A Phase II Study of a Modified Pegylated Liposomal Doxorubicin (PLD), Bortezomib and Dexamethasone Regimen for Patients
with Previously Untreated Multiple Myeloma (MM)
James R. Berenson,1, 2, 3
,
Ori Yellin,1
, Chien-Shing Chen,4
g, Ravi Patel,5
, Alberto Bessudo,6
, Ralph V. Boccia,7
p, Hank H. Yang,8
g, Donald Colbourn,9
, Jacqueline Hilg
qger,10
,
Regina A. Swift2
1Oncotherapeutics, Los Angeles, CA, 2James R. Berenson, MD, Inc., Los Angeles, CA, 3Institute for Myeloma and Bone Cancer Research, Los Angeles, CA, 4Loma Linda University Cancer Center, Loma Linda, CA, 5Comprehensive Blood and Cancer Center, Bakersfield, CA,
6Pacific Oncology Hematology Associates, Encinitas, CA, 7Center for Cancer and Blood Disorders, Bethesda, MD, 8Oncology Care Medical Associates, San Gabriel, CA, 9Capitol Hematology Oncology, Roseville, CA, 10Millennium Pharmaceuticals, Inc., Cambridge, MA
INTRODUCTION
STUDY DESIGN
RESULTS
ADVERSE EVENTS
Despite recent advances in the treatment of MM, the disease
This was a phase II, open-label, multicenter study designed to
Table 1: Patient Demographics (n=35)
Table 4: Current Patient Status (n=35)
Grade 3 adverse events included:
remains incurable and many of the most effective, newer
evaluate the efficacy and safety of PLD given in combination with
Median Age (years)
65 (range: 42-82)
Active on the DVD regimen
6
· 2 reversible neutropenia, 2 reversible anemia, 2
combination therapies are accompanied by significant side
bortezomib and intravenous dexamethasone to patients with
Male : Female
23 : 12
Off-Study
29
peripheral neuropathy, 2 pneumonia, 2*
effects that have a major negative impact on the patient's quality
previously untreated multiple myeloma. Patients were able to
hyponatremia, 1 reversible thrombocytopenia, 1*
ISS Stage (at study entry)
Progressive Disease on DVD
4
of life. Pegylated liposomal doxorubicin (PLD) and bortezomib
receive a maximum of eight treatment cycles in this study or were
I8
Completed 8 Cycles or Reached Max
DVT, 1* Elevated ALT, 1* rib pain, 1* abdominal
have shown anti-MM efficacy in the laboratory and for the
22
treated to maximum response plus two cycles.
II
12
Response
pain, 1* atrial fibrillation, 1* gallstones, 1*
treatm
ea ent
e of
o pr
p evi
e ously trea
e t
a ed
ed MM pa
p ti
a ent
e s, leading to FDA
III
15
Adve
Advers
r e
s Eve
Ev nt
ent
1*
tenosynov
tenosy
itis
nov
approval for patients who have failed one prior therapy. Using
15
Death
1
our severe combined immunodeficiency-hu murine models of
Serum M-protein (g/dl)
Inclusion criteria
PI Decision (Non-compliance)
1
Grade 4 adverse events included:
human MM, we have previously demonstrated that lower doses
Median
3.23
· Male or female patients 18 years of age
*1 patient had worsening SOB due to known interstitial fibrosis and
· 1* shortness of breath
of PLD administered daily are more effective and better tolerated
Range
0.00 - 7.70
· Symptomatic, previously untreated MM with measurable
was removed due to eventual PI decision
than higher amounts given weekly. Moreover, the combination of
Urine M-protein (mg/24h)
*Judged to be not related to study medication
disease
bortezomib and dexamethasone has been shown to be effective
Median
109
Table 5: Survival of Patients (n=35)
· Karnofsky performance status >60
for previ
prev ously
iously untreated MM patients
patients. Prior
Prior studies by our group
Rang
R
e
ang
0 ­ 25,296
Peripheral neuropath
pp
y (31%):
Progressive
Progressiv Di
D sease On or Off
Of Study
Study (n)
(n)
7
group
· Life-expectancy
ex
>3
>3 months
months
have shown that combining chemotherapy including PLD with
Serum Creatinine (mg/dL)
· Grade 1 (n=6, 17%)
Completed Cycles (n)
bortezomib administered at 1.0 mg/m
· Grade 2 (n=3, 9%)
2 on days 1, 4, 8, and 11 of
Median
1.1
Median
7
Exclusion criteria
a 28-day cycle rather than the standard 1.3 mg/m
· Grade 3 (n=2, 6%)
2 on the same
Range
0.6 - 2.3
· POEMS syndrome
Range
1-8
days of a 21-day schedule is effective for MM patients with
· Plasma cell leukemia
Follow-up (mo) (n=35)
relapsed or refractory disease and associated with a reduction in
Table 2: Patient Responses (n=35)
Others:
· Patients with a prior malignancy within the last 5 years (except
Median
10
the incidence and severity of peripheral neuropathy.
Complete Response (CR)
· One (3%) case of grade 1 hand-foot syndrome
for basal or squamous cell carcinoma, or in situ cancer of the
7* (20%)
Range
1-21+
(n
(no serum
serum M pr
- otei
pr
n)
otei
· No case of stomatitis reported
cervix)
Very Good Partial Responses (VGPR)
· Impaired cardiac function or clinically significant cardiac
Figure 1: Time to Progression (n=35)
OBJECTIVES
2 (6%)
(> 90% decrease in serum M-protein)
disease
100
SUMMARY
Partial Response (PR)
· Screening echocardiogram or MUGA evidence of LVEF below
90
16 (46%)
ssion
80
The primary objective of this study was to:
(50-74% decrease in serum M-protein)
re
70
This Phase II study evaluated the combination of low
institutional normal
· Determine the response rate [combined complete response
Minor Response (MR)
· Active infection, known HIV infection, or known active hepatitis
rog
60
dose PLD with low dose bortezomib and
P
(CR) + very good partial response (VGPR) + partial response
5 (14%)
50
(25-49% decrease in serum M-protein)
B or
or C viral
viral infection
/o
infection
w
40
intravenous dexamethasone for pat
p ients with
(PR) + minimal response (MR)] of the combination of PLD,
t
Objective Response (CR+VGPR+PR+MR)
30 (86%)
· Female subject is pregnant or breast-feeding
30
previously untreated MM.
bortezomib and dexamethasone (DVD) for patients with
20
rcen
Stable Disease (SD)
· Grade 2 peripheral neuropathy
10
Pe
previously untreated MM.
3 (9%)
· Patients who have undergone major surgery
(change in M-protein + 25%)
00
2
4
6
8
10
12
14
16
18
20
· High response rate (86%)
· Severe hypercalcemia
Disease Control (CR+VGPR+PR+MR+SD)
33 (94%)
Time (mo)
· 26% CR + VGPR
The secondary objectives of this study were to:
Progressive Disease (PD)
· Durable responses
· Assess the safety and tolerability of the DVD regimen for
2 (6%)
Figure 2: Overall Survival (n=35)
(>25% increase in M-protein)
· Only 7 patients with progressive MM to date
patients with
with previ
prev ously
iously untreated MM.
90
a
· Very well tolerated
· Determine the time to response, duration of response, time to
TREATMENT
TREA
SCHEMA
*4 CRs were IF 3 CRs were IF+ and 1 was confirmed by bone
100
Vll t l
t
SCHEMA
*4 CRs were IF-, 3 CRs were IF+, and 1 was confirmed by bone
marrow biopsy.
b c
80
· 22 (63%) patients completed 8 cycles or
progression of disease, progression-free survival, and overall
DVD was administered in the following order:
70
reached max response
survival of the DVD regimen for patients with previously
urvival
60
1. Dexamethasone 40 mg IV
Table 3: Duration of Response (mo) (n=30)
S
50
· Median number cycles was 7
untreated MM.
2. Bortezomib 1.0 mg/m2 IV push
Median
Not reached
40
rcent
· Only 31% of patients experienced any grade of
3. PLD 5.0 mg/m2 IV
Range
1-15+
e
30
P
20
peripheral neuropathy (6% grade 3)
10
· Only one cas
ca e
se of hand-
hand foot syndrome
y
All three drugs were administered on days 1, 4, 8, and 11 of a
0 0
5
10
15
20
25
30
35
· AEs related to and possibly related to study
28-day cycle.
Time (mo)
medications were predictable and reversible
a. Patient died due to unknown cause
b. & c. Patients died due to progressive MM
Author Disclosures: James R. Berenson, MD is a speaker for, consultant for, and receives research funding from Millennium Pharmaceuticals and Centocor Ortho Biotech
Abstract 8134
Funding provided by Millennium Pharmaceuticals and Centocor Ortho Biotech
Presented at the 2010 American Society of Clinical Oncology Annual Meeting, June 4- 8, 2010, Chicago, IL

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