Final Results: Multicenter Trial   of DVd vs VAd in Newly Diagnosed Multiple Myeloma         Robert M. Rifkin, MD    Rocky...
Study Rationale•       VAD widely used as first-line therapy:    -     Rapid response; 50%-80% response rate    -     Effi...
Replacing Conventional          Doxorubicin with DOXIL                   Changing VAd to DVd                              ...
Study Rationale  • Phase II Study of DVd (N = 33)*       - Lower dexamethasone dose       - Response rate             • 88...
Study Design and Treatments          Phase III, multicenter, randomized study    DVdD: DOXIL 40 mg/m2             DVd     ...
Study Objectives• Primary endpoints  - Objective response rate (modified SWOG)  - Clinical benefit (incidence of):    •   ...
DemographicsParameter                        DVd (n = 97)   VAd (n = 95)Gender, m/f                         57/40         ...
Response Rates                                      DVd          VAdResponse                            (n = 97)     (n = ...
Clinical Benefit                                       DVd        VAdIncidence                            (n = 97)   (n = ...
Progression-free Survival                                                                      DVd                        ...
Overall Survival                                                           DVd                                            ...
Adverse Events: All Grades                            DVd        VAd                          (n = 97)   (n = 95)   P-valu...
Adverse Events: Grades 3/4                          DVd        VAd                        (n = 97)   (n = 95)   P-valueNeu...
Adverse Events: Cardiac                               DVd (n = 97)    VAd (n = 95)                                Grade 3/...
Drug Administration• Significant advantages of DVd vs VAd      - Fewer cycles administered in hospital setting:        3.6...
Conclusions• DVd and VAd have comparable efficacy• Safety profile:  - Advantages with DVd    •   Less neutropenia    •   L...
Conclusions• Patient convenience  - DVd is an outpatient regimen requiring:    • Fewer hospital days for drug administrati...
Planned DOXIL Myeloma Trials• First-line trial:     Thal + Dex          vs     DOXIL + Thal + Dex          vs     DOXIL + ...
AcknowledgmentsWe gratefully acknowledge the patients and families whomade this study possible.Participating investigators...
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Final results from a phase III randomized study comparing DVd with VAd in first-line multiple myeloma.

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Final results from a phase III randomized study comparing DVd with VAd in first-line multiple myeloma.

  1. 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. 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 2 Rifkin et al. DVd vs VAd
  3. 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. 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 Rifkin et al. DVd vs VAd
  5. 5. Study Design and Treatments Phase III, multicenter, randomized study DVdD: DOXIL 40 mg/m2 DVd d d dV: vincristine 1.4 mg/m2d: dexamethasone PO 40 mg Days 1-4 Day 1 Day 2 Day 3 Day 4 …Day 5-28 VAd d d d dA: 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 5 Rifkin et al. DVd vs VAd
  6. 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 Rifkin et al. DVd vs VAd
  7. 7. DemographicsParameter DVd (n = 97) VAd (n = 95)Gender, m/f 57/40 58/37Mean 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) 7 Rifkin et al. DVd vs VAd
  8. 8. Response Rates DVd VAdResponse (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 8 Rifkin et al. DVd vs VAd
  9. 9. Clinical Benefit DVd VAdIncidence (n = 97) (n = 95) P-value*Neutropenia (grade 3/4), % 10.3 24.2 .01Documented sepsis, % 3.1 7.4 .21Antibiotic treatment, % 62.9 68.4 .45Hospitalization 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. 9 Rifkin et al. DVd vs VAd
  10. 10. Progression-free Survival DVd VAdSurvival probability Log-rank P = .83 Progression-free survival (%) 1y 2y DVd 70.1% 39.9% VAd 66.8% 33.6% Progression-free survival (days) 10 Rifkin et al. DVd vs VAd
  11. 11. Overall Survival DVd VAdSurvival probability Log-rank Overall survival (%) P = .71 1y 2y DVd 88.9% 85.2% VAd 84.5% 79.9% Survival time (days) 11 Rifkin et al. DVd vs VAd
  12. 12. Adverse Events: All Grades DVd VAd (n = 97) (n = 95) P-valueInjection-site reaction 3% 12% .027Alopecia 20% 44% <.001Hand-foot syndrome 25% 1% <.001Asthenia 55% 47% NSAnemia 35% 44% NSFever 26% 30% NSConstipation 44% 44% NSNeutropenia 18% 28% NSNausea 50% 44% NSStomatitis 29% 21% NS 12 Rifkin et al. DVd vs VAd
  13. 13. Adverse Events: Grades 3/4 DVd VAd (n = 97) (n = 95) P-valueNeutropenia 10% 24% .01Anemia 12% 12% NSAsthenia 7% 4% NSDeep thrombophlebitis 4% 7% NSHand-foot syndrome 4% 0% NSNausea 7% 3% NSPain 5% 11% NSPneumonia 6% 6% NSStomatitis 1% 2% NSSyncope 3% 4% NS 13 Rifkin et al. DVd vs VAd
  14. 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 -2Mean % ∆ in -2.3absolute -3 LVEF -3∆ in LVEF -4 -4 -3.4from -4.5 -5 -5baseline -6 P <.01 -6 -7 -6.3 -7 14 Rifkin et al. DVd vs VAd
  15. 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 Rifkin et al. DVd vs VAd
  16. 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 16 Rifkin et al. DVd vs VAd
  17. 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 17 Rifkin et al. DVd vs VAd
  18. 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 18 Rifkin et al. DVd vs VAd
  19. 19. AcknowledgmentsWe gratefully acknowledge the patients and families whomade 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. YunusStudy Sponsors: Tibotec Therapeutics and ALZACorporation and in particular: Pam Jacobs, Chinglin Lai,Colin Lowery, and Mark Wildgust 19 Rifkin et al. DVd vs VAd

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