Doxil, Vincristine, Reduced
Frequency Dexamethasone and
Revlimid (DVd-R)
A Phase 1/2 Trial in Advanced
Relapsed/Refractory Multiple Myeloma
Patients
Cleveland Clinic Myeloma Research
Program
Cleveland, OH
CCF
DVd Experience
VAD based
Doxorubicin
Liposomal doxorubicin
Doxorubicin 40 mg/m2
IVPB
Vincristine 2.0 mg total IVP
Dexamethasone dose reduction
Dexamethasone 40 mg PO qd X 4 days
q 4 wk x 6 min and best resp + 2
PR%
CR %
New
66
121
61
132
Conclusions
48
33
· Safe and manageable
· Efficacy comparable
· Less use of growth factors
· Less # of days in hospital for complications
· MVD reduction
·CR, NCR rates were low
1. Hussein MA, et al. Cancer. 2002;95:2160-2168.
CCF
2. Dimopoulos MA, et al. Ann Oncol. 2003;14:1039-1044.
3. Rifkin R et al. ASCO 2004.
Mechanism of Action of Immune Modulators
C. Cytokine Effect
MM Cells
IL-6
TNF
B. Effect on
A. Direct Effect
Adhesion
IL-1 Bone Marrow
ICAM-1
Stromal Cells
Bone Marrow
Vessels
VEGF
IL-2
bFGF
NK Cells
IFN
T Cell Co-
D. Anti-Angiogenic Effect
E. Immune Effect
Stimulation
CCF
Raje N, Anderson K. N Engl J Med. 1999;341:1606-1609.
DVd-T Study Design
Doxorubicin 40 mg/m2
IVPB
D1
Vincristine 2.0 mg total
IVP
D1
q 28 x 6 cycles min
Dexamethasone 40 mg
PO
D1-4 days
Thalidomide 50 mg/day start PO
D1-28
Best response + 2
50 mg increment (max 400 mg)
Maintain
Thalidomide
q day at MTD
Prednisone
50 mg qod
Supportive Care
Amoxacillin 250mg BID
Acyclovir 400mg BID
ASA 81 mg qd
Growth Factor for WBC <5000
CCF
Neeraj R.Agrawal, et al Blood 102:237a, 2003
DVd-T Response
Best Response
New (n = 49)
Rel/Ref (n = 50)
CR
9 (25%)
4 (8%)
52%
46%
nCR
14 (29%)
19 (38%)
PR
19 (39%)
17 (34%)
Overall RR
42 (86%)
40 (80%)
Time to First Response
1.1 mo
1.8 mo
Time to Best Response
4.2 mo
4.0 mo
CCF
Neeraj R.Agrawal, et al Blood 102:237a, 2003
Incidence of DVT based on ASA
Use
.01
0.8
tVTE)
1s
to
.60
(time
tion
0.4
funcaliv
Surv
.20
ASA from start
ASA after start
never had ASA
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Years
CCF
Group 1or 2 vs 3 0.0009 ; 0.0025
Group 1&2 vs 3 p=0.0001
Group 1vs 2&3 p=0.01
Revlimid; Rationale
Revlimid is 50 to 2000 times more potent than Thalidomide
In stimulating T-cell proliferation triggered via the T-cell
receptor
In augmenting IL-2 and IFN- production
Better tolerated
Revlimid phase I trial showed responses of at least 25%
reduction in paraprotein in 17 (71%) of 24
DVd-T is effective positively influencing PFS in the
Relapsed/Refractory patients
CCF
DVd-R in Patients with Relapsed/Refractory
Multiple Myeloma
Objectives
Phase 1 trial to define
MTD of Revlimid in combination with DVd-R
Safety of the combination
Phase 2 to define
Efficacy of the combination
CR/NCR
Over all response rate
PFS and OS
CCF
DVd-R; Study Design
Eligibility
1. Relapsed / Refractory with active disease
2. ECOG PS 0-3
3. Informed consent
Response
·
SWOG criteria
CCF
Patient Demographics
Age
59.4 (40-73)
3 = 2 Pts
Stage (SWOG)
4 = 22 Pts
2 microglobulin
5.6 (2.6-9.4)
Response Status
18/24 Refractory
CCF
Treatment regimen
Doxil
40 mg/m2
IVPB
D1
Vincristine 2.0 mg total
IVP
D1
q 28 x 4 cycles min
Dexamethasone 40 mg
PO
D1-4
Revlimid (Phase1) PO daily X 21 days
Best response + 2
Maintain
Revlimid (MTD) q day X21/28 days
Prednisone
50 mg qod
Supportive Care
Amoxacillin 250mg BID
Acyclovir 400mg BID
ASA 81 mg qd
Growth Factor for WBC <5000
CCF
Grade 3/4 Toxicity Therapy Related
Toxicity
Grade 3/4
Neutropenia
11(48%)
Neutropenic Fever
2 (9%)
Neurologic events
3 (14%)
Tumor lysis
2 (9%)
Hyper-Coagulation Events
2 (9%)
CCF
Response Rate
Type of Response
n (%)
Complete remission
3 (13%)
37%
Near complete remission
6 (24%)
Partial remission
10 (45%)
Stable disease > 25%-< 50%
3 (13%)
Stable disease < 25% (non-
2 (5%)
responder/Progressor
CCF
Over All survival
Overall Survival
1
0.9
0.8
0.7
y
0.6
lilitbab
ro 0.5
lPaiv
rv 0.4
uS
0.3
0.2
0.1
0
0
14
28
42
56
70
84
98
112
126
140
154
168
182
196
210
224
238
252
266
280
294
308
Days on Treatment
SURVIVAL
95% LCL
95% UCL
CCF
DVd-R Conclusion
Revlimid at 10mg is the MTD in combination
with the DVd in relapsed/Refractory MM
DVd-R is an extremely effective regimen with
a SWOG response rate >66%
CR+NCR of 37 % in refractory stage 4
patients with minimal toxicity
Incidence of DVT on low dose ASA is as
expected in this patient population
Phase 2 in progress
CCF
THE CLEVELAND CLINIC
FOUNDATION
MMCRP
Myeloma Multidisciplinary
Clinical Research Program
www.clevelandclinic.org/myeloma
Hem/Onc
Mohamad Hussein M.D.
Steven Andresen M.D.
Alan Lichtin M.D.
Ron Soebecks D.O.
Mary Ann Karam R.N.
Janice Reed R.N.
Beth Faiman R.N.
Shannon Brulinski R.N.
Orthopedic Surgery
Isador Lieberman M.D.
Mary Kay Reinhardt, R.N.
Neurology
Robert Shields, Jr. M.D.
Nephrology
William Braun M.D.
Martin Schreiber M.D.
Radiation Oncology
Jay Ciezki M.D.
Neuro-radiology
Thomas Masaryk M.D.
Jean Schils M.D.
Palliative Medicine
Susan LeGrand M.D.
Therapeutic Apheresis
Anna Koo M.D.
Infectious Diseases
Carlos Isada M.D.
Pathology
Eric Hsi M.D.
James Cook M.D.
Endocrinology/
Transplantation Center/
CCF
Metabolic Bone Center
Angelo Licata M.D., PhD
www.clevelandclinic.org/myeloma