Bortezomib, IV cyclophosphamide, and
dexamethasone (VelCD) as induction therapy in
newly diagnosed multiple myeloma: Results of
an interim analysis of the German DSMM XIa trial
S Knop, P Liebisch, H Wandt, M Kropff,
W Jung, N Kroeger, O Sezer, C Straka,
G Fingerle Rowson, H Einsele
on behalf of DSMM
Orlando/FL, 31 May 2009
Financial Disclosure
Honoraria by Janssen-Cilag and Celgene
Bortezomib, dexamethasone & oral cyclophosphamide
in relapsed multiple myeloma
Design of the phase II "DSMM VI" trial :
Patients: n=50; median age: 63 years
FISH 13q-: 46%
Median number of previous treatments: 2 (1 - 9)
Bortezomib 1,3 mg/m² IVP
Dexamethasone 20 mg orally
X 8
Cyclophosphamide 50 mg orally
Day
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
3 x Vel d 1/8/15/22, q d43
Results:
Median EFS: 12 months
Median OS: not reached at 15 mo median f/u
Response: 82% with at least PR; CR rate 12%
Kropff M. et al., BJH 2007
DSMM XI Trial: VelCD as an induction regimen
Major inclusion criteria
Patients < 60 yrs with newly diagnosed MM
Treatment indication as per presence of CRAB criteria
No previous therapy except dex 160 mg and/or plasmapheresis and/or irradiation
Creatinine clearance > 30 ml/min
Negative pregnancy test and use of adequate contraceptive methods
Major exclusion criteria
Non-secretory myeloma
Peripheral neuropathy > grade 2 according to NCI-CTC
End points
I
Define the Cy-MTD in patients with newly diagnosed MM
II
Safety and efficacy of the regimen
Kropff M. et al., Ann Hematol 2009
VelCD induction: dose definition for IV
Cyclophosphamide
Bortezomib 1,3 mg/m² IVP
x 3
Cyclophosphamide IV*
Tag
Dexamethasone 40 mg PO
1 2 3 4 5 6 7 8 9 10 11 12
q d22
Cyclo-MTD:
900mg/m², selected from 3 dose levels
DLTs:
Leuko-/neutropenia (n=6),
Pneumonia (n=1)
Median TTR:
63 days
PBSC harvest:
28/28 pts (median of 1 apheresis)
Kropff M. et al., Ann Hematol 2009
DSMM XI Trial:
VelCD
VelCD
Study Schedule
VelCD
IEV
1. HD-Mel
high risk
200 mg/m²
standard risk
cytogenetics
cytogenetics
HLA-identical MRD or MUD
2. HD-Mel
yes
no
200 mg/m²
allo-RIC
2. HD-Mel 200 mg/m²
R
R
R
Nil
Vel weekly x 4
Nil
Vel weekly x 4
Nil
Vel weekly x 4
Patient characteristics, n=200
Age (mean + SD) [years]
52.4 + 6.8
Age classes [n (%)]
- <21-39 years
10 (5)
- 40-49 years
51 (25.5)
- 50-59 years
139 (69.5)
Gender distribution (female/male) [%]
46.5 / 53.5
Durie&Salmon Stages [N (%)]
-II
49 (24.5)
-III
148 (74.0)
- missing
3 (1.5)
Type of MM [N (%)]
-IgG
114 (57.0)
-IgA
41 (20.5)
-IgD
4 (2.0)
-IgM
1 (0.5)
- Light chain myeloma
39 (19.5)
- missing
1 (0.5)
Patient characteristics, n=200
2-microglobulin [mg/l]
Mean + SD, range
3.75 + 3.38, range 1.0 ­ 35.9
Cytogenetic subgroups [n (%)]
­ No FISH abnormalities
51 (25.5)
­ 13q-deletion
55 (27.5)
­ 17p-deletion
20 (10.0)
­ t(4;14)
16 (8.0)
­Other
48 (24.0)
­ Unclassifiable
18 (9.0)
­ Missing
40 (20.0)
Treatment feasibility
Part I
Part II
Total
Dose definition
n = 170
n = 200
n = 30
3 cycles completed [n (%)]
22 (73.3)
156 (91.8)
178 (89.0)
Premature termination [n (%)]
8 (26.7)
14 (8.2)
22 (11.0)
- Progressive disease [n (%)]
0 (0.0)
2 (1.1)
2 (1.0)
- Death [n (%)]
0 (0.0)
2 (1.1)
2 (1.0)
- Toxicity [n (%)]
7 (23.3)
4 (2.4)
11 (5.5)
- Other adverse events [n (%)]
0 (0.0)
5 (2.9)
5 (2.5)
- Protocol violation [n (%)]
3 (10.0)
0 (0.0)
3 (1.5)
- Other [n (%)]
0 (0.0)
4 (2.4)
4 (2.0)
Serious adverse events
Part I
Part II
Total
Dose definition
n = 170
n = 200
n = 30
SAEs [n (%)]
8
76
84
patients with SAE [n (%)]
8 (26.7)
41 (24.1)
49 (24.5)
- SAEs due to infection
3 (37.5)
24 (31.6)
27 (32.1)
[n (% of all SAEs)]
-SAEsdue to
thromboembolism
0 (0.0)
1 (1.0)
1 (0.5)
[n (% of all SAEs)]
Kropff M. et al., Ann Hematol 2009
Adverse events
Adverse events
Total [n (%)]
Grade 3 [n (%)]
Grade 4 [n (%)]
Leukopenia
111 (55.5)
43 (21.5)
19 (9.5)
Neutropenia
19 (9.5)
8 (4.0)
5 (2.5)
Thrombocytopenia
74 (37.0)
9 (4.5)
1 (0.5)
Anemia
45 (22.5)
9 (4.5)
1 (0.5)
Nausea
51 (25.5)
4 (2.0)
-
Diarrhea
41 (20.5)
2 (1.0)
-
Constipation
38 (19.0)
-
-
Vomiting
21 (10.5)
4 (2.0)
-
Polyneuropathy
25 (12.5)
1 (0.5)
-
Paraesthesia
44 (22.0)
2 (1.0)
3.5%
-
Hypoaesthesia
16 (8.0)
1 (0.5)
-
Infections/infestations
94 (47.0)
8 (4.0)
-
Herpes zoster
12 (6.0)
2 (1.0)
-
ITT population, n = 200, according to investigator assessment
Response to treatment on study day 63
(Interim analysis; investigator-based assessment n = 200)
80
70
71.5
60
50
40
30
20
10
12.5
5.5
8.5
2.0
0
CR
PR
MR
SD
PD
ORR 84%
Response to VelCD
by cytogenetic subgroup on study day 63
Response: CR + PR
Molecular
(assessment by investigator)
cytogenetics / FISH
YES , n (%)
NO, n (%)
Normal, n = 51
44 (86.3)
7 (13.7)
Abnormalities, n = 91
75 (82.4)
16 (17.6)
13q-, n = 55
45 (81.8)
10 (18.2)
t(4;14), n = 16
15 (93.8)
1 (6.3)
17p-, n = 20
14 (70.0)
6 (30.0)
Other, n = 48
42 (87.5)
6 (12.5)
Unclassifiable, n = 18
15 (83.3)
3 (16.7)
Missing, n = 40
34 (85.0)
6 (15.0)
Overall, n = 200
168 (84.0)
32 (16.0)
Conclusions

3 cycles of VelCD induction in MM before HD-MEL
-isamong themostactiveregimens
- may overcome traditional poor-risk cytogenetics except 17p-
- is safe
low mortality of 1%
low risk of hospitalization due to infection
low incidence of severe, acceptable rates of mild/moderate polyneuropathy
very low risk of thromboembolism
- is feasible in an outpatient setting

More accurate response assessment (VGPR) underway

Final analysis of VelCD induction to be presented at ASH 2009
... 50 dsmm centers
· rostock · greifswald
· lübeck
Chair
· 2 x hamburg
Hermann Einsele, MD, Würzburg
· oldenburg
· bremen
Christian Straka, MD, Berg
· berlin
Coordinating secretary
·
· potsdam
hannover
· munster
Stefan Knop, MD, Würzburg
· magdeburg
· wuppertal
· goslar
·
· göttingen
duisburg · dortmund
Study coordination
· halle/saale
· essen
Martina Haase, Würzburg
· eisenach
Mareike Väthröder, Würzburg
· cologne
Iqbal Hügel, Würzburg
· frankfurt
· wiesbaden
· trier
· mainz
· kaiserslautern
würzburg
· homburg
· saarbrücken
· bad friedrichshall· erlangen
· nuremberg
· ludwigsburg
· 3 x stuttgart
· tübingen
· ulm · augsburg
· offenburg
· 5 x munich
· freiburg
· kempten
vienna
merano
bolzano
graz