Final Results: Multicenter Trial
of DVd vs VAd in Newly
Diagnosed Multiple Myeloma
Robert M. Rifkin, MD
Rocky Mountain Cancer Centers,
US Oncology, Denver, CO
On behalf of the C2000-003 Study Group
Rifkin et al. DVd vs VAd
Study Rationale
·
VAD widely used as first-line therapy:
-
Rapid response; 50%-80% response rate
-
Efficacious cytoreductive therapy prior to stem
cell transplantation
·
Decreased popularity due to:
-
Inconvenience of 96-h doxorubicin/vincristine
continuous infusion
-
Toxicity: neutropenia, cardiac, alopecia
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Rifkin et al. DVd vs VAd
Replacing Conventional
Doxorubicin with DOXIL
Changing VAd to DVd
DOXIL
(Pegylated liposomal doxorubicin)
· Longer half-life (>55 hours)
Polyethylene
- Once monthly dosing that
glycol
mimics continuous infusion
· Improves safety
- Less neutropenia
- Less alopecia
Liposome
- Lower risk of cardiac toxicity
Conventional
doxorubicin
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Rifkin et al. DVd vs VAd
Study Rationale
· Phase II Study of DVd (N = 33)*
- Lower dexamethasone dose
- Response rate
· 88% (12% CR, 76% PR)
· Median TTP, 23.1 months
· 3-year survival: 67%
- Safety
· Hand-foot syndrome: Grade 3/4 (18% / 3%)
· Neutropenia: Grade 3/4 (21% / 9%)
· Mucositis: Grade 3 (12%)
* Hussein M, et al. Cancer. 2002.
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Rifkin et al. DVd vs VAd
Study Design and Treatments
Phase III, multicenter, randomized study
DVd
DVd
d
d
d
D: DOXIL 40 mg/m2
V: vincristine 1.4 mg/m2
d: dexamethasone
PO 40 mg Days 1-4
Day 1
Day 2
Day 3
Day 4
...Day 5-28
VAd
d
dd
d
A: Adriamycin
9 mg/m2/d (96-h infusion)
(Vincristine infusion)
V: vincristine 0.4 mg/d
(Adriamycin infusion)
(96-h infusion)
d: dexamethasone PO
Day 1
Day 2
Day 3
Day 4
...Day 5-28
40 mg Days 1-4
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Rifkin et al. DVd vs VAd
Study Objectives
· Primary endpoints
- Objective response rate (modified SWOG)
- Clinical benefit (incidence of):
· Hospitalization due to AE
· Documented sepsis
· Antibiotic use
· Grade 3/4 neutropenia
- Statistically powered for equivalence
· Secondary endpoints:
- Progression-free and overall survival
- Safety and tolerability
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Rifkin et al. DVd vs VAd
Demographics
Parameter
DVd (n = 97)
VAd (n = 95)
Gender, m/f
57/40
58/37
Mean age, y (range)
60 (37-84)
60 (44-81)
KPS, n (%)
60
9 (9.3)
8 (8.4)
70-80
35 (36.1)
36 (37.9)
90-100
53 (54.6)
51 (53.7)
Prior radiation therapy, n (%)
21 (21.6)
15 (15.8)
Lytic lesions, n (%)
0-3
54 (55.7)
47 (49.5)
>3
41 (42.3)
47 (49.5)
% plasma cells in BM,
40.0 (26.0)
41.7 (24.5)
mean (SD)
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Rifkin et al. DVd vs VAd
Response Rates
DVd
VAd
Response
(n = 97)
(n = 95)
P-value*
Overall response
43 (44.3%)
39 (41.0%)
.66
CR
3 (3.1%)
0 (0)
Remission
15 (15.5%)
15 (15.8%)
PR
25 (25.8%)
24 (25.3%)
Stable disease
38 (39.2%)
46 (48.4%)
Progression
2 (2.1%)
0 (0)
Not evaluable
14 (14.4%)
10 (10.5%)
* Two-sided Fisher's exact test.
· Patients proceeding to transplant: 35% DVd and 37% VAd
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Rifkin et al. DVd vs VAd
Clinical Benefit
DVd
VAd
Incidence
(n = 97)
(n = 95)
P-value*
Neutropenia (grade 3/4), %
10.3
24.2
.01
Documented sepsis, %
3.1
7.4
.21
Antibiotic treatment, %
62.9
68.4
.45
Hospitalization due to AE, %
36.1
35.8
1.00
Mean days in hospital due
7.3
9.1
<.001
to AE
* Two-sided Fisher's exact test.
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Rifkin et al. DVd vs VAd
Progression-free Survival
DVd
VAd
probability
Log-rank
P = .83
Survival
Progression-free survival (%)
1 y
2 y
DVd
70.1%
39.9%
VAd
66.8%
33.6%
Progression-free survival (days)
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Rifkin et al. DVd vs VAd
Overall Survival
DVd
VAd
probability
Log-rank
Overall survival (%)
P = .71
1 y
2 y
DVd
88.9%
85.2%
Survival
VAd
84.5%
79.9%
Survival time (days)
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Rifkin et al. DVd vs VAd
Adverse Events: All Grades
DVd
VAd
(n = 97)
(n = 95)
P-value
Injection-site reaction
3%
12%
.027
Alopecia
20%
44%
<.001
Hand-foot syndrome
25%
1%
<.001
Asthenia
55%
47%
NS
Anemia
35%
44%
NS
Fever
26%
30%
NS
Constipation
44%
44%
NS
Neutropenia
18%
28%
NS
Nausea
50%
44%
NS
Stomatitis
29%
21%
NS
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Rifkin et al. DVd vs VAd
Adverse Events: Grades 3/4
DVd
VAd
(n = 97)
(n = 95)
P-value
Neutropenia
10%
24%
.01
Anemia
12%
12%
NS
Asthenia
7%
4%
NS
Deep thrombophlebitis
4%
7%
NS
Hand-foot syndrome
4%
0%
NS
Nausea
7%
3%
NS
Pain
5%
11%
NS
Pneumonia
6%
6%
NS
Stomatitis
1%
2%
NS
Syncope
3%
4%
NS
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Rifkin et al. DVd vs VAd
Adverse Events: Cardiac
DVd (n = 97)
VAd (n = 95)
Grade 3/4
Grade 3/4
Congestive heart failure
0%
2%
Cardiomyopathy
0%
1%
DVd
VAd
DVd
VAd
0
0
-1
-1
-2
-2
Mean
% in
-2.3
-3
absolute
-3
LVEF
in LVEF -4
-3.4
-4
from
-5
-4.5
-5
baseline
-6
P <.01
-6
-6.3
-7
-7
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Rifkin et al. DVd vs VAd
Drug Administration
· Significant advantages of DVd vs VAd
- Fewer cycles administered in hospital setting:
3.6% vs 31.7% of cycles (P <.001)
- Fewer study drug administration days required:
1.3 vs 5.2 days per cycle (P <.001)
- Fewer cycles administered via a central line:
45% vs 96% (P <.0001)
- Fewer patients required growth factor support:
46% vs 61% (P <.03)
P-values: Wilcoxon 2-Sample test
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Rifkin et al. DVd vs VAd
Conclusions
· DVd and VAd have comparable efficacy
· Safety profile:
- Advantages with DVd
· Less neutropenia
· Less need for growth factor support
· Less alopecia
· Less decrease in LVEF
· No congestive heart failure or cardiomyopathy
· Fewer days in hospital due to AE
- Disadvantages with DVd
· More hand-foot syndrome
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Rifkin et al. DVd vs VAd
Conclusions
· Patient convenience
- DVd is an outpatient regimen requiring:
· Fewer hospital days for drug administration
· Fewer overall days for drug administration
- Administration advantages with DVd:
· Fewer patients require central line
· 1-hour infusion vs 96-hour infusion
· Fewer injection-site reactions
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Rifkin et al. DVd vs VAd
Planned DOXIL Myeloma Trials
· First-line trial:
Thal + Dex
vs
DOXIL + Thal + Dex
vs
DOXIL + Vincristine + Thal + Dex
· Relapsed/refractory trial:
Bortezomib
vs
DOXIL + Bortezomib
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Rifkin et al. DVd vs VAd
Acknowledgments
We gratefully acknowledge the patients and families who
made this study possible.
Participating investigators: M. Hussein, S. Gregory, A.
Mohrbacher, A. Briggs, H. Burris, C. DeCastro, M. Gautier,
J. Gurtler, Y-H. Chen, L. Heffner, J. Wall, K. Stewart, J.
Ganey, D. Vafai, J. Hajdenberg, B. Mason, T. Pluard, R.
Smith, D. Gravenor, J. Gandhi, J. Kirshner, F. Yunus
Study Sponsors: Tibotec Therapeutics and ALZA
Corporation and in particular: Pam Jacobs, Chinglin Lai,
Colin Lowery, and Mark Wildgust
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Rifkin et al. DVd vs VAd

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