Carfilzomib, Thalidomide and Dexamethasone
(Carthadex) for induction and consolidation in
transplant eligible patients with multiple
myeloma
A phase 2 trial of Erasmus MC and the
European Myeloma Network EMN
Pieter Sonneveld, Emilie Häcker, Sonja Zweegman,
Marie-Jose Kersten, Edo Vellenga, Marinus van
Marwijk-Kooy, Okke de Weerdt, Sarah Lonergan,
Antonio Palumbo, Henk Lokhorst
Proteasome targets
Potential
UB enzymes E1, E2 and
E3-UB-Ligases
Therapeutic Targets
Deubiquitylating
Ub
ATPases/
Ub
Enzymes (DUBs)
Ub
Cdc48
Immunoproteasome
P5091 target USP-7
ATP
ADP
PR-924
Poly-ubiquitinated proteins
(proteasome substrates)
19S
Six Protease
activities
5, 5i
Bortezomib,

20S

1,5
20S
1, 1i
Carfilzomib,
2, 2i
CEP-18770,
19S
Marizomib all sub
units:
Free Ub
for re-cycling
Degraded protein
26S PROTEASOME
1

---

Background
­ Bortezomib based regimens are the most effective and
therefore 1st choice induction treatment prior to high-dose
therapy in patients who are transplant eligible
­ Bortezomib/ Thalidomide/ Dexamethasone (VTD) gives the
highest CR rate after induction and after HDM/ASCT
­ VTD is also an effective consolidation treatment which
results in a further improvement of CR and a reduction of
Minimal Residual Disease
­ Carfilzomib is a next generation Proteasome Inhibitor
Cavo et al. Lancet 2010;376: 2075-85
Goals of the Carthadex trial
­ To investigate if Carfilzomib can safely and
effectively be used as a Proteasome Inhibitor in a
VTD-like induction regimen before, and
consolidation treatment after high-dose therapy in
newly diagnosed patients who are transplant eligible
­ To determine the response rate (ORR), CR and VGPR
of Carfilzomib/ Thalidomide/ Dexamethasone after
induction, after HDM/ASCT and after consolidation
­ To determine toxicity and safety
­ To determine clinical and molecular (FISH, GEP) risk
factors for outcome
2

---

Trial design
Investigator initiated open label phase 2 trial
Patients with symptomatic newly diagnosed MM
Endpoints:
Overall response and (n)CR/VGPR
Progression-free survival
Safety and toxicities
Prognostic factors
Data from safety evaluation after 20 patients were
included: basis for ASH 2011 abstract
This presentation based on 45 patients evaluable for
response and safety
In-/exclusion criteria
Inclusion
Newly diagnosed symptomatic Multiple Myeloma
Age 18 ­ 65 yr
ISS stage I, II & III
Exclusion
Severe organ dysfunction
Creatinin clearance < 15 ml/min
­ Non-secretory MM
­ AL-amyloidosis
­ Waldenstrom's macroglobulinemia or IgM MM
3

---

Treatment schedule
Carfilzomib
Carfilzomib
20/27mg/m2 days
27mg/m2 days
1,2,8,9,15,16 of a 28
1,2,8,9,15,16
day cycle.
of a 28 day cycle.
HDM
Thalidomide
Thalidomide
200m
200 mg days 1-28 of Stem
50 mg days 1-28 of
Cell
g/m2
a 28 day cycle
a 28 day cycle
Harvest
ASCT
Dexamethasone
Dexamethasone
40 mg days
40 mg days
1,8,15,21 of a 28
1,8,15,21 of a 28
day cycle
day cycle
4 cycles.
4 cycles.
Patient characteristics
Patients
%
M/F
31/14
69/31
Age median (range)
57 (29 ­ 66)
WHO PF
0
28
62
1
15
33
2
2
5
IgA
8
18
IgG
21
47
IgD
1
2
LC
11
24
ISS stage
I
17
37
II
17
37
III
11
26
4

---

Flow in protocol per 22-nov-2011
Stage of treatment
Patients
Off treatment
#
Cycle 1
45
2 (SAE, Ref)
Cycle 2
37
0
Cycle 3
29
0
Cycle 4
22
1 (PD)
SC Harvest
16/16
1 (PD)
HDM/ASCT
8/8
0
Consolidation
4/4
0
WHO grading of adverse events
Toxicities
Grade 1+2
Grade 3
%
%
PNP
24
0
Tumor Lysis
04
Syndrome
GI
4
4
Skin
2
2
Infection
4
4
5

---

Polyneuropathy
Type of PN
# (%)
Treatment
PN resolved
change
None
34 (76)
No
NA
Peripheral
7 (16)
1 pt Thal
1/7
grade 1
reduced
Peripheral
4 (9)
3 pts Thal
3/4
Grade 2
reduced
Autonomic
0
NA
NA
Central
0
NA
NA
Best response during induction
Response
Patients #
%
CR/sCR
7 (4/3)
16
VGPR
13
29
PR
17
38
MR
1
2
ORR
38
84
SD
5
11
NE
2
4
6

---

Cumulative Response per cycle (%)
100%
2
9
10
11
90%
25
80%
CR/sCR
30
70%
39
VGPR
60%
67
PR
35
50%
MR
40%
50
36
SD
30%
20%
2
20
PD
16
3
10%
0
11
5
0
NE
4
0
10
0%
00
0
3
0
5
C1
C2
C3
C4
Response per FISH group
(38/45 tested)
Signal
Patients
VGPR/CR
ORR
#
# / %
# / %
none
17
10 / 59
15 / 88
-13/13q-
8
4 / 50
8 / 100
t (4;14)
2
2 / 100
2 / 100
del 17p
5
2 / 40
3 / 60
ampl 1q
5
3 / 60
5 / 100
7

---

Conclusions
· Carthadex induction is feasible and tolerable
· Response after induction is rapid and equals
VTD
· Occasional TLS, none with ample hydration
· PNP only grade 1+2 mostly Thalidomide related
· Successful stem cell harvest in 16/16 patients
· HDM/ASCT completed in 8 patients with normal
recovery and standard clinical course
· Longer follow-up needed for major conclusions
Acknowledgements
Pieter Sonneveld1, Emilie Häcker1, Sonja Zweegman2, Marie-Jose
Kersten3, Edo Vellenga4, Marinus van Marwijk-Kooy5, Okke de
Weerdt6, Sarah Lonergan1, Antonio Palumbo7, Henk Lokhorst8
1. Erasmus MC, Rotterdam, the Netherlands
2. VUMC, Amsterdam, the Netherlands
3. AMC, Amsterdam, the Netherlands
4. UMCG, Groningen, the Netherlands
5. Isala Clinics, Zwolle, the Netherlands
6. Anthonius Hospital, Nieuwegein, the Netherlands
7. University of Torino, Italy
8. UMCU, Utrecht, the Netherlands
The European Myeloma Network
HOVON Myeloma Working Group
Onyx Pharmaceuticals
8

---