PAD Combination Therapy
(PS-341/Bortezomib, Adriamycin and
Dexamethasone) for Previously Untreated
Patients With Multiple Myeloma
J. D. Cavenagh,1 R. Popat,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
Updated Abstract
Background: The most favourable outcomes for patients with multiple myeloma (MM) are seen in
those achieving a complete or near complete response following initial therapy. Therefore, it is
logical to explore strategies aimed at improving initial response rates. Bortezomib has shown
significant activity in patients with advanced MM and was superior to pulsed dexamethasone in this
setting. Additional efficacy is seen when dexamethasone is combined with bortezomib and in vitro
synergy is observed with cytotoxic agents such as doxorubicin. On this basis, the PAD regimen was
investigated as front-line therapy for patients with MM.
Aims: The primary objective of this phase I/II study was to assess the feasibility of harvesting
peripheral blood stem cells (PBSC) after PAD, with secondary objectives being assessments of
safety, toxicity, response rate (RR), progression free survival, and overall survival.
Methods: Patients with previously untreated MM were eligible. Patients were treated with 4 × 21
day cycles of PAD comprising bortezomib 1.3 mg/m2 on days 1, 4, 8 & 11 along with
dexamethasone 40 mg on days 1­4, 8­11, & 15­18 during cycle 1 and days 1­4 during cycles 2­4.
During days 1­4 of each cycle, patients also received 0 mg/m2, 4.5 mg/m2 or 9 mg/m2 of
doxorubicin at levels 1, 2 & 3 respectively. Following harvesting, patients received high-dose
melphalan (MEL200) with PBSC rescue. Gene expression profiling was performed on purified
plasma cells from diagnostic samples for pharmacogenomic analysis.
Results: 21 patients were enrolled (19 male, 2 female, median age 55 years [range 36-66]). All 21
completed PAD with a 95% CR/PR rate. 20 of 21 patients mobilised PBSC successfully (median
collection 3.75 x 106 CD34+ cells/kg, range 1.6­10.4), and these 20 patients received MEL200 with
median neutrophil (> 0.5 ×109/L) and platelet engraftment (> 20 × 109/L) of 15 (1­24) and 13 (10­
33) days respectively. Three months after PBSC transplantation (n = 20) or PAD (n = 1), 20 of 21
patients achieved at least a PR (CR 9, nCR 3, VGPR 5 & PR 3).Toxicities have generally been
acceptable with 15 grade 3 events in 12 patients: 7 infections, 4 episodes of shingles, 1 nausea and
vomiting, 1 neuropathy, 1 postural hypotension, 1 hyperglycemia, and 1 atrial fibrillation. Overall,
48% of patients experienced sensory or painful neuropathy which was of Grade 1 severity in 43% of
patients. Of note, neuropathic symptoms are improving in all patients after completion of therapy.
Summary: PAD is well tolerated in the majority of patients, is highly effective and does not
prejudice subsequent PBSC collection. PAD should be further evaluated as first-line therapy in
prospective randomised trials.
Background
·
Bortezomib (VELCADE®, formerly PS-341) is a selective reversible proteasome
inhibitor (Ki = 0.6 nM) with demonstrated activity in the treatment of relapsed
and/or refractory multiple myeloma in two phase 2 trials (SUMMIT and CREST)1,2
·
Additional responses were reported from SUMMIT when dexamethasone was
added to bortezomib in patients who had progressive disease after 2 cycles or
stable disease after the first 4 cycles3
·
Significant in vitro synergy with bortezomib and anthracyclines has been
observed,4 and in clinical investigations, the combination of bortezomib and the
anthracycline pegylated liposomal doxorubicin (Doxil®) demonstrated activity
with manageable toxicity5
·
Preclinical data suggest bortezomib does not affect murine hematopoietic stem
cells; peripheral blood stem cell mobilisation and successful engraftment have
been reported in multiple myeloma patients anecdotally after bortezomib6
·
The rate of complete response (CR) has varied between 27% and 44% in major
clinical trials following high dose chemotherapy and peripheral blood stem cell
transplantation (PBSCT)7-9
·
These observations provide a rationale to study the use of bortezomib,
doxorubicin (Adriamycin®), and dexamethasone (PAD) prior to PBSCT in
previously untreated patients with myeloma
Objectives
· Primary objectives
­ Evaluate feasibility of collecting peripheral
blood stem cells after PAD
­ Assess engraftment after high-dose therapy
· 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: selected inclusion/exclusion criteria
­ Inclusion
· Newly diagnosed myeloma requiring therapy whereby
PBSCT is considered appropriate
· Measurable serum and/or urine paraprotein
· ECOG performance status 0­3
­ Exclusion
· Previous treatment for myeloma with the exception of 4
days of dexamethasone treatment of up to 40 mg/day,
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 (0, 4.5,
9.0 mg/m2/day) on days 1­4
­ Dexamethasone 40 mg po
· Cycle 1: days 1­4, 8­11, and 15­18
· Cycles 2 to 4: days 1­4
Treatment
Day
Cycle 1
1
48
11
15
18
21
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Doxorubicin
Day
Cycles 2­4
1
48
11
15
18
21
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Doxorubicin
Sequential Dose Escalation
Scheme
Study Drug Doses
No. of Patients
Bortezomib, Dexamethasone,
Additional
Doxorubicin,
Initial
Dose
Enrolment
mg/m2
mg
mg/m2
Enrolment
Group
for DLT
11.3
40
0
3
2
2
1.3
40
4.5
3
2
31.3
40
9
14
NA
Sequential Dose Escalation
Scheme
­ 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 will not occur
­ DLT assessed at cycle 1 regardless of relation to drug
· Grade 4 neutropenia for at least 7 days
· Grade 4 thrombocytopenia for at least 7 days
· Nonhaematologic toxicity of grade 3/4 not ameliorated by
symptomatic measures, excluding nausea and vomiting
Peripheral Blood Stem Cell Harvest
and Transplant
­ Day 1: cyclophosphamide 1.5 g/m2 with hydration and
MESNA
­ Days 4­12: G-CSF (Lenograstim, 263 µg sc, Chugai
Pharma, UK) daily until completion of harvest
­ PBSCH performed according to routine clinical practice
and ideally continued until 4 × 106 CD34+ cells/kg
collected; transplant possible with > 1 × 106 cells/kg
­ High-dose melphalan (MEL200) and PBSCT
Evaluation
·
Primary efficacy analyses
­ PAD therapy will be considered to have adversely affected stem cell
mobilisation if > 10% of patients fail to mobilise > 2 x 106 CD34+ cell/kg
­ Assessment of engraftment (daily blood counts post-engraftment)
· Neutrophil recovery: 1st of 3 consecutive days with ANC > 0.5 × 109
cells/L
· Platelet recovery: 1st of 3 consecutive days with > 20 × 109 cells/L
·
Secondary efficacy analysis
­ Response assessed using EBMT criteria modified to include VGPR10,11
· CR: lack of detectable paraprotein by electrophoresis and
immunofixation, < 5% plasma cells with normal morphology in the bone
marrow
· nCR: immunofixation positive but otherwise fulfilled all CR criteria
· VGPR: 90% decrease in serum paraprotein
· PR: > 50% decrease in serum paraprotein and/or > 90% decrease in the
level of Bence Jones protein
·
Safety: adverse events were graded using the NCI-CTC version 2.0
Baseline Demographics and
Disease Characteristics
Characteristic
N = 21
Median age, y (range)
55 (37­66)
Male gender, n
19
Isotype, n
IgG, n (:)
13 (10:3)
IgA, n (:)
5 (1:4)
Light chain, n (:)
3 (1:2)
Durie-Salmon stage, n
I
1
II
14
III
6
SWOG stage, n
I
4
II
10
III
6
IV
1
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)
Response to PAD and Mel200/PBSCT
(N = 21)
PAD
MEL200/PBSCT*
Response
n (%)
n (%)
CR
5 (24)
9 (43)
nCR
1 (5)
3 (14)
VGPR
7 (33)
5 (24)
PR
7 (33)
3 (14)
SD
1 (5)
1 (5)
· Response summary following PAD/MEL200/PBSCT*
­ 95% CR + PR
­ 57% CR + nCR
* Two patients declined PBSCT and one failed to mobilize
Serum Myeloma Protein Response
90
IgG
80
L
IgG
g/ 70
IgA
60
IgA
Protein, 50
Mean ± SEM
eloma 40
My 30
20
Serum
10
0
P
3
r
C
C
e
y
y
C
C
m
t
c
c
y
y
t
r
ra o
e
l
l
c
c
e
e
n
n
a
le
le
s
t
t
1
2
m
3
4
h
p
s
e
la
n
p
n
t
o
ta s
t
t
ion
· Mean M-protein levels decreased significantly following cycle 1 of
treatment and continued to decrease after subsequent cycles
Response Post-PAD and Post-Transplantation by Dose Level
Response After
Dose level
Patient No.
Response After 4 Cycles
MEL200/PBSCT
1 (no dox)
PR
1VGPR
VGPR
2CR
3
CR
CR*
2 (dox 4.5)
4
PR
VGPR
VGPR
5CR
PR
6PR
7PR
PR
3 (dox 9.0)
8PR
VGPR
9nCR
nCR*
10
VGPR
nCR
11
VGPR
VGPR
12
CR
CR
13
SD
SD
14
VGPR
nCR
15
VGPR§
CR
16
CR
CR
17
PR
PR
18
PR
VGPR
19
CR
CR
20
CR
CR
21
VGPR
CR
*Declined MEL200/PBSCT.
After 2 cycles.
Failed to mobilise.
§After 3 cycles
· Improvements in response following PBSCT
­ Dose level 1: two of 3 patients improved
·VGPR CR
·PR VGPR
­ Dose level 2: two of 4 patients improved
·VGPR CR
·PR VGPR
­ Dose level 3: 6 of 14 patients improved
·VGPR CR (2 patients)
·VGPR nCR (2 patients)
·PR VGPR (2 patients)
Peripheral Blood Stem Cell Harvest
and Transplantation
· All patients underwent PBSC mobilisation
· Median cell retrieval: 3.75 × 106 CD34+/kg (range 1.6­10.4)
· Median number of harvests: 2 (range 1­6)
· All patients underwent attempted PBSC mobilisation
­ 20 of 21 patients successfully 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
­ CD34+ cell counts were > 2.0 × 106 in 18 of 20 patients, but below that
threshold in 2 patients
· One patient had lumbosacral XRT before PAD
· One patient underwent PBSCT after 1.9 × 106 CD34+ cells were
collected
· Median time to neutrophil engraftment (> 0.5 ×109/L) : 15 days (range, 1­24)
· Median time to platelet engraftment (> 20 × 109/L): 13 days (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
· 15 serious adverse events occurred in 12 patients
Drug-
Event
No. of Pts Dose level
related
Agent
Peripheral neuropathy
1
3
Yes
Bortezomib
Postural hypotension
1
3
Yes
Bortezomib
Nausea and vomiting
1
2
Possible
Bortezomib
Shingles
3
2 (n = 1)
Possible
Bortezomib
3 (n = 2)
Line infection
3
1 (n = 2)
No
NA
3 (n = 1)
Other infection
4
2 (n = 1)
No
NA
3 (n = 3)
Atrial fibrillation
1
3
No
NA
Hyperglycemia
1
1
Yes
Dexamethasone
NA = not applicable.
Neuropathy
Sensory Neuropathy,
Painful Neuropathy,
N = 21
n (%)
n (%)
Grade
1
9 (43)*
9 (43)
3
1 (5)
1 (5)
Onset at PAD
Cycle
1­2
5 (24)
1 (5)
3­4
5 (24)
9 (43)
Melphalan
1 (5)
2 (10)
*Two patients at dose level 1, 2 patients at dose level 2 and 5 patients at dose level 3
One patient at dose level 1, 4 patients at dose level 2, and 4 patients at dose level 3
One patient at dose level 3
·
Frequency of sensory neuropathy: 48%
·
Frequency of painful neuropathy: 48%
·
Neuropathic symptoms improving in all patients after
completion of therapy
Conclusions
· PAD combination therapy is an effective regimen for previously
untreated patients with multiple myeloma
­ 95% CR/PR rate: 24% CR and 5% near CR after PAD alone
· PAD does not prejudice subsequent PBSCT
­ 20 of 21 patients had stem cells mobilised
­ 18 of 20 patients received PBSCT
­ 95% CR/PR rate: 43% CR and 14% near CR after PAD + PBSCT
· Major toxicity is painful neuropathy
­ Primarily grade 1
­ Generally appeared in cycle 3 or 4
­ Neuropathic symptoms are improving in all patients after
completion of therapy
· PAD should be further evaluated as first-line therapy in prospective
randomised trials
References
1. Richardson et al. N Engl J Med. 2003;348:2609-2617.
2. Jagannath et al. Br J Haematol. 2004;126:165-172.
3. Jagannath et al. Hematol J. 2004; 5 Suppl 2:S130.
4. Mitsiades et al. Blood. 2003;101:2377-2380.
5. Orlowski et al. Blood. 2003;102:449a.
6. Fitzgerald et al. Proceedings of the American Society of Blood
and Marrow Transplantation. 2002.
7. Alexanian et al. Bone Marrow Transplant. 2001:27:1037-1043.
8. Child et al. N Engl J Med. 2003;348:1875-1883.
9. Segeren et al. Blood. 2003:101:2144-2151.
10. Bladé et al. Br J Haematol. 1998;102:1115-1123.
11. Attal et al. N Engl J Med. 2003;349:2495-2502.

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