RESPONSE OF NEWLY-DIAGNOSED MYELOMA
WITH 1q21 AMPLIFICATION TO BORTEZOMIB-
BASED PAD INDUCTION THERAPY
Joshua, D1, Bashford J2, Szer J3, Horvath N4, Spencer A5, Hertzberg
M6, Ashurst E7, Wade J7, Copeman MC7, Prince HM8
(1) Royal Prince Alfred Hospital, Camperdown; (2) The Wesley Hospital, 451 Coronation Drive, Auchenflower QLD
4066; (3) Royal Melbourne Hospital, Grattan St, Parkville VIC 3050; (4) Royal Adelaide Hospital, North Terrace,
Adelaide SA 5000; (5) The Alfred Hospital, Commercial Rd, Prahran VIC 3181; (6) Westmead Hospital, Hawkesbury
Rd, Westmead NSW 2145; (7)Janssen-Cilag Australia Pty. Ltd., 66 Waterloo Rd, North Ryde NSW 2113, Australia. (8)
Cabrini Hospital,
p, 183 Wattletree Rd, Malvern VIC 3144, Australia
1
DISCLOSURES
· This study was funded by Janssen-Cilag Pty Ltd,
Australia.
2
1q21 AMPLIFICATION PREDICTS POORER
SURVIVAL IN NEWLY-DIAGNOSED MYELOMA
·
Chromosome 1q21 amplification is found in 43% of newly-
diagnosed myeloma cases
·
Pd
Pre i
dicts sht
horter EFS
EFS
d
an OS
OS t
a 5 years
·
Predicts lack of benefit of thalidomide for 5 year EFS
Hanamura I et al. Blood, 1 September 2006, Vol. 108, No. 5, pp. 1724-1732.
1Q21 AMPLIFICATION IN RELAPSED MYELOMA PREDICTS
POORER RESPONSE TO SINGLE-AGENT BORTEZOMIB
In a Viennese study of 1q21 amplification in relapsed MM treated with
single-agent bortezomib:
·
44% of cases had 1q21 amplification
qp
by i-FISH
·
Responses were lower (30% vs 58%)
·
Survival was shorter if 1q21 was amplified
Drach J et al. Blood. 2006, November 16; 108 (11): Abstract #3398
BORTEZOMIB-BASED COMBINATION THERAPY MAY
OVERCOME ADVERSE EFFECTS OF 1q21
In 28 relapsed myeloma cases treated with bortezomib-based combination
therapies:
·
39% of cases showed 1q21 amplification
·
Responses were similar (55% vs 65%) and
·
Survival was no different, if 1q21 were amplified
* Median survival >20m (NR)
Sagaster V et al. Haematologica 2007; 92[suppl.2]:149. Abstract 0405
STUDY OBJECTIVES
Primary objective:
·
Compare the
the ORR*
ORR following PAD
PA
induction
induction therapy between
patients with and without amplification of 1q21 in their marrow at
baseline
Secondary Objectives:
·
Compare the ORR to PAD induction 3 months post-ASCT; EFS and
OS at 2 years;
years;
·
Data presented is a preliminary analysis of evaluable patients to
dt
date
6
* ORR= Overall Response Rate by IMWG criteria
METHODS
·
Multi-centre, Phase II trial in 108 newly-diagnosed transplant-
eligible myeloma patients
·
Patients were categorised according to their 1q21 status (as
determined by FISH) at baseline
·
Patients were prescribed four 21-day cycles of PAD:
­ bortezomib 1.3mg/m2 on Days (D) 1,4,8 and 11
­ doxorubicin 20mg/m2 on D1 and 4, and
­ dexamethasone 20mg on D1,2,4,5,8,9,11 and 12)
·
Responding patients could proceed to stem cell harvest, high-dose
melphalan (200mg/m2) and autologous stem cell transplantation
according to institutional protocols.
7
RESULTS
· 108 patients recruited, of which 104 are included in this
report
· The proportions
pp
of patients
p
who were evaluable for
1q21 status and who completed PAD induction or
discontinued during this phase are shown in the patient
flow
· 97/104 (93%)
() evaluable for 1q21
q
amplification:
p
27
(28%) showed 1q21 amplification, 70 (72%) lacked
1q21 amplification
8
PATIENT FLOW
Enrolled
n=108
FISH not tested / unavailable
n=4
1q21
q
FISH tested
n=104
Test failed
n=7
1q21 NOT amplified
1q21 Amplified
n=70 (72%)
n=27 (28%)
Discontinued due to
Discontinued due to
AE
AE
n=3
n=6
Completed PAD
Completed PAD
(1 death)
induction
(1 death)
induction
n=66
n=23
Efficacy results
Efficacy results
currently available
currently available
n=48
n=15
9
PATIENT DEMOGRAPHICS AND
BASELINE CHARACTERISTICS
1q21 NOT amplified
1q21 Amplified
Characteristic
(n=66)
(n=23)
Age (years SD)
58.2 9.9
58.2 7.5
Sex n(%)
Male
42 (64%)
15 (65%)
Female
24 (36%)
8 (35%)
ISS stage at diagnosis n(%)
Stage 1
33 (50%)
5 (22%)
Stage 2
22 (33%)
13 (57%)
Stage 3
10 (15%)
4 (17%)
Unknown
1 (2%)
1 (4%)
Demograp
gphic data is shown for those patients for whom FISH is available and who completed PAD induction
10
RESULTS - EFFICACY
· Efficacy results are reported for the first 63 patients
who hav
a e co
c m
o pl
p et
e ed
ed PAD induction and have FISH
results available:
­ 15 / 15 (100%) of patients with 1q21 amplification responded
to PAD induction
­ 44 / 48 (92%) of patients who lacked 1q21 amplification
responded to PAD induction
· At present there is
is no
no indication
indication of deeper responses in
patients with or without 1q21 amplification.
11
RESPONSE BY 1q21 STATUS
92%
100%
(44/48)
(15/15)
100%
80%
(%)
n=22
e
n22
e
n=10
60%
PR
Rat
VGPR
onse
sCR/CR
p
40%
n=13
Res
n=2
20%
n=9
n=3
0%
1q21 NOT Amplified (n=48)
1q21 Amplified (n=15)
12
SAFETY
·
34 (31.5%) patients experienced 78 severe adverse events. Most common
were constipation (6
(6 events)
events), peripheral neuropathy (5 events), neutropenia
(3 events), and back pain (3 events).
·2 (1.9%)
9%) patients
ts died during PAD therapy (one patient due to cardiac
ac
amyloidosis, cardiac failure congestive, oedema, pneumonia, renal failure
and ventricular arrhythmia and the other due to cardiac arrest and
pulmonary embolus)
·
In addition, 7 (6.5%) patients permanently discontinued PAD therapy due to
adverse events (acute febrile neutrophilic dermatosis (n=1); cardiac failure
(n=1); hypertension (n=1);
(n=1); peripheral neuropathy (n=2); orthostatic
hypotension (n=1); and peripheral sensory neuropathy (n=1))
13
ADVERSE EVENTS
MedDRA Preferred
No events
Grade 1Grade 2Grade 3Grade 4
Ter
Te m
Anaemia
14
4
8
2
0
22
Neutropenia
13
4
3
2
Thrombocytopenia
4
0
1
2
1
Peripheral Neuropathy*
43
30
8
5
0
Peripheral Neuropathy**
17
13
3
10
(sensory)
* There were 43 adverse events of peripheral neuropathy in 33 / 108 patients.
** There were 17 adverse events of sensory peripheral neuropathy in 15 / 108 patients.
14
CONCLUSIONS
·
This analysis shows there is no evidence that 1q21 amplification is
associated with lower response
response to
to 4 cycles of PAD
PA
induction
induction
therapy for patients with newly-diagnosed myeloma
·
Further follow-
follow up of patients in
in this
this trial
trial is ongoing to determine if
patients with 1q21 amplification have shorter progression-free
survival after PAD induction
·
In this study, 4 cycles of PAD induction therapy were delivered with
high efficacy and acceptable safely to newly-diagnosed myeloma
patients
15