose-limiting toxicity; G, grade
Lenalidomide plus bortezomib:
bl
base iline characteristi
tics
Baseline characteristics, n=28
Relapse MM, n
12
Relapse/refractory MM, n
26
Male, %
65.8
Md
Me i
dian age (
)
range , years
60 (37 79)
-
Prior therapies, median (range)
5 (1-13)
Richardson PG, et al. Blood. 2006;108:a
Lenalidomide plus bortezomib:
safety outcomes
Sft
Safety
t
ou comes
G3 hyponatremia
bor 1.3 mg/m2 + len 10 mg
HZV reactiti t
va ition,
b1
bor 1 3
.
/ 2
mg/m +l
+ len 15
15 mg
G4 neutropenia
Maximum tolerated
tolerated
bor 1 0
. mg/m2
mg/m + len
len 15 mg
dose
Dose reductions
bort=
bort 5l
5, en=
len 6, both=
both 5
Discontinuations
1 with dexamethasone
Bort, bortezomib; len, lenalidomide;
MTD, maximumm tolerated dose; dex,
Richardson PG, et al. Blood. 2006;108:a
Lenalidomide plus bortezomib:
efficacy outcomes
Efficacy
t
ou comes
ORR (95% CI), %
58 (46-75)
CR, %
6
Median DoR, months
6
Ther
e apy 1 yr, %
y,%
30
Objective response, n/N (%)*
10/14 (71)
*in patients receiving
pg dexamethasone
ORR, overall response rate; CR,
Richardson PG, et al. Blood. 2006;108:a
complete response;
Lenalidomide plus bortezomib:
response rates
Len
Bort 1.0 mg/m2
Bort 1.3 mg/m2
5 mg
2 PR, 1 MR
1 CR, 2 PR
10 mg
1C
1n R2
CR, 2 PR
PR
2P
2 Pr, 2M
2 R
MR, 1 SD
SD, 1P
1 D
PD
15 mg
2 PR, 4 MR, 7 SD,
2 PR, 5 SD
1P
1 D
PD
Lenalidomide plus
plus bortezomib with/without dexamethasone is well tolerated and
very active with durable responses in heavily pre-treated patients with relapsed
and/or refractory MM
PR, partial response; MR minimal
response;
Richardson PG, et al. Blood. 2006;108:a
PR complete response; nCR near
Lenalidomide plus bortezomib plus
dt
dexame h
thasone: st d
u y design
Phase I study
Relapse/refractory MM following 1-3 prior lines of therapy (N=65)
Up to 8 cycles of:
Bortezomib
Bortezomib 1 0
. on
on days
days 1481
1, 4, 8, 1
11
Lenalidomide 15 mg on days 1-14 of 21-day cycle
Dexamethasone 40/20 mg cycles 1-4/5-8 on days of/after bortezomib
After cycle 8 patients with
with stable
stable or
or responding disease:
disease:
Lenalidomide (days 1-14), bortezomib (days 1, 8) and dexamethasone 10 mg (days 1, 2, 8 and 9)
Concomitant antiviral and anti-thrombotic prophylaxis
Response assessed
assessed by
by modified
modified EBMT and Uniform criteria
criteria
NCI CTCAE v3.0 used for toxicity assessment
Primary endpoint: TTP
Secondary endpoint: response
response rate
rate, DOR
DOR, PFS, OS
OS
TPP, time to progression; DOR, duration of
Anderson KC et al. J Clin Oncol 2008;26
response; PFS, progression free survival; OS,
Lenalidomide plus bortezomib plus
dt
dexame h
thasone: baseliline d
h
emograp i
hics
Baseline characteristics
Relapse MM
MM, n
24
Relapse/refractory MM, n
17
Male, %
66
IgG MM, %
63
Durie-Salmon stage III, %
59
Median age, years
67
Prior therapies, median
2
Subtypes of prior therapies, %
Lenalidomide
2
Bortezomib
68
Dexamethasone
90
Thalidomide
78
SCT
32
SCT,
Cycles of treatment, median
7
Anderson KC et al. J
stem cell
Clin Oncol
Lenalidomide plus bortezomib plus
dexameth
thasone: efficacy outcomes
Efficacy outcomes
ORR (95% CI), %
73 (55.6-85.1)
PR, %
55
VGPR/nCR/CR, %
36
Median DoR (95%
(95% CI), weeks
weeks
39 (13 5
. 63)
-
Median TTP, PFS and OS
not yet reached
ORR, overall response rate; PR, partial
response; VGPR, very good partial
response; nCR, near complete response;
Anderson KC et al. J Clin Oncol 2008;2
Tanespimycin + Bortezomib
Synergistic Anti-
Anti myeloma Activity
Activity
In vitro cytotoxicity model using
Induction of Hsp70 seen at 2 hrs;
myeloma cell lines: synergy
Hsp90 transcription increase occurring
4
~ -8h
8 hrs f l
oll
i
ow ng t
i
anesp myci /
n BZ
/BZ
control) 120
of 100
80
(%
val 60
40
Survi 20
0
AG
ntrol
341
A
17-AAG
Co
PS
17-
PS-341+
Tr
T anscription / Translation
Translation Regulation
Signal Intensity
Mitsiades CS et al. Blood 2006 Feb 1;107(3)
Bortezomib plus tanespimycin:
std
tudy design
Dose escalation and dose confirmation with two different
formulations of tanespimycin
Days 1, 4, 8, 11 of every 21-day cycles
Dose escalating phase (n
(n=36):
Tanespimycin 100-340 mg/m2 as 1-hour infusion plus bortezomib 0.7-1.3 mg/m2
Dose confirmation phase (n=27):
Cremophor (n=13) vs suspension formulation without steroid premedication (n=14)
Richardson PG et al. Blood 2007;110:a
Bortezomib plus tanespimycin:
saft
fety
t
ou comes
No G3 neurotoxicity with any dose
Recommended dose
Tanespimycin
Bortezomib
340 mg/m2
1.3 mg/m2
No difference in toxicity between 2 formulations
G3/4 thrombocytopenia
yp
with
Cremophor
p
Suspension
p
tanespimycin formulations
15%
12%
Diarrhea Dizziness Nausea AST Vomiting Fatigue
ALT
Peripheral
oedema
39%
27%
23%
23%
23%
19%
19%
19%
ALT, alanine aminotransferase; AST,
Richardson PG et al. Blood 2007;110:a
if
Bortezomib plus tanespimycin:
response rates
Bortezomib refractory
3 DR
Bt
Bortezomib
ib-naïC
ïve, Cremophor f
l
ormu t
a ition, n
CR
2
PR
2
MR
4
Bortezomib-naïve, suspension formulation, n
CR
1
PR
2
MR
1
Ongoing Phase 3 trial of Bortezomib plus tanespimycin
versus Bortezomib in relapsed myeloma
DR, durable response.
Richardson PG et al. Blood 2007;110:a
Rodent Model of Neuropathy
Bortezomib 0.2 mg/kg IV Bolus and KOS-0953 20.0 mg/kg 60 min IV Infusion
(q2wkx3) in Male Sprague Dawley Rats
Average Group Sensory Threshold Readings Over Time (g) 0706-001#3
)
study ongoing
g
66.0
(d 62.0
hols 58.0
e
Thr
54.0
ry
n=6
Control
o
50.0
s
n=6
Bortezomib
ne
n=6
Combination
46.0
S
42.0
roupG 38.0
ge
34.0
raev 30.0
A
7 8 9 10 1112 131415 1617 1819 202122 2324 252627 28 29 3031 323334 3536 37 38 3940
Study Day
·
Rats were treated with saline (control)
(control), bortezomib (0
(0 2
. mg/kg)
mg/kg), or
or bortezomib
(0.2 mg/kg) plus tanespimycin (20 mg/kg). Sensory thresholds were measured
using a von Frey Anesthesiometer
·
Combination of tanespimy
pycin with bortezomib demonstrated a lack of
neurotoxicity compared to bortezomib alone, indicating a neuroprotective
effect of tanespimycin
Richardson et al, ASH 2007
Akt Inhibitor Perifosine Enhances
Bortezomib-Induced Cytotoxicity in MM Cells
Bt
Bortezomib
ib
Bortezomib
048h
p-Akt
caspase
Akt
Perifosine
Akt
apoptosis anti-apoptosis
8h CP
BP+B
120
24h Perifosine (M)
p-JNK1/2
100
0
caspase-8
80
5
CF
control60
PARP
75
7.5
CF
40
%
C: control
20
0
B: Bortezomib (10 nM)
05
7.5
PP
P: Perififosine (5
(5 M)
Bortezomib (nM)
M)
Bortezomib
Hideshima et al. Blood 2006; 107: 4053-52
Bortezomib plus perifosine:
std
tudy design
Phase I/II study
Relapse or relapse/refractory MM previously treated with
bortezomib (N=18)
Perifosine 50 mg or 100 mg daily
Bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, 11 in 21-day cycles
Dexamethasone 20 mg on days of/after each bortezomib dose in patients with PD
NCI CTCAE v3.0 used for toxicity assessment
DLT
DL any G
ht
non-hematologic toxi i
c tity, G4 neutropenia for 5d
5 days
and/or neutropenic fever or platelets <10,000/mm3 on >1 occasion
despite transfusion
Response assessed
assessed by
by modified
modified EBMT and Uniform criteria
criteria
Richardson P et al. Blood 2007;110:ab
Bortezomib plus perifosine:
bl
base iline characteristi
tics
Baseline characteristics
Relapse/refractory MM, n
14
Male, %
61
Median age (range), years
64 (42-
(42 87)
Prior therapies, median (range)
5 (2-7)
Subtypes of prior therapies, %
Bortezomib
100
Dexamethasone
89
Thalidomide
67
Lenalidomide
33
SCT
56
SCT, stem cell transplant
Richardson P et al. Blood 2007;110:ab
Bortezomib plus perifosine: safety
Safety outcomes
Grade 3/4 AEs, %
Fatigue
6
Thrombocytopenia
25
Anaemia
13
Dose reductions, n
Perifosine
1
Bortezomib
3
Bortezomib plus perifosine: efficacy
efficacy
Response (n=15)
(n=15)*
N(
N %)
(%)
Duration (weeks)
PR (peri+bor)
2 (13)
24, 13+
MR (peri+bor)
1 (7)
10+
MR (peri+bor+dex) 2** (13)
38+, 18+
SD (peri+bor)
3 (20)
18+, 16+, 13+
SD (peri+b
i+bor+dex)
3 (20)
(20)
38, 22+, 12+
Perifosine in combination with
with bortezomib (with/without
(with/without dexamethasone)
was well tolerated and active in mostly relapsed/refractory MM patients
*Dexamethasone added to 6 patients
**patients refractory to prior bort+dex
Richardson P et al. Blood 2007;110:ab
SD stable disease defined as <25%
Perifosine Bortezomib Dexamethasone (n =72)
Richardson et al, ASH 2008 Abstr 870
Median 5 prior lines of treatment
Median # of
of prior
prior Bz lines of treatment: 2
Overall Response Rate: 38%
Median TTP: 6 3
. mos
mos
Bortezomib Refractory Pts (n = 52)
Over
Oe all
a Respo
esp n
o se
se Rate
at :
e 31%
3%
Median TTP: 6.2 mos
Toxicities manageable
mib and perifosine
p
versus
MM ongoing for FDA approval
Richardson et al, ASH 2008 Abstr 870
Blockade of Ubiquinated Protein Catabolism
Protein
Ub Ub
protein aggregates
(toxic)
Ub
Ub
Ub
26S proteasome
Ub
HDA
Bortezomib
C6
Ub Ub
Tubacin
Trials of LBH
LBH, SAHA
HDA
d
an SAHA with
ith
dynein
C6
Bortezomib ongoing
Ub Ub
Lysosome
Aggresome
Aggresom
HDA
Ub Ub
dynein
Ub Ub
C6
Ub
Ub
Microtubule
At
Autophagy
Hideshima et al, Clin Cancer Res;2005; 11: 8530
Catley et al, Blood 2006; 108: 3441-9.
Bt
Bortezomib
ib l
p us vorinostat A: st d
u y design
Phase I
Relapsed/refractory MM
Maximum tolerated dose, pharmacokinetics, pharmacodynamics
Bortezomib 1 3
. mg/m2
mg/m on days 1, 4, 8 and 11
11 of a 21
21-day cycle
Vorinostat 100-400 mg days 4-11
Badros AZ et al., J Clin Oncol 2008;26:
Bortezomib plus vorinostat A:
bl
base iline characteristi
tics
Baseline characteristics, n=23
Median age (range), years
54 (39 78)
-
Median time from diagnosis to study
5.3 (1.5-9)
(range), years
IG
IgG, n
11
IgA, n
4
Light chain,
g, n8
Complex karotype, n
14
Prior therapies, median (range)
7 (3-13)
Pi
Prior th
therapies, n
Thalidomide
23
Lenalidomide
17
SCT
20
Badros AZ et al., J Clin Oncol 2008;26:
Bortezomib plus vorinostat A:
A: safety
Safety
Maximum tolerated dose
bortezomib 1.3 mg/m2
+ vorinostat 400 mg
Grade 3/4 AEs, n
Requiring transfusion
13
Growth factors
6
Fatigue
11
Diarrhea
5
Atrial fibrillation
1
Shingles
1
Pneumonia
2
Badros AZ et al., J Clin Oncol 2008;26:
Bt
Bortezomib
ib l
p us vorinostat A: response rates
Prior
ORR
N=
VGPR
PR
SD
PD
bortezomib
Naïve
41
2
1
Prior
10
1
2
5
1
42%
treatment
Refractory
9
3
4
1
Badros AZ et al., J Clin Oncol 2008;26:
Bt
Bortezomib
ib l
p us vorinostat B: st d
u y design
Phase I, multicenter, open-label trial (N=34)
Bortezomib 0.7, 0.9, 1.1 or 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle
Vorinostat 200 mg bid or 300-400 mg daily for 14 days
Cycles repeated every 21 days for 8 cycles or until PD or intolerable toxicity
Dexamethasone 20 mg (days 1-4 and 17-20) could be added to patients with PD
Weber D et al., Blood 2008;112:ab
Bortezomib plus vorinostat B:
B: safety
Safety outcomes
Highest dose
bort 1.3 mg/m2 + vorin 400 mg
Maximum tolerated dose
Not determined
Dose limiting toxicities
G3 transient AST elevation
bort 0.9 mg/m2 + vorin 400 mg
G4
G throm
o bocytopenia
bort 1.3 mg/
g/m2 +vorin 400
o00 mg
Drug-related AE, %
Nausea
62
Diarrhea
59
Thrombocytopenia
50
Vomiting
50
Weber D et al., Blood 2008;112:ab
Bortezomib plus vorinostat B:
B: efficacy
efficacy
Efficacy outcomes
Ol
Overa lll, %
PR
26
MR
21
SD
53
Prior bortezomib (n=13), %
PR
39
MR
8
SD
54
Median (95% CI) DoR, days 89 (9-369)
The combination of bortezomib and vorinostat is active for treatment of MM, even
among patients with prior exposure to bortezomib
Weber D et al., Blood 2008;112:ab
Vorinostat-Bortezomib
Weber et al ASH
2008 Abstr 871
Effective for treatment of relapsed/refractory MM
Overall response
response (PR
(PR + CR) ~38-
38 43%
> SD ~90%
Effective
Ef
despite prior bortezomib therapy
therapy
Overall response ~29-35%
SD ~41-
41 53%
Overall response refractory pts > PR ~29-38%
SD refractory pts ~42-50%
Well Tolerated Fatigue, Diarrhea, thrombocytopenia
Phase III trial of Bortezomib and SAHA versus
Bortezomib in relapsed MM ongoing for FDA
approval
CNTO 328 + Bz in Relapsed/
Refractory MM: Ph II Trial
CNTO 328: anti-IL-6 mAb
Has terminal half-life of ~ 16-18 d
CRP is a biomarker for anti-IL-6 therapy[1]
Shown to enhance bz effect in MM cells[2]
Two-part phase II trial including bz-naive pts with relapsed/refractory MM
who received 1-3 lines of previous treatment
Part 1
·
CNTO 328 6 mg/kg IV, every 2 wks + bz 1.3 mg/m2 IV d 1, 4, 8,
11, every 3 wks
·
N = 21
·
Safety run-in
Part 2
·
Bz ± CNTO 328 (N = 270)
·
Pts randomized 1:1 to receive
Bz + CNTO
CNT 328
Bz + placebo
1. Rossi JF, et al. Bone Marrow Transplant. 2005;36:771-779. 2. Voorhees PM, et al.
Clin Cancer Res. 2007;13:6469-6478. 2. Rossi J, et al. ASH 2008. Abstract 867.
CNTO 328 + Bz in Relapsed/
Refractory MM: Part 1 Results (Ph II)
Response, n
70
Grade 3
(N = 21)
60
Grade 4
50
CR
3
29%
3
ORR
40
57%
VGPR*
3
(%) 30
20
PR
6
Pts 10
SD
6
0
PD
3
* VGPR defined as > 90% reduction in
serum M-spike.
Median TTP: 8.7 mos (1.2-22.4)
Part 2 of study ongoing
Rossi J, et al. ASH 2008. Abstract 867.
Conclusions and Future directions
directions
Best combinations are informed by preclinical
ti
ra
l
ona e
N
l
ove combi
ti
na on therapies result
lt in encouraging
results, including high response rates and
manageable toxicity
Further studies are ongoing to further optimize the
id
regimens and ensure th
th t
a
t
pa i
tients receive more
effective and well-tolerated treatment
United Nations Against Myeloma:
Jerome Lipper and Lebow Bench to Bedside Research Team
Kenneth Anderson
Anderson
Nikhil Munshi
Paul Richardson
Teru Hideshima
Robert Schlossman
Constantine Mitsiades
Steven Treon
Dharminder Chauhan
Irene Ghobrial
Noopur Raje
USA
Japan
Jacob Laubach
Klaus Podar
Greece
Deborah Doss
Ruben Carrasco
Kathleen Colson
Paola Neri
Mary McKenney
Giovanni Tonon
Kim Noonan
Marc Raab
Stacey Chuma
Simona Blotta
UK
Canada
Ta
T iwan
Kathy McCormick
James Bradner
Muriel Gannon
Ruben Carrasco
Janet Kunsman
Patrick Hayden
Diane Warren
Hiroshi Ikeda
Andrea Freeman
Steffen Klippel
India
Farzana Masood
Germany
Merav Leiba
Tk
Turkey
Laura Lunde
Joseph Negri
Bobbie O'Brien
Doug McMillian
Edie Weller
Yutaka Okawa
Katie Loftus
Iris Breikeutz
Rachel Loftus
Samantha Pozzi
Italy
Austria
Australia
Renne Leduc
Masood Shammas
Sarah Dean
Tanyel Kiziltepe
MeghanRourke
Yu-Tzu Tai
Shannon Viera
Sonia Vallet
Christine Rubio
Ajita Singh
Israel
Lisa Popitz
Mohan Brahmandan
China
Ireland
Jeffrey Sorrell
Weihua Song
John Feather
Mariateresa Fulcinitti
Nicole Carreau
Brianna Harris
Bortezomib combination studies
studies summary
Reference
Treatment combination
OR,
%
Richardson PG et al.,
2006
Lenalidomide + bortezomib
58
Anderson KC
KC et
et al
al.,
Lenalidomide + bortezomib +
3
2008
dexamethasone
7
Richardson PG et al.,
2007
Bortezomib + tanespimycin
50
Richardson P et al.,
2007
Bortezomib + perifosine
56*
Badros AZ et al., 2008
Bortezomib + vorinostat
43
Weber DM et al., 2008
Bortezomib + vorinostat
24
Palumbo AP et al., 2007 Bortezomib + melphalan + prednisone
+ thalidomide
67
*ORR included minor response
1. Richardson PG et al. Blood 2006; 2. Anderson KC et al. J Clin Oncol 2008;
3. Richardson P et al. Blood 2007; 4. Richardson P et al. 2007; 5. Badros AZ
J Clin Oncol 2008; 6 Weber DM et al Haematologica 2008;
Lenalidomide combination
combination studies overview
Richardson PG et al.,
2006
Lenalidomide + bortezomib
Anderson KC
KC et
et al
al.,
2008
Lenalidomide + bortezomib + dexamethasone
Baz R et al., 2006
Doxorubicin + vincristine + dexamethasone +
lenalidomide
Knop S et al., 2008
Lenalidomide + dexamethasone + adriamycin
Morgan GJ et al., 2006 Lenalidomide + dexamethasone +
cyclophos
yp
phamide
p
Palumbo et al., 2008
Lenalidomide + melphalan + prednisone +
thalidomide
1. Richardson PG et al. Blood 2006; 2. Anderson KC et al. J
Clin Oncol 2008; 3. Baz R et al. Ann Oncol 2006; 4. Knop S
et al Haematologica 2008; 5 Morgan GJ et al Blood 2006;
Lenalidomide combination
combination studies summary
Reference
Treatment combination
OR, %
Richardson PG et
al., 2006
Lenalidomide + bortezomib
58
Anderson KC et al.,
Lenalidomide + bortezomib +
2008
dexamethasone
73
2008
dexamethasone
Baz R et al., 2006
Doxorubicin + vincristine +
dexamethasone + lenalidomide
75
Lenalidomide + dexamethasone +
Knop S et al., 2008
Lenalidomide + dexamethasone
adriamycin
85
Morgan GJ et al.,
Lenalidomide + dexamethasone +
2006
cyclophosphamide
65
yp
p
Palumbo et al., 2008 Lenalidomide + melphalan + prednisone +
thalidomide
91
1. Richardson PG et al. Blood 2006; 2. Anderson KC et al. J
Clin Oncol 2008; 3. Baz R et al. Ann Oncol 2006; 4. Knop S
et al Haematologica 2008; 5 Morgan GJ et al Blood 2006;
Combination therapy
therapy in
in relapse/refractory MM
MM
Reference
Treatment combination
OR,
%
Richardson PG et al., 2006
Lenalidomide + bortezomib
58
Anderson KC et al., 2008
Lenalidomide + bortezomib +
dexamethasone
73
Richardson PG et al., 2007
Bortezomib + tanespimycin
tanespimycin
50
Richardson P et al., 2007
Bortezomib + perifosine
56*
Badros AZ et al., 2008
Bortezomib + vorinostat
43
Weber DM et al., 2008
Bortezomib + vorinostat
24
Palumbo AP et al., 2007
Bortezomib + melphalan + prednisone +
thalidomide
67
Doxorubicin + vincristine + dexamethasone +
Baz R et al., 2006
Doxorubicin + vincristine + dexamethasone
lenalidomide
75
Knop S et al., 2008
Lenalidomide + dexamethasone + adriamycin
85
Morgan GJ et al., 2006
Lenalidomide + dexamethasone +
2006
lh
cyclophosph
i
am d
65
ide
Palumbo et al., 2008
Lenalidomide + melphalan + prednisone +
thalidomide
91