The Tr
T eatment
r
of Relapsed and
Refractory Myeloma: Focus on
Bortezomib and Bortezomib-based
Combinations
PG Richardson, R Schlossman, I Ghobrial
Ghobrial,
CS Mitsiades, T Hideshima, D Chauhan, N Munshi,
KC Anderson
Jerome Lipper Multiple Myeloma Center
Dana-Fb
Farber Cancer Instit
tit t
u e
Kos, June 2007

---

Multiple Myeloma: Current Treatment
Adapted from
from NCCN Practice Guidelines
Guidelines (2007)
Diagnosis
· Survival 3-5 yrs
Relapsed Disease
Relapsed/Refractory Disease
· Survival < 6 mos without Rx
· Transient response
· Shorter TTP
· ~12,000 deaths per yr
· Survival 1-3 yrs
· Survival 6-9 mos
Initial Therapy
Salvage Therapy:
· Cyclophosphamide
Non-
· Repeat primary therapy (if relapse > 6 mos)
Transplant
· Melphalan, prednisone
Candidate
· Cyclophosphamide, VAD, liposomal doxorubicin
+/- th lid
a omide,
· Etoposide, dex, cytarabine, cisplatin
+/- bortezomib,
· Thalidomide +/- dex
+/- lenalidomide
· Lenalidomide +/- dex
· VAD, liposomal
p
· Bortezomib +/-
+/ dex; Bortezomib combinations
doxorubicin
· Other novel therapies (clinical trials)
· Dexamethasone (dex)
· Thalidomide + dex
· Stem cell harvest, subsequent auto
· Bortezomib + dex
SCT (single vs double) +/- maintenance
· Bortezomib combos
(thalidomide, bortezomib, lenalidomide)
· Lenalidomide + dex
Transplant
· Investigational therapy (eg, allo-SCT)
Candidate

---

Relapsed/Refractory MM: Factors associated
with Poor Prognosis
·
Refractory to prior
yp
treatment (relapsed
p
and refractory)
·
Age >65 yrs: majority of pts with MM are older
(median age at diagnosis ~70 yrs)
·
Increased 2
M, decreased serum albumin, low platelet count
2M, decreased serum albumin, low platelet
·
Cytogenetic abnormalities [ eg Ch 13 del, t (4,14)]
·
Renal dysfunction
­ up to 50% f
o
t
p s with MM
MM have
l
rena d f
ys
t
unc i
tion
­ between 20­30% of pts have concomitant renal failure
·
Extensive Bone Disease; Extra-Medullary MM
Unmet need for new agents to treat these pts
Barlogie et al. Blood 2004;103:20­32
Kyle et al. Mayo Clin Proc 2003;78:21­33
Fonseca et al. Cancer Res 2004;64:1546­58
Kumar et al. Mayo Clin Proc 2004;79:867­74
Kyle. Stem Cells 1995;13(Suppl 2):56­63
Facon et al. Blood 2001;97:1566­71
Bladé et al. Arch Intern Med 1998;158:1889­93

---

Bortezomib Targets MM Cells in the
BM Microenvironment
MM Cell Growth
TNF
A. Bortezomib
C. Bortezomib
VEGF
IL-6
B. Bortezomib
ICAM-
ICAM 1
VCAM-1
Bone Marrow
VEGF
Stromal Cells
Bone Marrow
bFGF
D. Bortezomib
Vl
Vessels
Hideshima et al. Cancer Res 2001; 61: 3071
Mitsiades et al. Blood 2002; 99: 4079
Hideshima et al. Oncogene 2001; 20: 4519
LeBlanc et al. Clin Cancer Res 2002; 277:1166

---

Bortezomib Effects on MM Cells
1. Downregulates adhesion molecules,
caspase dependent cleavage of IL-6R
2. Activates JNK, increased ROS,
mitochondrial release of cyto C/Smac,
caspase 9>8, caspase 3 cleavage
cleavage
3. Induces p53+/- apoptosis
4. Induces
Induces cleavage of
of Mcl
Mcl-1
5. Inhibits DNA repair (ATM, DNA PKcs
cleavage)
6. Induces apoptosis of endothelial cells,
osteoclasts
7. Induces osteoblasts, new bone formation

---

Bortezomib (PS-341, VelcadeTM):
Bench to
to Bedside
Bedside in Relapsed/
Refractory Myeloma
· 2000: Preclinical Studies, Phase I Trials
· 2001: Phase II Trials, 256 pts (SUMMIT + CREST)
· SUMMIT St
St d
u y: 35% CR+PR MR
+
i
l
nc 10% CR/ CR
n
(modified EBMT criteria)
· 2002 - 03: APEX Phase III Study, 669 pts
· Accelerated Approval (FDA) in rel/refy MM 2003
· EMEA Approval 2004
· Full Approval (FDA) in relapsed MM 2005
Hideshima et al. Clin Cancer Res 2001; LeBlanc et al. Cancer Res 2004
Orlowski et al. JCO 2003; Richardson et al. NEJM 2003; Jagannath et al. BJH 2004;
Richardson et al. NEJM 2005

---

Phase 3 Trial: APEX
· International, randomized,
,, open-label
p
study in
relapsed or refractory MM (N = 669) comparing
single agent bortezomib to HD dex
· Endpoints
­ Primary: TTP
­ Secondary: survival, response rate (RR) and duration,
time to skeletal events (TSE), grade 3 infection, safety
· Companion crossover study available to pts
progressing on HD dex
Richardson et al. NEJM 2005

---

Time to Progression (N = 669)
78% improvement in
d
me i
dian TTP with bortezomib
ib
p < 0.001
Median TTP: Bortezomib 6.2 mos
Dexamethasone 3.5 mos
Richardson et al. NEJM 2005

---

Updated APEX efficacy data
Response rates
· ORR with Bortezomib improved
p
from 38% to 43%
Updated analysis
Primary analysis
P<0.0001
60
50
43%
%
38%
40
30
27% PR
25% PR
18% <1% nCR
sponse 20
Re 10
7% nCR
7% nCR
16% PR
<1% CR
9% CR
6% CR
0
Bortezomib
Bortezomib
Dex
Richardson et al. Blood in press

---

Updated Results of APEX Trial
a
SURVIVAL
Ol
Overa lll and 1-YS
Year Survival
29.8 mos
23.7 mos
P=.0272
­
Superior survival despite > 62% of HD dex pts crossing over to bortezomib
1-yr
i
surv
l
va rate: 80% vs 6 %
7 ; P = 0 0002
.
Richardson et al. Blood, in press

---

Prognostic Factors Associated
with Response Rate
Rate in
in SUMMIT
SUMMIT
· No significant difference in response rate by:
- Number or type of prior therapy
-KPS
- 2M

level
- Presence of chromosome 13 deletion
· High CR Rate in Light Chain Disease
Disease
· Lower RR* (multivariate analysis): >50% BMPC
Age > 65 yrs
(but age not a factor for TTP, OS)
* P < 0.05
Richardson et al, Blood 2005

---

APEX subgroup analysis: high-risk
disease
Response to bortezomib by prognostic factor
Age 65 yrs
11
n= 6
11
Age <65 yrs n=199
M>25
/L n=230
2M >2.5 mg/L
2M 2.5 mg/L n=77
Refractory to
to prior
prior treatment n=199
Not refractory to prior treatment n=116
0
20
40
60
% CR + PR
Richardson et al. BJH 2007

---

Del(13) in Multiple Myeloma
APEX: Matched-
Matched Pairs Analysis
Analysis
Del(13) Associated with Poor Survival in
D l
e (13)
l(13) Has No I
t
mpac on S
i
urv
l
va in
Dex-Treated Patients
Bortezomib-Treated Patients
No
D l
e (13)
l(13)
deletion
(n = 9)
No deletion
(n = 24)
(n = 17)
fPatients
fPatients
o
Del(13)
o
(n = 12)
Proportion
HR (95% CI) = 9.31 (1.88, 46.06); P = .0020
Proportion
HR (95% CI) = 1.61 (0.35, 7.46); P = 0.79
Time, d
Time, d
Jagannath et al. Leukemia 2006

---

Tolerability and efficacy of bortezomib
in pts with renal
renal impairment
Subanalysis of SUMMIT and CREST
·
Toxicity profile
profile similar in
in pts
pts with normal vs
vs impaired
impaired
renal function
·
Mean serum creatinine appears unaffected by bortezomib
·
Proteasome activity in
in blood
blood assay unaffected by renal function
function
·
Comparable RR in pts with compromised
renal function
Creatinine clearance
n
ORR (%)
(mL/min)
>80
105
45
51­80
99
33
50
52
25
<30
10
30
Jagannath et al. Cancer 2005;103:1195­200

---

Bortezomib in MM pts with
renal failure
failure requiring dialysis
· Retrospective analysis of 24 pts treated with
­ Single-a
g
gent
g
bortezomib
­ Bortezomib combinations (+ dex + thal/dex + thal/doxorubicin)
· Number of therapies prior to bortezomib: median 2 (range
0 6)
­
­ 1 pt newly diagnosed
ORR
OR
78%
CR
28%
nCR
nC
6%
PR
44%
0
2040
6080
Best response (%)
Chanan-Khan et al. Blood 2007

---

Effects of bortezomib on
osteoblast and
and osteoclast function
Bortezomib
· Signifi
g
cantly decr
dec eased NTX levels,
s, indicating
inhibitory effect on osteoclastic bone
resorption1
­ after high
high dose therapy
therapy, resulted in 32% decline in
in
NTX excretion
· Significantly increased levels of osteocalcin
db
ifi
lk li
h
h t
(BAP)2
and bone-specific alkaline phosphatase (BAP)
­ increase of osteoblast markers seen in both
responders, non-responders
1Peles et al. JCO 2006;433s (Abstract 7548)
2Heider et al. Blood 2005;106 (Abstract 3457)

---

Alkaline phosphatase levels during
bortezomib treatment
treatment in APEX
Alkaline phosphatase (ALP) and
and response in
in 315 pts
80%
60%
40%
CR/PR, P<0.0001
20%
PR, P<0
P
0001
.
0%
CR, P=0.1476
>25% ALP
<25% ALP
25%
25
increase
increase in ALP from
from baseline
baseline to
to wk
wk 6 strongly
associated with CR + PR, longer TTP
Markers of
of osteoblastic
osteoblastic activation (such
(such as ALP) during bortezomib treatment
treatment
may predict response, response duration in pts with MM
Zangari et al. BJH 2005

---

Extramedullary disease
· Extramedullary disease usually associated
with poor prognosis1
· Response to chemotherapy generally poor1
· Response to chemotherapy generally poor
· Resistance to chemotherapy frequent1
· Thalidomide may be less effective1,2,3
· Recent reports suggest that Bortezomib is
active4
1Damaj et al. Eur J Haematol 2004; 73:402­6
2Blade et al. Br J Haematol 2001;113:422­4
3Rosinol et al. Haematologica 2004;89:832­6
4Laura et al. Eur J Haematol 2006;76:405­8

---

PET/CT in Extramedullary MM
Axial fused FDG PET/CT and rotatating MIP images of 51 year old pt
with rel/refy IgA MM reveals multifocal hepatic plasmacytomas with
moderately intense FDG accumulation.

---

Apoptotic Signaling Triggered by
Conventional and
and Novel Agents
Hideshima & Anderson. Nat Rev Cancer 2002;2:927-937

---

Preclinical Rationale for
Combination Therapy in Clinical Tr
T ials
r
Low-dose bortezomib enhances and restores
sensitivity to DNA damaging chemotherapy
(doxorubicin)
120
100
(-)
vival
Dox
v 80
(+)
80
60
sur% 40
20
0
02
0
2
5
10
10
Bortezomib (nM)
Mitsiades et al. Blood 2002;101:2377

---

Bortezomib Combination Trials for
Relapsed/Refractory MM
MM
No. of
Study
Regimen
Evaluable CR/nCR
Pts
PR CR+PR
Orlowski
Blood 2005
Bortezomib + PLD
22
36%
36%
73%
Berenson
JCO 2006
Bortezomib + Melphalan
3415%
32%
47%
JCO 2006
ote o
b
e p a a
3
5%
3%
Zangari
Bortezomib + Thalidomide ±
ASH 2005
Dexamethasone
85
16%
39%
55%
Chanan-Khan
Bt
Bort
i
ezom b
ib + PLD
PLD +
ASH 2006
Thalidomide
17
23%
42%
65%
Hollmig
Bortezomib + Doxorubicin +
ASH 2004
Thalidomide + Dexamethasone
14
0%
50%
50%
ASH 2004
Thalidomide
Dexamethasone
Richardson
ASH 2006
Bortezomib + Lenalidomide
36
6%
52*%
58%
Orlowski. Blood. 2005;105:30;58; Berenson. J Clin Oncol. 2006; Zangari. ASH. 2005 (abstr 2552);
Chanan-Khan. ASH. 2006 (abstr 3539); Hollmig. ASH. 2004 (abstr 2399); Richardson. ASH. 2006
(abstr 405).

---

Bortezomib Combination Trials for
Relapsed/Refractory MM (cont.)
No. of
Study
Regimen
Evaluable Pts
CR/nCR
PR
CR+PR
Berenson Bortezomib + Arsenic Trioxide +
15
0%
13%
13%
ASH 2005
Ascorbic Acid
Bortezomib +
Reece
Cyclophosphamide +
37
38%
46%
84%
ASH 2006
Prednisone
Bortezomib +
Popat
Low-dose Melphalan +
18
5%
33%
38%
ASH 2005
Dexamethasone
Palumbo
Bortezomib + Melphalan +
30
17%
50%
67%
ASH 2006
Prednisone + Thalidomide
Kropff
Bortezomib + Dexamethasone +
50
10%
66%
76%
ASH 2005
Cyclophosphamide
Terpos
Bortezomib + Melphalan +
53
11%
48%
60%
ASH 2006
Dexamethasone + Thalidomide
Berenson. ASH. 2005 ; Reece. ASH. 2006 ; Popat. ASH. 2005 ; Palumbo. Blood. 2006 [Epub ahead of
print]; Kropff. ASH. 2005 ; Terpos. ASH. 2006

---

DOXIL-MMY-3001 Study Desig
ygn
BZ 1.3 mg/m2 D 1, 4, 8, 11 every 21d for up to
R
8 cycles
A
N
D
Treated until:
D
646 pts: Relapsed
-PD
Primary
O
and/or refractory MM
- Unacceptable
endpoint:
M
Stratifications:
toxicity
TTP
I
1. B2M (2.5, >2.5 but
- 8 cycles
Secondary:
Z
5.5, >5.5)
administered
OS, ORR,
A
2. Response vs. PD
(continued if MM
on initial therapy
safety
T
still responding)
I
O
N
BZ as above + Pegylated liposomal
doxorubicin 30
30 mg/m2
mg/m on D4
Orlowski et al ASH 2006

---

Prior Therapies
BZ
PLD + BZ
(N = 322)
(N = 324)
# of
of prior
prior therapies
1 line
34%
34%
2 lines
66%
66%
Corticosteroids
99%
99%
Alkylating agents
90%
92%
Anthracyclines
67%
68%
Thalidomide/lenalidomide
43%
40%
Stem cell transplant
54%
57%
Orlowski et al ASH 2006

---

Time to Progression
100
PLD + Bortezomib
80
9.3 mos
on-Free
60
Progressi
Bortezomib
tsP 0
65
6.5 mos
mos
of
Percent 042
Statistical analysis:
HR (95% CI) 1.82 (1.41-2.35)
0
p = 0.000004
0
100
200
300
400
500
Days
Orlowski et al ASH 2006

---

PLD + Bortezomib: Efficacy Data
Response Rates
Bortezomib
PLD + Bortezomib
(%)
N=310
N=303
P
Total (CR/nCR/PR)
44
52
0.05
CR + nCR
13
17
PR
31
35
CR+VGPR*
20
30
0.007
Overall Survival % (median follow-up 14 months)
Censored
82
75
Died
18
25
HR (95% CI)
1.41 (1.002; 1.97) p < 0.05
* IMWG 2006 criteria
Harousseau, ASCO 2007, abstract # 8002

---

Bortezomib, Melphalan, Prednisone, and
Thalidomide (VMPT)
(VMPT) for
for Relapsed/Refractory MM
4-drug combination evaluated for relapsed/refractory MM as 2nd-line (n=14)
or 3rd-line (n=16) therapy
Six 5-wk cycles
11221
3 4 5
5
15
322
22 23
23­­35
35
Bortezomib
1.0, 1.3, 1.6 mg/m2
Melphalan
6 mg/m2
Periodste
Prednisone
R
60 mg/m2
Thalidomide
50 mg/d
g
· MTD of bortezomib was 1.3 mg/m2
· Grade 3/4 AEs in 5% of patients were neutropenia (43%);
thrombocytopenia (33%);
(33%); anemia (16%); Herpes zoster (7%)
Palumbo A et al. Blood. 2007

---

VMPT for Relapsed/Refractory MM:
Best Response
Response
All Patients
VMPT
VMPT
(n=30)
2nd-Line
3rd-Line
(n=14)
(n=16)
CR or VGPR, n (%)
13 (43)
8 (57)
5 (31)
PR, n (%)
7 (23)
3 (21)
4 (25)
SD, n (%)
8 (27)
3 (21)
5 (31)
PD, n (%)
2 (7)
0
2 (13)
Time to Best Response
68%
30
25
(% 20
ts 15
ien 10
Pat
5
0
12
3
4
5
6
Treatment Cycle
Palumbo A et al. Blood. 2007

---

Bortezomib-based Novel Combination Therapies
Based upon gene profiling:
Bortezomib + Hsp90 inhibitor (eg tanespimycin)
Based upon cell signaling:
Bortezomib + Doxil
Bortezomib + Thalidomide
Bortezomib + Akt inhibitor (eg perifosine)
Bortezomib + Lenalidomide
Bortezomib + NPI-0052
Bortezomib + HDAC6 inhibitor (eg SAHA, LBH)
Bortezomib + Smac
Smac peptides
peptides
Bortezomib + Bcl 2 inhibitors
Bd
Based upon
l
corre t
a i
tive
i
sc ence:
Bortezomib + p38 MAPK inhibitor (eg SC469)

---

Phase I Trial of Tanespimycin (KOS-953) +
Bortezomib in Relapsed/Refractory MM
MM
Objective: Define phase II dose of bortezomib (Vel) + KOS-953
Step-wise dose escalation: Vel (0.7, 1.0, 1.3 mg/m2) as IV bolus followed by
1-hr infusion of KOS-953 (100, 150, 220, 275, 340 mg/m2); days 1, 4, 8, 11 q21 d
· R(
Responses CR
(CR, PR
P
PR, MR
M )
MR)
d
occurre
t
a
l
a llll dose
d
EBMT Criteria
80
levels of KOS
KOS--953
953 with Ve
V l
e 1.0 mg/m2
· 1.3 mg/m2 Ve
V l
e + 340 mg/m2 KOS
KOS--953
953 is being
60
ex
e pa
xp n
paa ded
nded
d
to assess tol
to e
l r
e ab
a ili
ab
b ty
ility
%
ts(
· No G3 PNY,
PNY manageable s/e
40
ien
· In those pts on BZ @ 1.0 or 1.3 mg/ (PR/CR):
Pat
­OVERALL
8 / 23
35%
20
­ 3 CR (1 CR, 2 nCR) 14%; 5 PR 22%
0
Vel
Ve -
l N
- a
N i
a v
i e
v
Vel
Ve -
l
Vel
Ve -
l
(n=7)
Refractory Pretreated
(n=6)
(n=13)
Richardson P et al. Blood. 2006;108:124a [abstract 406]

---

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
24h
24
CP
BP+B
120
Perifosine (M)
p-JNK1/2
100
0
5
caspase-8
80
7.5
CF
60
PARP
control
CF
40
%
C: control
20
B: Bortezomib (10 nM)
0
05
7.5
P: Perifosine (5 M)
Bortezomib (nM)
Hideshima et al. Blood 2006; 107: 4053-52

---

Perifosine + Bortez: Phase I Study
· Combination well tolerated to date, active in
highly pre
pre-treated pt population (78%
(78% relapsed /
refractory)
· Overall Response Rate (CR + PR + MR): 5/16
(31%)
· Stable Disease in 6/16 pts (38%)
· Responses across all
all cohorts ­ higher toxicity
toxicity
with 100 mg perifosine
· Phase II dose: Perifosine 50 mg qd +
2
bortezomib 1.3 mg/mm days 1, 4, 8, 11 for 21
day cycle
· Phase II open and
and enrolling at
at 12+ sites
IMMW, KOS 2007

---

Rationale: Preclinical Combination of
Lenalidomide + Bortezomib
50
Bortezomib-resistant pt cells
Lenalidomide
40
100
0 M
5 M
,%h
80
%
30
deat
60
Cell
Growth, 40
20
20
10
0
0
10
20
Bortezomib, nM
0
Mitsiades et al. Blood 2002;99:4525-30.
Len = lenalidomide; Bz = bortezomib
Hideshima et al. unpublished data.

---

Phase I Trial of Lenalidomide With
Bortezomib (Rev/Vel) in Relapsed and
Refractory MM
Bortezomib
Lenalidomide, mg/day
(mg/m2) IV
510
15
20
1.0
Cohort 1
Cohort 3
Cohort 5
Cohort 7
13
1.3
Cohort 2
Cohort 4
Cohort 6
Cohort 8
8 cohorts of 3­6 pts, with additional 10 enrolled at MTD
21-day cycle*
1
4
8
11
14
21
B
B
B
B
Lenalidomide daily
*For a maximum of 8 cycles; Dex added (20 mg, days of and day following
bortezomib) for ps with PD: extension phase for pts in response
Richardson PG et al. ASH 2006

---

Lenalidomide + Bortezomib (Rev/Vel) in Relapsed
and/or Refractory MM: Baseline Characteristics
Characteristics
Characteristic
(n=38)
Median age, yr (range)
60 (37­79)
Prior therapies:
Male, n (%)
25 (66)
Myeloma type, %
100
IgG
68
90
80
IgA
24
70
%
s(
60
Durie-
Durie Salmon stage III at
ent
50
42
tie
diagnosis, %
40
Pa
30
Disease status, n (%)
20
10
Relapsed
12 (32)
0
Relapsed and
Bortezomib Lenalidomide Thalidomide
SCT
26 (68)
refractory
Median # prior
p
5(
5 1
(1 13)
­
therapies, n (range)
Richardson PG et al. Presented at ASH 2006

---

Lenalidomide + Bortezomib (Rev/Vel) in Relapsed
and/or Refractory MM
MM
Dose
EBMT Response
No. of
Cohort Bort (mg/m2)/
(n=36 evaluable)
Cycles
Len (mg)
(mg)
CR
CR
n
PR MR SD
PD
1
1.0/5
20­22
2
1
2
1.3/5
16­20
1
2
3
1.0/10
12­18
1
2
4
1.3/10
3­12
2
2
1
1
5
1.0/15
3­8
2
4
7
1
6
1.3/15
1­2
2
5
58%
·
Toxicities
­ Grade 3/4 neutropenia; grade 3/4 thrombocytopenia
­ No significant PNY, fatigue ( grade 3)
­ Thrombotic events rare
­ DLTs: hyponatremia (cohort 4); Herpes zoster infection, neutropenia
(cohort 6)
Richardson PG et al. ASH 2006

---

Conclusions
·
Combination of lenalidomide and bortezomib ± dex:
­ Wl
We lll t l
o erated in t
p s with
ith heavil
ily pre-tt
treat d
e rel
d
apse
d
an
relapsed and refractory MM
­ Active in pts who had received prior lenalidomide,
bortezomib, thalidomide, or SCT
·
MTD defined as lenalidomide 15mg/bortezomib 1.0 mg/m2
·
58% response
t
ra e (CR
(CR PR
+
MR)
+
, i
l
nc 6%
6% CR/ CR
n
, 33% PR
·
DOR 8 mos (2-18)
·
Dex added
added in
in 15
15 pts
pts with PD
PD
­ 40% achieved PR + MR

---

Future Directions: Bortezomib & Lenalidomide as
"Backbone Agents"
Agents
in MM
· Phase 2/3 studies in relapsed and relapsed
refractory MM
· Phase 1/2 study in newly-diagnosed pts
· Combination with low-dose dex
("dex sparin
(p
g"
g )
· Combination with conventional (eg
(g
doxorubicin) and other novel therapies

---

Bortezomib, Thalidomide, Lenalidomide,
Doxorubicin, Melphalan and Other
Combinations: Targeting Host-Tumor
Interactions in Relapsed, Refractory MM
· A new treatment paradigm targeting both the
tumor cell and its bone marrow micro-
environment
· Tailored approaches now feasible to provide
for new, more specific and less toxic
bi
com nation therapies
· Challenges incl d
u e optimal sequencing,
drug resistance and side effect management

---

Improving Outcome in MM: The Impact of
Novel Therapies in
in Relapsed/Refractory
Relapsed/Refractory MM
MM
·
59 yr old gentleman artist, DSS3a IgGk MM (ISS 2),
Ch 13 d l
e +; t 11
11,14
14 neg; CD
CD 20
20 +
1998 ­ 2007
­
VAD ~ PD
­
HD Cyclophosphamide ~ PD
­
Thalidomide ~ PR
(6 mos)
­
IFN ~ PD
­
Rituxan ~ PD
­
Bortezomib ~ PR
(> 6 mos)
­
2 ME 2 ~ SD
(36 mos)
­
Lenalidomide ~ PR
(44 mos)
­
Bortezomib combination
(next!)

---

---

---

How to Tell if Your Boat is Too Small...

---

Clinical Investigators in Relapsed/Refractory MM - A Global Network: Leadership,
including Anderson KC., Dalton W., Harousseau J., San Miguel J., Kyle R.
APEX/ SUMMIT/CREST/ VISTA
VIST /
A/ Combination
Combination Studies Investigators: Sponsors including
including
Millenium; Celgene; J & J; Novartis; Kosan; Keryx
Advocacy/Support MMRF; MMRC; IMF
Abubakr Y.
Reece D.
Cavenagh J.
Glass J.
Agura E.
Lacy M.
Richardson P.
Cavet J.
Goldschmidt H.
Alexanian R.
Lenhoff S.
Rowe J.M.
Chanan-Khan A.
Gordon P.
Alsina M.
Limentani S.
Schilder R.
Coiffier B.
Gramatzki M.
Andre M.
Lokhorst H.
Schmidt W.
Comenzo, R.
Gruber A.
A.
Al
Attal M
Lonial S
M.
.
Schuster M.
Craddock, C.
Gyan E.
Avigan D.
Ludwig H.
Sezer O.
Dearden C.
Hamm J.
Barlogie B.
Mandelli F.
Shadduck R.
Delforge M.
Hegewisch-Becker
Baccarani M.
Marie J.P.
Shustik C.
Densmore J.
Hideshima T.
Bahlis N.
Marsden G.J.
Siegel D.
Dispienzeri, A
Huber C.
Barbui T
Martin T.
T.
Singhal S.
Doyen C.
Hulin C.
Barton, K.
Mason J.
Sonneveld P.
Durk H.
Hussein M.
Belch A.
Mateos S.
Sotto J.J.
Durie, B
Ifthikharuddin J.
Beksac M
Mavromatis B.
Stadtmauer E.
Ehninger G.
Irwin D.
Bensinger W.
Mitsiades, C.
Stewart, K
Einsele H.
Jackson G.
Ben-YehudD.
Morris C.
Tarantolo S.
Engelhardt M.
Jagannath S.
Mi
Morrison V
Berdeja J.
.
Van Droogenbroeck
Facon T.
Jagasia M.
Berenson, J.
Nieswiesky R.
Van Oers M.H.
Fay J.
Jakobowiak A.
Bjorkstrand
Nowrousian M.
Vellenga E.
FehrenbacheL
Klein A.
Bladé J.
Orlowski R.
Vesole D.
Feremans W.
Kobbe G.
Boccadoro, M.
Pecora A.
Vij R.
Fermand J. P.
Kovacs M.
BF
Phelan J
Boue F.
.
WM
Wang M.
Fernandez H.
Krishnan A.
Bourhis J.
Posada, J.
Zachee P.
Fonseca, R
Kropff M.
Bron D.
Rahemtulla A.
Zangari M.
Giguere J.
Kuter D
Rai K.
Catlett J.
Zeldenrust, S
Glasmacher A.
Rajkumar V.
Zonder, J

---

United Nations Against Myeloma
Jerome Lipper Bench to Bedside Research Team
Kenneth Anderson
Jeffrey Sorrell
Paul Richardson
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Muriel Gannon
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Amy Potenza
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Constantine Mitsiades
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Shannon Viera
Nicholas Mitsiades
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Diane Warren
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Reshma Shingapure
Andrea Freeman
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Christine Rubio
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---