final results from a phase iii randomized study comparing dvd with vad in first-line multiple...

Rifkin et al. DVd vs VAd

Final Results: Multicenter Trial of DVd vs VAd in Newly

Diagnosed Multiple Myeloma

Robert M. Rifkin, MDRocky Mountain Cancer Centers,

US Oncology, Denver, CO

On behalf of the C2000-003 Study Group

2Rifkin 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


Replacing Conventional Doxorubicin with DOXIL

Changing VAd to DVdDOXIL

(Pegylated liposomal doxorubicin)• Longer half-life (>55 hours)

- Once monthly dosing that mimics continuous infusion

• Improves safety- Less neutropenia- Less alopecia- Lower risk of cardiac toxicity

Conventional doxorubicin

Liposome

Polyethylene glycol


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.


Study Design and Treatments

Phase III, multicenter, randomized study

DVdD: DOXIL 40 mg/m2

V: vincristine 1.4 mg/m2

d: dexamethasone PO 40 mg Days 1-4

dddDVd

Day 1 Day 4 …Day 5-28Day 2 Day 3

(Vincristine infusion)(Adriamycin infusion)

d d ddVAdA: Adriamycin

9 mg/m2/d (96-h infusion)

V: vincristine 0.4 mg/d(96-h infusion)

d: dexamethasone PO 40 mg Days 1-4

Day 1 Day 4 …Day 5-28Day 2 Day 3


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


Demographics

Parameter DVd (n = 97) VAd (n = 95)

Gender, m/f 57/40 58/37Mean age, y (range) 60 (37-84) 60 (44-81)KPS, n (%)≤6070-8090-100

9 (9.3)35 (36.1)53 (54.6)

8 (8.4)36 (37.9)51 (53.7)

Prior radiation therapy, n (%) 21 (21.6) 15 (15.8)Lytic lesions, n (%)

0-3>3

54 (55.7)41 (42.3)

47 (49.5)47 (49.5)

% plasma cells in BM, mean (SD)

40.0 (26.0) 41.7 (24.5)


Response Rates

ResponseDVd

(n = 97)VAd

(n = 95) P-value*Overall response 43 (44.3%) 39 (41.0%)

Progression 2 (2.1%) 0 (0)Not evaluable 14 (14.4%) 10 (10.5%)

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%)

.66

* Two-sided Fisher’s exact test.

• Patients proceeding to transplant: 35% DVd and 37% VAd


Clinical Benefit

Incidence DVd

(n = 97)VAd

(n = 95) P-value*Neutropenia (grade 3/4), % 10.3 24.2 .01

.21

.45

1.00

<.001

Documented sepsis, % 3.1 7.4

Antibiotic treatment, % 62.9 68.4

Hospitalization due to AE, % 36.1 35.8

Mean days in hospital due to AE

7.3 9.1

* Two-sided Fisher’s exact test.


Progression-free Survival

Progression-free survival (days)

Surv

ival

pro

babi

lity

DVdVAd

Log-rankP = .83

Progression-free survival (%)1 y 2 y

DVd 70.1% 39.9%VAd 66.8% 33.6%



Overall Survival

Survival time (days)

DVdVAd

Log-rankP = .71

Overall survival (%)1 y 2 y

DVd 88.9% 85.2%VAd 84.5% 79.9%Su

rviv

al p

roba

bilit

y



Adverse Events: All Grades

DVd(n = 97)

VAd(n = 95) P-value

Injection-site reaction 3% 12%44%

Hand-foot syndrome 25% 1% <.001Asthenia 55% 47% NS

Fever 26% 30% NS44%

44%Neutropenia 18% 28% NSNausea 50% 44% NSStomatitis 29% 21% NS

Alopecia 20%.027

<.001

NSAnemia 35%

NSConstipation 44%


Adverse Events: Grades 3/4

DVd(n = 97)

VAd(n = 95) P-value

Neutropenia 10% 24%Anemia 12% 12% NS

Hand-foot syndrome 4% 0% NS

Stomatitis 1% 2% NS

Asthenia 7% 4% NS7%

3%Pain 5% 11% NSPneumonia 6% 6% NS

Syncope 3% 4% NS

Deep thrombophlebitis 4%

.01

NS

Nausea 7% NS


Adverse Events: Cardiac

DVd (n = 97) VAd (n = 95)

Grade 3/4 Grade 3/4Congestive heart failure 0%

0%2%

Cardiomyopathy 1%

-2.3

-4.5

-7

-6

-5

-4

-3

-2

-1

0DVd VAd

Meanabsolute∆ in LVEFfrombaseline

P <.01

-3.4

-6.3-7

-6

-5

-4

-3

-2

-1

0DVd VAd

% ∆ inLVEF


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


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


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


Planned DOXIL Myeloma Trials

• First-line trial:Thal + Dex

DOXIL + Thal + Dex

DOXIL + Vincristine + Thal + Dex • Relapsed/refractory trial:

Bortezomib

DOXIL + Bortezomib

vs

vs

vs


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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