Lenalidomide, Bortezomib, Pegylated Liposomal
Doxorubicin and
and Dexameth
hasone in Newly Diagnosed
Diagnosed
Myeloma: Updated Results of Phase I/II MMRC Trial
AJ J k b
i k1 DR
2
AJ. Jakubowiak1, D. Reece , CC H f
i t 3 SL
il4
, CC. Hofmeister3 , S. Lonial ,
T. Zimmerman5, E. Campagnaro1, R. Schlossman6, J. Laubach6,
NS. Raje7, T. Anderson1, K. Griffith1, M. Hill1, C. Harvey1, A. Dollard6,
S Wear8 TBock9 C Tendler1
S. Wear , T. Bock , C. Tendler 0 D-L Esseltine11 SL Kelley8
, D-L. Esseltine , SL. Kelley ,
M. Kaminski1, KC. Anderson6, and PG. Richardson6
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 2Princess Margaret Hospital,
Toronto, ON 3
ON, Ohio State University, Columbus, OH
H 4
H, Winship Cancer
Cancer Institute, Atlanta, GA 5
GA, University
of Chicago Medical Center, Chicago, IL, 6Dana-Farber Cancer Institute, Boston, MA, 7Massechusettts
General Hospital, Boston, MA, 8Multiple Myeloma Research Consortium, Norwalk, CT, 9Celgene, Inc,
Summit, NJ, 10Centocor Ortho Biotech, Bridgewater, NJ, 11Millennium Pharmaceuticals, The Takeda
Oncology Company, Cambridge. MA
RATIO
ONALE
·
Recent studies suggest that the achievement of superior response to
initial treatment, particularl
,p
y the achievement of at least VGPR, is
associated with superior outcome in multiple myeloma1,2,3
·
RVD regimen of Lenalidomide (Revlimid®), Bortezomib (Velcade®), and
Dexamethasone and VDD regimen (Velcade, Doxil®, Dexamethasone)
are very active in f
tli
ron ne MM
MM i
w th
ith PR or b t
e t
tter f
o 100%
i
us ng RVD
RVD
d
an
high VGPR and CR/nCR rates3,4
·
We hypothesized that combining 4 drugs from the RVD and VDD into
one RVDD regimen may
may further imp
imp
prove VGPR
VGPR and
and CR/nCR rates
rates
·
Pre-clinical studies show superior activity of RVDD compared to 2- and
3-drug combinations of drugs used in RVDD5
·
Here we present efficacy
efficacy and toxici
toxiciity data
data of
of both phase I and
and II
portions of the RVDD regimen in newly diagnosed MM
1. Harousseau et al. ASH 2008, ASH/ASCO Joint Symposium
2. Cavo
Cavo et al. ASH 2008, Abstract #158
3. Jakubowiak et al. J Clin Oncol, 2009 Oct 20;27(30):5015-22. Epub 2009 Sep 8.
4. Richardson, et al. ASH 2008, Abstract #92
5. Jakubowiak et al. IMW, Washington, DC 2009
OBJEC
CTIVES
Primary
· Determine the MTD of the RVDD combination
· Determine the rate of VGPR (>90%disease reduction)
Secondary
· Determine the overall response rate PR
· Evaluate TTP, DOR, PFS, and OS
· E
l
va
t
ua e th
the t l
o
b
era ilit
bility a dt
nd t
i
ox i
c t
ity
· For patients proceeding to autotransplant, evaluate
the impact
impact of RVDD on sstem cell mobilization
mobilization and
and
harvest
· Evaluate prognostic markers and markers of
di
pre
ti
c on f
o response
ELIGIBILITY
Key inclusion criteria:
· Transplant and non-transplant patients with newly diagnosed
MM requiring first line therapy
therapyy1
y
· Measurable disease as per IMWG Criteria1
· Karnofsky/ECOG
y
performance status >60/0-2
· EF > 50%
Key exclusion criteria:
· Grade > 2 peripheral neuropathy
· ANC < 1.0, Hgb < 8.0 g/dl, platelets < 50,000 (or unable to
maintain platelets > 50,
p,000 with platelet transfusions)
p)
· Creatinine > 2.5
· Serious co-morbidities
1. Durie et al. Leukemia 2006;20;1467-73.
Treatment Schema
Initial Treatment: Dose escalation of Len and PLD: up to eight 21-day cycles
14
8
11
14
21
Bz
Bz
Bz
Bz
Dex
Dex Dex
Dex
De
Dex
Dex
x Dex
PLD
Len
Maintenance: 21-day cycles up to progression or toxicity
14
8
11
14
21
Bz
Bz
Dex D
Dex Dex
Dex
Len
·
Dex
Dex, 20
20 mg/day
mg/day days
days 1245891
1, 2, 4, 5, 8, 9, 1
11, and
and 112; 10 mg, cycles 5
5 8, and
and maintenance
·
Pts PR may proceed to ASCT after 4 cycles
·
Maintenance therapy permitted in pts SD after completion of 8 cycles
·
DVT prophylaxis required with Lovenox or ASA
Phase I Do
Do
ose Levels
Levels
Dose level
Len
Bortezomib
Dex*
PLD
1
15 mg/day
1.3 mg/m2
20 mg
20 mg/m2
2
20 mg/day
13
1.3 m / 2
20
20
/ 2
mg/m2
20 mg
20 mg/m
3
25 mg/day
1.3 m
mg/m2
20 mg
20 mg/m2
mg/m
20 mg
20 mg/m
4
25 mg/day
1.3 mg/m2
20 mg
30 mg/m2
* 20 mg Dex, cycles 14, and 10 mg Dex, cycles 58 and maintenance
Updated Enrollmen
Enrollmen
nt to Phase I and
and II
· Phase I and II enrollment are complete (N=72)*
TITE-CRM Design
Phase I Enrollment
N=40*
·
Continued enrollment
·
MTD: DLT <20%
Dose level 1
4
Dose level 2
10
Dose level 3
20
Lenalidomide 25 mg
Dose level 4
6
Bortezomib 1.3 mg/m2
Dexamethasone 20 mg
Phase II E
l
nro lllment
N38**
PLD 30
/
mg
2
N=38**
m
*Two patients were not evaluable for DLT per protocol and were replaced
**Including 6 patients
patients treated
treated at Level 4 (MTD)
(MTD)
Assessments
· Toxicities were
were graded b
by NCI CTCAE v3.0
· Responses assessed by EBMT1 criteria and IMWG
Uniform Criteria
Criteria (UC)2
(UC) (m
modified to include nCR;
CR but immunofixation-positive for M-protein)
· Response assessments for evaluable pts were
confirmed by 2 assessments
1. Bladé et al. Br J Haematol 1998;102:1115-23.
2. Durie et al. Leukemia 2006;20;1467-73.
Patient Character
Characterristics (Phase I/II)
Characteristic
N=72
Median age, years (range)
(range)
60 (29-77)
Male, n (%)
41 (56.9)
Myeloma type
type, n (%)
IgG
51 (70.8)
IgA
12 (16.7)
light chain
5 (7.0)
light chain
4 (5.6)
ISS stage
stage II/III, n (%)
(%)
38 (52 7
. )
7)
Durie-Salmon stage II/III, n (%)
60 (83.3)
13q del or
or t(4;14) or t(14;16) or 17p
33 (45 8
. )
8)
KPS 80%, n(%)
36 (50.0)
Treatment to D
Date Phase I/II
· Median treatment duratio
on: 4 cycles (range 1-20)
Completed 4 cycles
66 (92%)
Completed 8 cycles
py
12 (17%)
()
Remain on treatment
24 (37%)*
· Discontinued/completed treatment
Proceeded to autotransplant
39 (54%)
Pt choice (prior to completion)
1 (1%)
Progressive disease
1 (1%)
Toxicities
0 (0%)
*3 pts have yet to complete 4 cycles and 18 pts have yet to complete 8 cycles
Toxicities ((Phase I/II)
Fatigue
Constipation
Se nsory Ne uropathy
Thrombocytope nia
*
Nause a/D
/ iarrhe a
Grade 3/4
Pne umonia/Infe ctions
Grade 1/2
PPE
Ne utrope nia
*
Cardiovascular
Painful Ne uropathy
DVT/PE
010
20
30
40
50
60
70
80
90
100
Pe rcentage of Patie nts
*No significant decline of ANC or platelets in consecutive cycles
Best Response to
to RVDD
RVDD Phase
Phase I/II
Response
All Pts
MTD Population
(n=70)*
(n=36)*
CR + nCR
33%
28%
VGPR
59%
56%
PR
97%
97%
*2 of 72 patients have yet to complete 2 cycles and are not included in analysis
Response to
to RV
RV
VDD by
by Subsets
Subsets
4
Cytogenetic
Response
cycles
abnormalities
(n=
(n 688)*
8)
(n=
(n 31)**
31)
CR + nCR
32%
35%
VGPR
57%
68%
PR
9%
97%
9%
97%
*Includes 2 pts who discontinued treatment earlier on intent to treat
**Includes pts with del 13q or t(4;14) or t(14;16) or 17p
Time to Event and
and
d Transplantation
Transplantation
· After median follow-up of 8.0 months
· Median TTP, PFS, and OS have not yet been reached
· Stem cell harvest was performed after completion of
median 4 cycles of RVDD therapy (range 3-8)
· 35/35 evaluable patients
patients had
had successful harvesting of
of peripheral
peripheral
blood stem cells.
· Median 7.10 x 106 CD34+ cells/kg
· 34 patients completed at
at lea
leaast single stem
stem cell
transplant
· No unexpected toxicities
RVDD Induction followed by ASCT*
Induction
Pt
Post-Tl
Transpl
t
an
100
100
86% >VGPR
80
65% VGPR
>
80
13%
60
60
23%
40
40
73%
20
42%
20
0
0
RVDD
RVDD
VGPR
CR/nCR
VGPR
CR/nCR
*Actual transplant patients (N=26)
(N=26)
Conclusions
· RVDD is active and is well-tolerated in newly
diagnosed MM
· PR 97%, > VGPR 59% in all pts after a median of 4
cycles of treatment in Phase I/II
· MTD established at Len 25 mg, Bz 1.3 mg/m2, Dex
20 mg, PLD 30 mg/m2
20 mg, PLD 30 mg/m
· Toxicities are manageable
· Stem cell mobilization has been
f
success ul in all
pts to date
· Pt
Post ASCT
ASCT improved VGPR
R 86%, CR/nCR 73%
Acknowledgements
· All of the Patients who have participated
pp
in this
study
· All of the Investigators,
g, Nursing Staff and Research
Support Staff
· The Multiple My
pyeloma Research Consortium, under
whom this multi-site trial is conducted
· The Research Tea
eams at C
Ceelge
gene Co
C rpo
op rat
oation
o ,
Centocor OrthoBiotech, and Millennium
Pharmaceuticals