This document summarizes the results of a phase 3 clinical trial comparing the efficacy and safety of DVd (pegylated liposomal doxorubicin, vincristine, dexamethasone) versus VAd (doxorubicin, vincristine, dexamethasone) as first-line therapy for multiple myeloma. The trial found that DVd and VAd had comparable response rates, progression-free survival and overall survival. DVd had advantages of less neutropenia, alopecia, cardiac toxicity and fewer hospital visits, while having more hand-foot syndrome. DVd also had benefits of more convenient outpatient administration.

1. 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

2. 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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3. 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 3
Rifkin et al. DVd vs VAd

4. 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. 4
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5. Study Design and Treatments
Phase III, multicenter, randomized study
DVd
D: DOXIL 40 mg/m2 DVd d d d
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 d d d
A: Adriamycin
9 mg/m2/d (96-h infusion)
(Vincristine infusion)
V: vincristine 0.4 mg/d
(96-h infusion) (Adriamycin infusion)
d: dexamethasone PO Day 1 Day 2 Day 3 Day 4 …Day 5-28
40 mg Days 1-4
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6. 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 6
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7. 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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8. 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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9. 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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10. Progression-free Survival
DVd
VAd
Survival probability
Log-rank
P = .83
Progression-free survival (%)
1y 2y
DVd 70.1% 39.9%
VAd 66.8% 33.6%
Progression-free survival (days)
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11. Overall Survival
DVd
VAd
Survival probability
Log-rank Overall survival (%)
P = .71 1y 2y
DVd 88.9% 85.2%
VAd 84.5% 79.9%
Survival time (days)
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12. 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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13. 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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14. 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
absolute -3 LVEF -3
∆ in LVEF -4 -4 -3.4
from -4.5
-5 -5
baseline
-6 P <.01 -6
-7 -6.3
-7
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15. 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 15
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16. 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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17. 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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18. 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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19. 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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