PAD Combination Therapy (Bortezomib/Formerly
PS-341, Adriamycin and Dexamethasone) for
Previously Untreated Patients With Multiple Myeloma
J. D. Cavenagh,1 N. Curry,1 J. Stec,2 C. Morris,3 M.
Drake,3 S. Agrawal,1 P. Smith,1 D. Schenkein,2 D.
Esseltine,2 H. Oakervee1
1St Bartholomew's Hospital, London, UK
2Millennium Pharmaceuticals, Inc., Cambridge, MA, USA;
3Belfast City Hospital, Belfast, UK
Background
· Bortezomib (VELCADE®, formerly PS-341): active in relapsed
and/or refractory myeloma in two phase 2 trials (SUMMIT and
CREST)1,2
· Additional responses in SUMMIT and CREST when
dexamethasone was added to bortezomib3
· Bortezomib and anthracyclines: in vitro synergy and clinical
activity in myeloma4,5
· Preclinical data suggest bortezomib does not affect murine
hematopoietic stem cells, and peripheral blood stem cell
mobilisation and successful engraftment have been reported in
patients with MM anecdotally after bortezomib6
· Provide a rationale to study the use of bortezomib, doxorubicin
(Adriamycin®), and dexamethasone (PAD) prior to peripheral
blood stem cell transplantation in previously untreated myeloma
1Richardson et al. N Engl J Med. 2003;348:2609-2617. 2Jagannath et al. Blood. 2002;100:812a. 3Jagannath et al. 9th Congress of the EHA. Abstract 369.
4Mitsiades et al. Blood. 2003;101:2377-2380. 5Orlowski et al. Blood 2003;102:449a. 6Fitzgerald M et al. 2002 Proceedings of the ASBMT.
Objectives
· Primary objectives
­ Evaluate feasibility of collecting peripheral blood
stem cells (PBSCs) after PAD
­ Assess engraftment after high-dose therapy (HDT)
· Secondary objectives
­ Assess safety and toxicity
­ Determine response rates, progression-free
survival, and overall survival
Methods
· Study design: nonrandomised, open-label, phase I/II study
· Patients
­ Inclusion
· Newly diagnosed myeloma requiring therapy whereby
stem cell transplantation is considered appropriate
· Measurable serum and/or urine paraprotein
· ECOG performance status 0­3
­ Exclusion
· Previous treatment for myeloma with the exception of 4
days dexamethasone treatment of up to 40 mg/day and
localised radiotherapy or plasmapheresis for treatment of
clinically significant hyperviscosity syndrome
· grade 2 peripheral neuropathy within 14 days before
enrollment
Treatment
· Induction (4 cycles prior to transplantation)
­ Bortezomib 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11
­ Doxorubicin administered by continuous infusion or IV push
to cohorts at escalating dose levels on days 1­4
­ Dexamethasone 40 mg PO
· Cycle 1: days 1­4, 8­11, and 15­18
· All subsequent cycles: days 1­4
Treatment
Day
Cycle 1
1
48
11
15
18
21
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Adriamycin
Day
Cycles 2­4
1
48
11
15
18
21
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Adriamycin
PAD Sequential Dose Escalation Scheme
Study Drug Doses
No. of Patients
Dose
Additional
Group
Initial
Bortezomib
Dexamethasone
Doxorubicin
Enrollment for
Enrollment
DLT
11.3
40
0
3
2
2
1.3
40
4.5
3
2
31.3
40
9
14
NA
· 3 patients enrolled at each dose level; if 1 DLT occurs, then an additional
2 patients would be enrolled at that dose level
· If 2 of 5 patients at a treatment level experience a DLT, then dose escalation
to the next treatment level wil not occur
Peripheral blood stem cell harvest
· Day 1: Cyclophosphamide 1.5 g/m2 with hydration and
MESNA
· Days 4­12: G-CSF (Lenograstim, 263 mcg sc, Chugai
Pharma, UK) daily until completion of harvest
· PBSCH performed according to routine clinical
practice and continued until 4 ×106 CD34+ cells/kg
collected
Analyses
· Primary efficacy analysis: PAD therapy will be
considered to have adversely affected stem cell
mobilisation if significantly > 10% of patients fail to
mobilise > 2 x 106 CD34+ cell/kg
· Secondary efficacy analysis: response assessed
using EBMT criteria modified to include VGPR ( 90%
decrease in serum paraprotein)1,2
· Safety: National Cancer Institute Common Toxicity
Criteria version 2.0
1Bladé et al. Br J Haematol 1998;102:1115-1123.
2Attal et al. N Engl J Med. 2003;349:2495-2502.
Baseline Demographics and Disease
Characteristics
Characteristic
N = 21
Median age, y (range)
55 (37­66)
Male gender, n (%)
19 (90)
Isotype
IgG, n (:)
13 (10:3)
IgA, n (:)
5 (1:4)
Light chain, n (:)
3 (1:2)
Stage
Durie-Salmon
n
SWOG
n
IA
1
I4
IB
0
II
10
IIA
13
III
6
IIB
1
IV
1
IIIA
4
IIIB
2
Baseline Laboratory Values
Characteristic, mean (range)
N = 21
Hemoglobin, g/dL
10.3 (6.0­14.4)
Platelet count, × 109/L
189 (75­452)
Serum creatinine, µmol/L
97 (67­510)
Serum calcium, mmol/L
2.4 (1.9­3.9)
C-reactive protein, mg/L
< 5 (< 5­34)
Lactate dehydrogenase, U/L
373 (173­665)
-microglobulin, mg/L
4.0 (1.8­36.2)
2
Serum albumin, g/L
38 (23­44)
Baseline Cytogenetics
· Metaphase: 3 of 14 abnormal
­ 44, XX, ­13, t(14;16), ­20
­ 42, X, ­Y, ­12, ­13, t(14;16), ­15
­ 49, XY, +5,+7,+9, ­16, +mar
· FISH: 4 of 18 abnormal
­ Del 13, 5­6 copies CCND1
­ Extra CCND1 (3 cases)
Level 1: No Adriamycin
Response
CD34+ cells × 106/kg
Response 3
After 4
(No. of harvesting
Mo Post-
Patient No.
Cycles
attempts)
Autograft
1
PR
4.2 (1)
VGPR
2
VGPR
2.7 (2)
CR
3
CR
1.6 (2)
NA
Level 2: Adriamycin 4.5
Response
CD34+ cells × 106/kg
Response 3
Patient No.
After 4
(No. of harvesting
Mo Post-
Cycles
attempts)
Autograft
4
PR
7.4 (1)
VGPR
5
VGPR
2.3 (2)
CR
6
PR
4.7 (1)
PR
7
PR
3.6 (2)
PR
Level 3: Adriamycin 9.0
Response After 4
CD34+ cells × 106/kg (No. of
Response 3 Mo
Patient No.
Cycles
harvesting attempts)
Post-Autograft
8
PR
1.9 (1)
VGPR
9
VGPR*
2.1 (1)
na
10
VGPR
4.7 (4)
VGPR
11
PR
0
na
12
CR
4.3 (4)
na
13
SD
3.7 (2)
na
14
VGPR
2.5 (3)
na
15
VGPR
2.8 (6)
na
16
VGPR
10.4 (2)
na
17
PR
na
na
18
PR
na
na
19
VGPR*
na
na
20
CR*
na
na
21
PR*
na
na
2 CR, 6 VGPR,
N = 14
5 PR, 1 SD
*After 1­2 cycles.
After 3 cycles.
na = not available.
Outcome After PAD Induction
· 95% CR/PR rate (3 CR, 8 VGPR, and 9 PR) after
1 cycle of treatment (n = 21)
­ 1 CR after PD alone
­ 2 CRs after PAD
· 94% CR/PR rate (2 CR, 7 VGPR, 8 PR) after 4
cycles (n = 18)
Serum/Urinary Myeloma Protein Response by PAD Cycle
90
Isotype
80
IgA
)
IgA
70
IgG
(g/L
IgG
60
-LC
rotein 50
-LC
P
Mean ±
40
SEM
eloma 30
My
20
10
0
Pre-Rx
#1
#2
#3
#4
Treatment Cycle
· Mean M-protein levels decreased significantly following cycle 1 of
treatment and continued to decrease after subsequent cycles
Serum/Urinary Myeloma Protein Response by PAD Cycle
120
Isotype
110
IgA
)
100
%
IgA
(
90
IgG
IgG
80
rotein
-LC
P
70
-LC
60
Mean ±
eloma
50
SEM
My
40
ine 30
20
Chang
10
0
Pre-Rx#1
#2#3
#4
Treatment Cycle
· M-protein levels decreased by a mean of 70% following cycle 1 of treatment
Peripheral blood stem cell harvesting
· Median cell retrieval: 3.6 x 106 CD34+/kg (range,
1.6­10.4)
· Median number of harvests: 2 (range, 1­6)
· 15 of 16 patients mobilised
­ One patient failed 2 attempts at stem cell harvest:
this patient was stage IIIB with a t(14;16)and
serum creatinine 510 µmol/L
Outcome after PBSCT
· 11 of 15 mobilised patients have received MEL200/PBSCT
· 8 of 11 assessable 3 months post MEL200
· All 8 assessable patients have achieved PR or better
­ CR in 2 patients
­ VGPR in 4 patients
­ PR in 2 patients
· Hematopoietic recovery (n = 11)
­ Median days until neutrophil count > 0.5 × 106/L = 17
(range, 1­24)
­ Median days until platelet count > 20 × 109/L = 13
(range, 10­33)
Toxicity
· No DLT in the first 2 treatment levels
· Discontinuations from treatment
­ One patient discontinued treatment after 2 cycles
due to postural hypotension
­ One patient discontinued treatment after 3 cycles
due to neuropathy
Serious Adverse Events
Event
No. of Patients
Drug-related
Postural hypotension
1
Yes
Shingles
4
Probable
Nausea and vomiting
2
Probable
Chest infection
1
No
Line infection
3
No
Atrial fibrillation
1
No
Neuropathy
· Frequency of sensory neuropathy: 52%
· Frequency of painful neuropathy: 43%
· Generally appeared in cycle 3 or 4
· Neuropathic symptoms improving in all patients after
completion of therapy
Frequency of Sensory
Frequency of Painful
N = 21
Neuropathy, n (%)
Neuropathy, n (%)
Grade
1
9 (43)
8 (38)
2 (10)
31 (5)
PAD Cycle
1­2
4 (19)
2 (10)
3­4
6 (29)
5 (24)
Melphalan
1 (5)
2 (10)
Conclusions
· PAD combination therapy is an effective regimen for
previously untreated patients with multiple myeloma
­ 94% CR/PR rate after 4 cycles
­ 15 of 16 patients mobilised, 11/15 transplanted
thus far
­ All 8 evaluable patients achieved PR or better
following PBSCT (2 CR, 4 VGPR, 2 PR)
· Major toxicity was painful neuropathy
· A second cohort is being recruited to receive a
reduced dose of bortezomib (1.0 mg/m2)
Response After PAD, Results of Mobilisation, and Response Post-Autograft by Patient
Response After 4
CD34+ cells × 106/kg (Number
Response 3 Mo Post-
Level
Patient No.
Cycles
of harvesting attempts)
Autograft
1
PR
4.2 (1)
VGPR
1 (No doxorubicin)
2
VGPR
2.7 (2)
CR
3
CR
1.6 (2)
NA
4
PR
7.4 (1)
VGPR
5
VGPR
2.3 (2)
CR
2 (Doxorubicin 4.5 mg/m2)
6
PR
4.7 (1)
PR
7
PR
3.6 (2)
PR
8
PR
1.9 (1)
VGPR
9
VGPR*
2.1 (1)
NA
10
VGPR
4.7 (4)
VGPR
11
PR
0
NA
12
CR
4.3 (4)
NA
13
SD
3.7 (2)
NA
14
VGPR
2.5 (3)
NA
3 (Doxorubicin 9.0 mg/m2)
15
VGPR
2.8 (6)
NA
16
VGPR
10.4 (2)
NA
17
PR
NA
NA
18
PR
NA
NA
19
VGPR*
NA
NA
20
CR*
NA
NA
21
PR*
NA
NA
*After 1­2 cycles.
After 3 cycles.
NA = not available.

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