Impact of novel agents
pg
in patients
p
with poor
p
prognosis MM defined by unfavorable
cytogenetics,
yg
renal failure and high
g age
g
Heinz Ludwig, Johannes Drach, Niklas Zojer
Department of Medicine I
Center for Oncology
Oncology and Hematology
Wilhelminenspital, and Department of Oncology, Medical
Clinc I, University Vienna, Austria
heinz.ludwig@wienkav.at
Ludwig Kos 2007
Impact of cytogenetic risk factors on outcome of
Bortezomib therapy in relapsed/refractory MM
Treatment of patients with acute renal failure
with Bortezomib or Bortezomib based combination
Treatment of elderly p
ypatients: A randomized trial
Induction:
Thal-Dex vs MP
Mit
Maintenance:
Thal-IFN vs IFN
Ludwig Kos 2007
Characteristics of patients with relapsed/refractory
MM treated with Bortezomib (n=62)
13q-normal, N=29
N=29
Del (13q)
(13q), N=33
N=33
Age (years)
63 (44-76)
66 (37-82)
Pt
Paraprot i
e n
IgG (%)
81
55
IgA (%)
15
35
Bence-Jones only (%)
4
5
Other (%)
(%)
05
b2-M (mg/l)
3.9 (1.3-11.1)
4.2 (1.4-44.4)
Albumin (g/dl)
3.9 (2.7-4.8)
3.8 (1.4-5.1)
BM Plasma cells, LDH, creatinine
ns.
Time from first line Tx to Bortezomib Tx
51 mos
p=0.02
26 mos
Prior therapies
therapies
3(
3 1-
(1 9)
Dexamethasone (%)
93
94
Thalidomide (%)
59
64
Anthracyclines (%)
66
61
Alk l
y ti
a ng
t
agen s (%)
(%)
62
58
High-dose therapy (%)
50
39
Ludwig Kos 2007
Response to Bortezomib according to
chromosome 13q status by
qy FISH (n=62)
ORR to Bortezomib: 52%
N=
N = 29
No Del
29
13q
60
Del 13q
N=29
3%
N=33
50
N=33
3%
ents 6%
6%
40
pati
MR
ing
38%
21%
38%
d 30
21%
PR
P = .66
CR/nCR
P=0.66
20
respon%
18%
18
10
%
14%
14%
0
ORR: 45%
ORR: 55%
Ludwig Kos 2007
Sagaster et al, Leukemia 2007
Duration of response and OS during Bortezomib
treatment according 13q status in patients with
relapsed/refractory MM
Duration of response in all patients:
Overall survival in all patients: 15.1
10.0 months
months
Duration of response of bortezomib
Overall survival of bortezomib
responsive patients
responsive patients
1,0
1,0
Del 13q
0,9
0,9
n = 15
0,8
0,8
0,7
Del 13q
0,7
,
median, 12.3 months
0,6
0,6
No 13q
0,5
0,5
n = 16
Patients
Patients
% 0,4
0,4
13q normal
%
03
0,3
03
0,3
Median, 9.3 months
n = 15
0,2
n = 16
0,2
0,1
P = .25
0,1
P = .69
0,0
0,0
0
5
10
15
20
25
30
35
40
45
50
0
5
10
15
20
25
30
35
40
45
50
Months
Months
Patients with del 13 not responding to Bortezomib
Ludwig Kos 2007
OS: 4.1 mos
Sagaster et al, Leukemia 2007
1q21 status and Bortezomib therapy
in relapsed/refractory myeloma - Patient characteristics
Bortezomib single agent
Bortezomib combination
N=46
N=28
1q21-normal,
1q21 gain,
1q21-normal, N
1q21 gain, N = 11
N = 26
N = 20
= 17
Age (years)
63 (49 82)
65 (40 79)
60 (37 82)
58 (37 79)
Paraprotein
IgG (%)
73
50
73
33
IgA (%)
23
38
20
44
BJ only (%)
0
12
0
22
Other (%)
4
0
7
0
ß2-M (mg/l)
3.8 (1.3-10.4)
6.16 (1.7-44.4)
3.2 (1.4-6.1)
4.3 (1.7-39.8)
2
(g )
(
)
(
)
(
)
(
Albumin (g/dl)
3.8 (1.4-4.8)
3.5 (2.9-4.1)
3.8 (1.4-4.5)
4.3 (2.7-6.0)
LDH (U/l)
214 (104-
186 (80-941)
179 (91-630)
179 (138-409)
630)
Creatinine
1.1 (0.7-8.8)
1.2 (0.7-8.7)
1.04 (0.8-8.81)
1.74 (0.8-5.9)
(mg/dl)
Ludwig Kos 2007
Response to Bortezomib or Bortezomib combinations in
refractory/relap
ypsed patients according to 1q21 status
70
Bortezomib single
Bortezomib
agent
combinations
60
12%
8%
50
P=0.06
P=0.72
MR
40
24%
27%
27%
PR
65%
30
58% 5%
54%
CR/nCR
20
15%
30%
29%
27%
10
23%
10%
0
N=26
N=20
N=17
N=11
Normal
Gain of
Normal
Gain of
1q 21
1q 21
Ludwig Kos 2007
Conclusion: Bortezomib in patients with unfavorable
cytog
ygenetics
Patients with del 13q
- had shorter time to start Tx with Bortezomib
- similar response rate compared to non del 13q patients
- similar duration of response
p
and OS
- not responding to Bortezomib show very poor survival
Patients with
with gain of
of 1q21
- poor results (ORR, TTF, OS) to single agent Bortezomib
- Bortezomib combinations seem to overcome negative impact of gain
of 1q21
q
- Two factor (1q21, low albumin) prognostic model distinguishes risk
groups
Ludwig Kos 2007
Treatment of patients with acute renal failure
with Bortezomib or Bortezomib based combination
Ludwig Kos 2007
Renal Failure
Renal failure is an important complication of
myeloma
Moderate renal impairment in 20-30% at
presentation
Severe renal failure in 3-5%
Renal impairment in up to 50% during follow
up
2-5% of myeloma patients require long-term
dialysis
Increased risk of early mortality
Ludwig Kos 2007
Pilot study: Reversal of Acute Renal Failure in 5 of 8
Patients with
with Bortezomib-Based Treatment
Treatment
Patients
·
Myeloma-induced acute renal failure
failure (ARF)
Newly diagnosed (n=7)
ARF developed during progressive disease (n=1)
Results
·
Restoring of
of renal
renal function in 5 of
of 8 patients
·
Decrease in the median creatinine level from 9.05 to 2.1 mg/dL
·
Improvement in renal function associated with objective tumor
response
3 CR/nCR, 1 VGPR, 1 PR (OR: 5/7)
Median time to MM response (PR): 43 days
Ludwig et al. Haematologica 2007. In press
Ludwig Kos 2007
Creatinine values in patients with acute renal failure
during treatment with Bortezomib-based regimens
/dL)g
(m
atinine
Cre
Ludwig et al. Haematologica 2007. In press
Ludwig Kos 2007
Phase II trial: Bortezomib-Doxorubicin-Dexamethasone
(BDD)
() for restoring renal function in patients with acute
renal failure
Rationale
High resp
gponse rate
Short time to initial response
Half life independent of renal clearance
Inhibition of NF B reduces peritubular inflammation
Primary objective:
Reversal of acute renal failure
Secondary objectives:
j
Tumor response, safety, PFS and OS
Enrollment Criteria
Newly diagnosed patients:
of GFR to < 50ml/min due to myeloma nephropathy
Previously treated patients with GFR of 60ml/min within last 4 weeks:
in GFR > 25% and to < 60ml / min, concomitantly with other signs of
tumor progression
Ludwig Kos 2007
Treatment regimen (BDD)
Bortezomib 1.0 (1.3) mg/m2, d 1, 4, 8, 11
Db
Doxoru i
bicin 9
/ 2
mg/m , d1
d 1, 4(
4 (81
8, 1)
11
Dexamethasone 40mg, d 1, 4, 8, 11
Restart day 22
Pt
Pa itient characteristitics
Number of patients
30
Age (median / range)
59 / 41-79
Gender (male / female)
43 % / 57 %
Stage I
13%
Stage II
17%
Stage III
70%
Paraprotein
IgG g/l
56.8 (23106)
Light chain only mg/24
mg/24 hrs
12.860 (1.202 51
.000)
Baseline GFR (median / range) ml/min
24 (4 48)
Ludwig Kos 2007
BDD therapy in patients with acute renal failure: Tumor
response and creatinine clearance
clearance (evaluable:
(evaluable: 3
cycles
15 patients)
Response Number of
% Increase in
Patients
creatinine clearance
CR/nCR
3
169 (122 - 688)
PR
6
92 5
. (5
(5 475)
MR
4
93 (0 - 231)
NC/PD
2
31 5
. (1
(1 62)
Total
13/15
0 - 688
Ludwig Kos 2007
Toxicity in patients with 3 cycles (n=19)
Parameter
Grade 1-2
Grade 3-4
Neutropenia
3
3
Thrombopenia
1
Infections
4 (3 Herpes
3 (1 generalized
zoster )
herpes simplex)
Cardiovascular
2
Diarrhea
1
Acute hearing
1
loss
Psychologic
1
distress
Weakness
W
1
2
GI bleeding
1
Toxic death
3*
*Protocol amendment: Bortezomib 1mg/m2, d 1, 4, 8, 11
Doxorubicin 9mg/m2, d 1, 4
Ludwig Kos 2007
Dexamethasone 40mg, d 1, 4, 8, 11
Conclusion: Bortezomib treatment in renal
failure
High chance of restoring renal function in case of
fast and significant tumor response
response
Half life of Bortezomib is independent of renal function,
Bortezomib exerts anti-inflammatory activity
Responses occured fast (median: 43 days)
Toxicity may be
be increased
increased with Bortezomib based
combination Tx
Ludwig Kos 2007
Treatment of elderly patients
Ludwig Kos 2007
Thalidomide (Thal)-Dexamethasone vs. MP for
induction and Thal-Interferon -2b vs. Interferon for
maintenance Tx in elderly patients with MM
Induction Phase
Maintenance Phase
Thalidomide
200
/d
mg , up to 400
/d
mg
Dexamethasone
Thal-IFN 2b
40mg, d1-4, 15-18,
100mg,
on odd cycles, only d1-4, q 28d
3 MIU, TIW
1R
1. R
d
an omisati
tion
2. Randomisation
Melphalan
0.25mg/kg, d1-4,
IFN-2b
Prednisone
3MIU, TIW
2mg/kg, d1-4, q 28-42d
All patients received Zoledronate, 4mg, q 4 weeks
Ludwig Kos 2007
Best Response to Treatment
MP
Thal/Dex
ORR: 51%
ORR: 68%
25
22
21
CR+NCR
CR+NCR
30%
19
19
20
30%
14%
17
CR
CR
16
NCR NCR
14
14
14
15
13
VGPR VGPR
11
PR
PR
10
MR
MR
8
7
SD
SD
5
PD/Failure
PD/Failure
5
0
CR
NCR
VGPR
PR
MR
SD PD/Failure
CR
NCR
VGPR
PR
MR
SD
PD/Failure
CR+NCR 14%
30%
p< .0025
ORR
51%
68%
p< .0044
Ludwig Kos 2007
Event-Free Survival
1
0,8
te
Ra
MP: n = 138, median 43 months
0,6
rvivalu 0,4 Thal/Dex: n = 136, di
me an 25
h
mont s
S
0,2
Logrank test: p = 0.07
0
0
10
20304050
60
Months
Ludwig Kos 2007
Overall Survival
10
1.0
MP: n = 137, 30 events, median = 57
57 9
. months
Thal/Dex: n = 134, 44 events, median = 44.6 months
0.8
te
ra 0.6
Logrank test: p = 0.029
rvivalu 04
0.4
S
0.2
0.0
0
5
10
15
20
25
30
35
40
45
50
55
60
Months
Ludwig Kos 2007
Overall Survival in Patients With
Age
g 72 and Age
g >72 Years
Age
g 72 years
Age > 72
72 years
1
MP: n = 78, median = 57.9
1
MP: n = 60, median = 46.5
Thal/Dex: n = 75, median = 50.0
Thal/Dex: n = 61, median = 25.4
ate 0,8
ate0,8
a
R
R
0,6
0,6
Thal/Dex
MP
urvival 0,4
urvivalS0,4
S
S
MP
0,2
Logrank test: p = 0.186
0,2
Logrank test: p = 0.0625
Thal/Dex
0
0
010
20
30
40
50
60
70
0
10
203040
5060
70
Months
Months
Ludwig Kos 2007
Higher Mortality Rate in Thalidomide-
Dexamethasone Treated Patients (31 vs. 17)
During First Year of Study
18
16
MP
14
Thal/Dex
12
10
8
6
4
2
0
1-3
>3-6
>6-9
>9-12
>12-24
>24
Months
Ludwig Kos 2007
Early Non-Myeloma Death Rate* in Relation to
Certain Parameters in Thal-Dex Treated Patients
0
1020
3040
< 75 y
Age
75 y
I / II
Stage
III
10 g/dl
Hb
g
Hb
> 10 g/dl
< 1,4 mg/dl
Creatinine
1,4 mg/dl
< 35g
3,5 /
g/dl
dl
Albumin
3,5 g/dl
< 5,5 g/dl
ß2-M
5,5 g/dl
01
0 - 1
ECOG PS
2 - 3
300 mg
Dose
200 mg
*19 Patients on Thal-Dex died due to other causes than myeloma during the first 12 months.
Ludwig Kos 2007
Multivariate Analysis of Risk Factors for Non-
Myeloma Related Mortality in Thal-Dex Treated
Patients
Odds Ratio
Parameter
(Confidence Significance
Interval)
Age 75
6.88
< 0.071
years
(0.84-52.6)
ECOG PS
8.50
< 0.032
2-4
(1.20-60.3)
9.62
HB 10
< 0.03
(1.25-76.92)
Ludwig Kos 2007
Overview of Patient Flow
ent
136 Thal-Dex
55 Thal-IFN-
274 patients
randomized
138 MP
53 IFN-
seassessm
Respon
274 included in
tl
present analysis
89 analyzed
by FISH
Ludwig Kos 2007
Overall Survival After Start of Thal-IFN or IFN
Maintenance Therapy
108 Patients with SD or better have been randomized
1.0
0.8
ateR
0.6
Thal-IFN
rvival
ÎFN
u
Logrank test: p = 0.95
S
95
0.4
IFN: n = 53, 7 events, median = 41.1 months
0.2
Thal/IFN: n = 55, 8 events, median = NA
0.0
0
5
10
15
20
25
30
35
40
45
50
55
60
Months
Ludwig Kos 2007
MP is Associated with Increased Overall Survival in Patients
Without Amplification of 1q21 and Possibly Without del 13
Gain of 1q21
No gain of 1q21
1.0
1.0
0.8
0.8
rate
MP
rate
MP
al 0.6
al 0.6
iv
iv
Surv
Logrank test: p = 0.63
Surv
Logrank test: p = 0.021
0.4
0.4
Thal-Dex
Thal-Dex
0.2
0.2
MP: n = 20, 3 events, median = NA
MP: n = 18, 5 events, median = NA
Thal/Dex: n = 22, 8 events, median = 44.3 months
Thal/Dex: n = 19, 8 events, median = 31.5 months
0.0
0.0
0
5
10
15
20
25
30
35
40
45
50
55
60
0
5
10
15
20
25
30
35
40
45
50
55
60
Months
Months
Del 13q
No del 13q
1.0
1.0
08
e 0.8
08
e
0.8
MP
rat
MP
al
rate
0.6
iv
al 0.6
iv
Surv
Logrank test: p = 0.4
Logrank test: p = 0.076
0.4
Surv 0.4
Thal-Dex
Thal-Dex
0.2
MP: n = 16, 4 events, median = NA
0.2
MP: n = 27, 5 events, median = NA
Thal/Dex: n = 15, 7 events, median = 35.2 months
0.0
Thal/Dex: n = 31, 10 events, median = 44.3 months
0.0
0
5
10
15
20
25
30
35
40
45
50
55
60
0
5
10
15
20
25
30
35
40
45
50
55
60
Months
Ludwig Kos 2007
Months
Conclusion: Thalidomide-Dexamethasone
in Com
Co pari
pa son
so with MP in elderl
de y pat
patients
ts
Thalidomide-
Thalidomide Dexamethasone
Higher Response Rate (68% vs. 51%)
Higher Rate of CR-NCR (30% vs. 14%)
Shorter Time to Response (6 vs.16; 16 vs. 25 wks.)
Similar PFS, shorter EFS
Shorter OS
OS in
in entire
entire population, no
no difference
difference in
in OS
OS in
in
patients 72 years
Ludwig Kos 2007
Thalidomide-Dexamethasone in
Com
Co pari
pa son
so with MP in elderly pat
patients
ts
Maintenance
No difference in OS between Thal-IFN and IFN maintenance
Toxicity
Cumulative incidence of DVT+PE (Thal-Dex: 15% vs. MP: 6%)
G 3 & 4 Leukopenia more frequent
pq
with MP
G 2-4 Neuropathy, Obstipation, Psychologic disturbances
(Infections,
(, Skin toxicity)
y) more frequent
q
with Thal-Dex
Ludwig Kos 2007
We Thank the Patients for Participating in the Study
Austria: Heinz Ludwig
Johannes Drach
Michael Fridrik
Heinz Gisslinger
Richard Greil
Irene Kuhn
Niklas Zojer
Czech Republic
Roman Hajek
Zdenek Adam
Ivan Spicka
Hungary
Miklos Egyed
Slovakia
Elena
ea Tot
othov
o a
and Croatia
Boris Labar
Branimir Jaksic
Rajko Kusec
Kusec
di
...and i
t
nves i
ti
t
ga ors in 24
24
t
cen ers
....and you for your attention!
Ludwig Kos 2007