Reduced Dose PAD Combination Therapy
(PS-341/ Bortezomib, Adriamycin and
Dexamethasone) for Previously Untreated
Patients with Multiple Myeloma
R. Popat,1 H.E. Oakervee,1 N. Curry,1 N. Foot,1 C. Morris,2
M. Drake,2 S. Agrawal,1 P. Smith,1 D. Schenkein,3
D-L Esseltine,3 J.D. Cavenagh1
1St. Bartholomew's Hospital, London, UK
2Belfast City Hospital, Belfast, UK
3Millennium Pharmaceuticals, Inc., Cambridge, MA, USA
Background
·
Bortezomib (VELCADE®, formerly PS-341) is a selective, reversible
proteasome inhibitor with demonstrated activity in relapsed and/or refractory
multiple myeloma1
·
There is emerging data from Phase I/II studies that bortezomib is effective
in untreated patients and does not prejudice peripheral stem cell
mobilisation or engraftment.
·
We have previously reported the results of the combination of the standard
dose bortezomib (1.3mg/m2), adriamycin and dexamethasone (PAD)2 in this
setting:
A response rate of 95% was seen (24% CR)
High dose melphalan with PBSCT led to further CRs (43%)
Toxicities were manageable.
Neuropathy main adverse event (43% Grade 1; 5% Grade 3)
·
CREST3 study demonstrated that responses are still seen at bortezomib
1.0mg/m2
·
Therefore this study utilises bortezomib 1.0mg/m2 with adriamycin and
dexamethasone in order to minimise toxicity.
Objectives
· Primary objectives
Evaluate feasibility of collecting peripheral blood stem
cells after reduced dose 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 1.0 mg/m2 by IV bolus on days 1, 4, 8,
and 11
Doxorubicin 9mg/m2 administered by continuous
infusion or IV push 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 1.0 mg/m2
Dexamethasone 40 mg
Doxorubicin
Day
Cycles 24
1
48
11
15
18
21
Bortezomib 1.0 mg/m2
Dexamethasone 40 mg
Doxorubicin
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
Reduced dose 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 VGPR4,5
· 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=20
Median age, y (range)
61 (34-65)
Male gender, n
9
Isotype, n
IgG, n(;)
11 (7:4)
IgA, n(:)
6 (4:2)
Light chain, n(:)
3 (1:2)
Durie-Salmon stage, n
I0
II
3
III
17
ISS, n
I10
II
7
III
3
Baseline Laboratory Values
Characteristic, median (range)
N=20
Haemoglobin, g/L
10.9 (6.9-17.4)
Platelet count, x 109/L
250 (111-469)
Serum creatine, mol/L
86 (63-318)
Serum calcium, mmol/L
2.47 (1.65-4.51)
C-reactive protein, mg/L
8 (0-161)
Lactate dehydrogenase, U/L
289 (197-650)
2-microglobulin, mg/L
2.7 (1.7-14.2)
Serum albumin, g/L
35 (30-43)
Baseline Cytogenetics
· Metaphase: 4 of 11 abnormal
51XX, + 5,9,11,15,19
54X, inc + 3,15,19,21 & del1p
Hypodiploid del 1,13,17
33 X inc del 13 & 17
· FISH: 4 of 11 abnormal
Extra copy CCND1 (2 additional
cases)
Del 13 &17p (2 cases as seen in
metaphase)
Patient Outcome
Trial
20
Entry
Withdrawn after <1 cycle with
1
line sepsis. Early progression
then died
Died after 1st cycle with
1
orthostatic pneumonia despite
PAD
achieving PR
Primary refractory to PAD, has
received MEL200/PBSCT
following alternate induction
2
Progression following 4xPAD
prior to MEL200/PBSCT
3
Not received
2 declined
MEL200/PBSCT
MEL200/
1 pending
13
PBSCT
Response to reduced dose PAD
and Mel200/PBSCT
Response
PAD* (N=19)
MEL200PBSCT**(N=13)
n(%)
n(%)
CR
2 (11)
6 (46)
nCR
1 (5)
1 (8)
VGPR
5 (26)
1 (8)
PR
9 (47)
5 (38)
MR
1 (5)
0 (0)
SD
0 (0)
0 (0)
PD
1 (5)
0 (0)
*19 patients evaluable (1 patient was taken off study during C1 due to line sepsis)
This patient required dexamethasone dose reductions and treatment delays due to
pyschosis
**13 patients evaluable for response to MEL200PBSCT
Response Summary
· Following PAD
· Following
89% CR + PR
MEL200/PBSCT
16% CR + nCR
100% CR + PR
·
1 study termination during cycle 1
54% CR + nCR
due to line related MRSA
septicaemia, subsequently had
·
Of the 7 not receiving PBSCT:
early progression (unevaluable)
1 had progressive disease after
PADx4 (treatment delay)
·
1 progression on PAD therapy ie
2 declined MEL200/PBSCT
primary refractory
· 1 remains in PR
·
1 died following 1 cycle having
· 1 remains in CR
achieved PR
2 died
1 received alternative induction,
followed by PBSCT to CR
Serum Myeloma Protein
Response
75
n
IgG
tei
ro
IgG
Pa
50
IgA
L
lom
IgA
e
g,
y
Light chain
M
25
Light chain
m
rueS
0
Pre Tx
1
2
34
3 months post transplant
Cycle
Peripheral Blood Stem Cell
Harvest and Transplantation
· 16 out of 20 underwent PBSC mobilisation following
PAD (2 died, 1 had progressive disease, 1 successful
harvest following alternate induction therapy)
· All successfully mobilised
· Median cell retrieval: 5.15 x 106 CD34+/kg (range 2.4-
16)
· Median number of harvests: 1 (range 1-3)
· Median time to neutrophil engraftment (>0.5 x 109/L): 15
days (range 6-28)
· Median time to platelet engraftment (>20 x 109/L): 18
(range 11-40)
Toxicity
·
1 discontinuation from treatment due to
MRSA line sepsis
·
3 serious adverse events:
Infection (2 cases: pneumonia, line sepsis)
One death due to orthostatic pneumonia
secondary to immobility and severe thoracic
cage disease.
·
Unlikely to be bortezomib related
Adverse Events
(N=20)
Neuropathy
Psychiatric
Fatigue
Thrombocytopenia
Grade1-2
Neutropenia
Grade 3-4
Occular
Liver Function Tests
Skin
Gastrointestinal
Infection
02
46
8
10
12
Number of Events
Neuropathy
Sensory
Painful
Neuropathy
neuropathy
n (%)
n (%)
N=21
Grade 1-2
2 (9)
2 (9)
Grade 3-4
0 (0)
0 (0)
All neuropathic symptoms are resolving following completion of therapy
Conclusions
· Reduced dose PAD combination therapy is an
effective regimen for previously untreated
patients with multiple myeloma
· Response rates are high:
89% CR+PR rate
· Stem cell mobilisation is unaffected
· 2 deaths seen
1 with orthostatic pneumonia related to
myeloma bone disease
1 progression following early withdrawal
secondary to line related MRSA septicaemia
Conclusions
· Improved toxicity profile compared to PAD
bortezomib 1.3mg/m2
· Minimal neuropathy seen at 1.0mg/m2 (19%)
compared with 1.3mg/m2 (48%)
· This supports the use of bortezomib dose
reduction from 1.3mg/m2 during PAD
combination therapy to manage toxicity
· The reduced dose PAD regimen may also be
used up-front in untreated patients with pre-
existing neuropathy
References
1.
Richardson et al., N Engl J Med. 2005;352:2487-98
2.
Oakervee et al., Br J Haematol. 2005;129:755-762
3.
Jagannath et al. Br J Haematol. 2004;126:165-172
4.
Bladé et al. Br J Haematol. 1998;102:1115-1123.
5.
Attal et al. N Engl J Med. 2003;349:2495-2502
Acknowledgements
· St. Bartholomew's and the Royal London
Charitable Foundation Research Advisory Board
· The Elimination of Leukaemia Fund
· Millennium Pharmaceuticals, USA
· Chugai Pharma, UK
A Phase I/II Study of Bortezomib and Low
Dose Intravenous Melphalan (BM) for
Relapsed Multiple Myeloma
R. Popat,1 H. E. Oakervee,1 N. Foot,1 S. Agrawal,1
P. Smith,1 C. Craddock,2 C. Williams,3 S. Basu,4
J. D. Cavenagh1
1St. Bartholomew's Hospital, London, UK
2University of Birmingham, UK
3Nottingham City Hospital, UK
4Royal Wolverhampton Hospitals, UK
Background
· Bortezomib (VELCADE®) is a selective reversible
proteasome inhibitor with demonstrated efficacy in relapsed
multiple myeloma
· The overall response rate (CR+PR+MR) as a single agent
was 35% in the SUMMIT1 study and 46% in the APEX2 study
· In-vitro studies including our own3-5, have demonstrated
potent synergy with other chemotherapeutic agents such as
melphalan
· Bortezomib has also been shown to overcome melphalan
resistance in cell line models
· It therefore follows that responses may be further improved by
the combination of such drugs
Objectives
· Primary Objectives
To determine the maximum tolerated dose of intravenous
melphalan when used in combination with Bortezomib (BM) in
patients with relapsed multiple myeloma (MM).
To assess the response rate in patients with relapsed MM to the
combination of BM.
· Secondary Objectives
To determine the progression free and overall survival (PFS and
OS) in patients treated with BM.
To assess the safety and tolerability of BM.
To assess the response rate, PFS and OS with BM plus
dexamethasone (BMD) in patients who fail to respond to BM
alone.
Methods
· A multi-centre non-randomised open label Phase I/II trial
in patients with relapsed MM
· Inclusion Criteria:
Relapsed MM, having achieved at least a minor response (MR)
of at least three months duration to the last line of therapy.
ECOG performance score 0-2.
Measurable serum or urinary paraprotein
· Exclusion Criteria:
Platelet count <100 x 109/L
Absolute neutrophil count <1.5 x 109/L
Serum creatinine of >170 mmol/l
Peripheral neuropathy Grade 2
Treatment
Bortezomib 1.3mg/m2 iv on Days 1,4,8 and 11
Melphalan iv on Day 2 at escalating dose levels to cohorts (see
below)
Each cycle lasted 28 days and neutrophils of >1.5 x 109/L and
platelets of >100 x 109 were required prior to the next cycle. If
not achieved, the cycle was delayed up to 2 weeks before
withdrawal from the study.
G-CSF (Lenograstim, 263mg s.c. Chugai Pharma, UK) was
given if the neutrophils fell below 0.5 x 109. If neutropenia
occurred in one cycle then G-CSF was used from Day 8 on all
subsequent cycles.
Dexamethasone 20 mg per day on the day of and the day after
each bortezomib injection was added for progressive disease
after two cycles or stable disease after four.
Treatment
Day
1 2
4 5
8 9
11 12
28
Bortezomib
Melphalan
Dexamethasone
( if required)
Sequential Dose Escalation
Scheme
· 3 patients enrolled at each dose level; if one patient
experienced a DLT during the first cycle, then a further
three patients would be entered at that level.
·If 2 at a treatment level experienced a DLT, then dose
escalation to the next treatment level would not occur.
· DLT was 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
Sequential Dose Escalation
Scheme
Treatment
Melphalan
Number of
Comments
Level
dose (mg/m2)
Patients
Expanded cohort as
1a
10
12
delays seen due to
haematological
toxicity. 1 DLT.
1
2.5
4
No DLT
2
5
4
No DLT
3
7.5
2
Currently recruiting
Evaluation
· Response rates to BM using EBMT criteria modified to include near
CR (nCR) and VGPR6,7
·CR: lack of detectable paraprotein by electrophoresis and immunofixation
and < 5% plasma cells with normal morphology in the bone marrow
·nCR: immunofixation positive but otherwise all CR criteria fulfilled
·VGPR: 90% decrease in serum paraprotein
·PR: > 50% decrease in serum paraprotein or a > 90% decrease in the level
of urinary light chains or both
·MR: 25-49% reduction in serum paraprotein or a 50-89% reduction in urinary
light chain excretion
·SD: Not meeting criteria for minimal response or progressive disease
·PD: >25% increase in serum paraprotein or urinary light chain excretion
confirmed on >1 sample
· Progression free and overall survival
· Safety and tolerability: adverse events graded using the NCI-CTC
version 2.0
· Response rate, PFS and OS with BM plus dexamethasone (BMD) in
patients who fail to respond to BM alone.
Baseline Demographics and
Disease Characteristics
Characteristic
N=22
Median age, y (range)
60 (40-73)
Male gender, n
13
Isotype, n
IgG, n (:)
16 (13:3)
IgA, n (:)
2 (1:1)
Light chain, n(:)
4 (3:1)
Median ECOG PS, n (range)
1(0-1)
Baseline Laboratory Values
Characteristic median (range)
N=22
Haemoglobin, g/L
11.3 (8-15.6)
Platelets x 109/L
168 (28-471)
Serum creatinine, mol/L
98 (74-198)
Serum calcium, mmol/L
2.32 (1.73-2.86)
C-reactive protein, mg/L
8 (<5-90)
Lactate dehydrogenase, U/L
400 (225-1221)
2-microglobulin, mg/L
3 (1.3-7.3)
Serum albumin, g/L
37 (23-42)
Baseline Cytogenetics
· Metaphase: 4 of 10 abnormal
53 XY, +3,9,11,15,19
55 Y +X, Complex: -13q;+3,5,7,9,11,16,18,21
42XY -13, dup1q, t(13;14)
Hypotetraploid, complex, 13q-, t(14;16)
· FISH: 3 of 11 abnormal
T (11;14)
Del 13, 5-9x CCND1
Del 13
Prior Therapies
Therapy
N=22
Corticosteroids
20
Alkylating agents
14
Anthracyclines
21
Thalidomide
13
Radiotherapy
4
Bortezomib
2
Stem cell transplantation
17
Median number of regimens
3 (1-5)
(range)
Best Overall Response to
Treatment*
Response
Number (%), N=21**
CR
1 (5)
nCR
0 (0)
VGPR
1 (5)
76%
PR
9 (43)
MR
5 (24)
SD
4 (19)
PD
1 (5)
*Response across all treatment levels
**1 unevaluable as not completed 1 cycle
Includes the addition of dexamethasone as per protocol
Best Response by Treatment Level
Melphalan mg/m2
Level
Median no. of
Response
cycles n (range)
1a
10
7 (1-8)
1 CR
1 VGPR
5 PR
2 MR
3 SD
1
2.5
2 (1-5)
1 PR
2 MR
1 PD
2
5
3 (3-4)
3 PR
1 SD
3
7.5
2
1 MR
Responses to bortezomib/
melphalan alone*
Response
Number (%),
N=21
CR
1 (5)
nCR
0 (0)
VGPR
1 (5)
62%
PR
7 (33)
MR
4 (19)
SD
4 (19)
PD
4 (19)
*Response across all
7 required addition of dexamethasone
treatment levels
·4 for progressive disease
·3 for stable disease
Efficacy
Median Time to Progression, m (range)
6.8m (1.4-NYR)
Median Overall Survival, m (range)
NYR (2.2-NYR)
Toxicity
· 1 DLT at level 1a (G3 SN/PN)
· Treatment delays due to haematological
toxicity led to melphalan dose reduction
· 11 discontinuations from treatment to date
(N=22)
4 due to progressive disease
5 due to peripheral neuropathy
1 following an MI
1 following GI bleed
Serious Adverse Events
7 serious adverse events in 22 patients
Event
No. of Pts
Dose level
Drug
Agent
Related
Pneumonia
4
1a (n=3)
No
1 (n=1)
Line
1
1a
No
Infection
GI Bleed*
1
2
Possible
Combination
Myocardial
1
1a
No
Infarction
* Pt had a normal platelet count
Adverse Events
N=22
Overall neuopathy
Thrombocytopenia
Neutropenia
Liver function tests
Nausea
Grade 1-2
Fatigue
Grade 3-4
Diarrhoea
Infection
Rash
(<2 Grade 1-2 events not shown)
MI
0
5
10
15
20
Number of events
Thrombocytopenia resulted in bleeding in only 1 patient
Onset of Neuropathy
(N=22)
Type of
Cycles 1-4
Cycles 5-8
neuropathy
N (%)
N (%)
Sensory:
Grade 1-2
8 (36)
3 (14)
Grade 3-4
4 (18)
0 (0)
Painful:
Grade 1-2
4 (18)
4 (18)
Grade 3-4
2 (9)
0 (0)
13 patients had prior therapy with thalidomide
Conclusions
· Bortezomib and melphalan therapy can be
safely given to patients with relapsed multiple
myeloma
· Overall response rates are 62% rising to 76%
with the addition of dexamethasone for stable or
progressive disease
· This compares favourably with the single agent
APEX study (equivalent response rate 46%)
Conclusions
· Haematological toxicity predominant Grade 3-4
adverse event
· This led to significant treatment delays at
melphalan 10mg/m2 requiring a dose reduction
of subsequent treatment levels. Minimal delays
seen up to melphalan 7.5mg/m2
· 18% Grade 3-4 neuropathy resulting in 5 study
withdrawals
References
1.
Richardson et al. N Engl J Med. 2003;348:2609-2617
2.
Richardson et al., N Engl J Med. 2005;352:2487-98
3.
Mitsiades et al., Blood. 2003;101:2377-2380
4.
Ma et al., Clin Cancer Res, 2003. 9(3): p. 1136-44.
5.
Popat et al., Blood. 2005; ASH abstract
6.
Bladé et al. Br J Haematol. 1998;102:1115-1123.
7.
Attal et al. N Engl J Med. 2003;349:2495-2502
Acknowledgements
· St. Bartholomew's and the Royal London
Charitable Foundation Research Advisory Board
· The Elimination of Leukaemia Fund
· Ortho-biotech, UK
· Chugai Pharma, UK