VelcadeDexamethasone versus VAD as Induction Treatment prior to ASCT in newly diagnosed MM' Updated

1
Velcade-Dexamethasone versus VAD as Induction
Treatment prior to ASCT in newly diagnosed MM.
Updated results of the IFM2005/01 trial.JL
Harousseau, C. Mathiot, M. Attal, G. Marit, D.
Caillot, C. Hulin, T. Facon, I. Webb, H.
Avet-Loiseau, P. Moreau
Inter
groupe Francophone du Myélome


2
It is time to say goodbye to VAD at least as
initial therapy for myelomaV. Rajkumar, Blood
2005 1062
3
Introduction

• The optimal Induction Therapy prior to ASCT
  should
• decrease tumor burden and increase CR/VGPR rate
• allow stem cell collection
• have acceptable toxicity
• In 2005 death of VAD as induction therapy was
  claimed due to results of Thal/Dex
• Randomized studies comparing Thal/Dex with Dex or
  VAD have shown
• superior response rate with Thal/Dex
• BUT
• No increase in the CR rate (Rajkumar JCO 2006)
• No increase in the CRVGPR rate after ASCT (Macro
  ASH 2006)
• Increase of DVT rate (Rajkumar JCO 2006, Macro
  ASH 2006)
• Thal/Dex may not be the optimal induction therapy
  ? other combinations are needed

4
Study Design

• Primary objective CRn-CR rate with VAD (A1A2)
  vs Vel-Dex (B1B2)
• Planned total enrollment 480 patients
• Randomization
• by ß2M level (gt3mg/L vs 3mg/L) presence of
  chromosome 13 abnormalities (by FISH)

A1
A2
B1
B2
Induction
VAD x 4
VAD x 4
Vel-Dex x 4
Vel-Dex x 4
Consolidation
DCEP x 2
DCEP x 2
Melphalan 200mg/m2 ASCT
Melphalan 200mg/m2 ASCT
Melphalan 200mg/m2 ASCT
Melphalan 200mg/m2 ASCT
Transplant 1
Second ASCT or RIC allo if ltVGPR
5
Study Design

• VAD regimen (28-day cycle)
• Vincristine 0.4mg/m2 and doxorubicin 9mg/m2, days
  14 continuous infusion
• Dexamethasone 40mg, days 14 (cycles 14), and
  days 912, 1720 (cycles 12 only)
• Vel-Dex regimen (21-day cycle)
• Bortezomib 1.3mg/m2, days 1, 4, 8, and 11
• Dexamethasone 40mg, days 14 (cycles 14), and
  days 912 (cycles 12 only)
• DCEP regimen (28-day cycle)
• Dexamethasone 40mg, days 14
• Cyclophosphamide 15mg/m2, etoposide 400mg/m2, and
  cisplatinum 10mg/m2, days 14 continuous infusion

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Baseline Patient Demographics and Disease
Characteristics
July 2005 January 2007 482 patients have been
enrolled
P value 0.23 0.53 0.73 0.86 0.91 0.95 0.37 0.26

Male, Mean (Median) Age, yr ISS stage III,
(vs stage I II) b2m gt 3 mg/L, Chr 13 del by
FISH, Mean (Median) Hb, g/dL Mean (Median) Cr,
mmol/L Mean (Median) Calcium, mmol/L
VAD (A1A2) N242 52.5 55.8 (57.1)
22.3 57.9 42.6 10.9 (10.8) 101.2 (87) 2.4 (2.3)
Vel-Dex (B1B2) N240 57.9 55.4
(57.2) 21.7 57.1 42.1 10.9 (10.9) 106.4 (87) 2.4
(2.4)
7
Response To Induction(Evaluable Patients)
VAD (A1A2) N219 3.2 7.8 19.2 65.8 25.6
4.1 2.7 1.8
Vel-Dex (B1B2) N223 9.9 19.3 46.6 82.5 1
1.2 4.5 0.5 1.3
P value 0.004 0.0004 lt 0.0001 lt 0.0001
CR CRnCR gt VGPR gt PR MRSD PD Death NE
Response by Investigator Assessment
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Impact of ISS on Post-Induction Responses
VAD n97 12.4 24.7 n82 7.3 17.1 n54 1.9
11.1
Vel-Dex n102 23.5 50 n81 19.75 46.9 n52
11.5 40.4
P value 0.029 0.0002 0.028 lt
0.0001 0.047 0.0005
ISS 1 CRn-CR VGPR ISS 2 CRn-CR VGPR ISS
3 CRn-CR VGPR
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Impact of b2M and Del (13) on Post-Induction
Responses
VAD N103 20.4 N139 17.8 N64 25 N65 21.5

Vel-Dex N101 54.5 N139 41 N65 46.2 N63
52.4
P value lt 0.0001 lt 0.0001 0.01 0.0003
Chr 13 (by FISH), VGPR deletion normal/NE b2
M?3 / Chr 13 normal VGPR b2Mgt3/ Del 13
VGPR
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Response to DCEP Consolidation(Treatment
Actually Received)
55.2
47.3
28.1
19.1
27.1
23.2
12.5
9.1
A1 VAD N110
A2 VAD DCEP N96
B1 Vel/Dex N112
B2 Vel/Dex DCEP N96
11
Response To DCEP Consolidation (Evaluable
population)
36
P0.47
33
16
17
P0.73
A1B1 - DCEP N222
A2B2 DCEP N220
12
Response to First ASCTAnalysis on Evaluable
Patients
Vel-Dex (B1B2) N223 18.8 35.0 63.2 84.3 2.
7 12.6
VAD (A1A2) N219 9.6 23.3 43.8 79 3.7 16.4

P value 0.0041 0.0063 lt 0.0001 NS
CR CR nCR gt VGPR gt PR MR/SD/PD NE
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Response to First ASCTASCT Actually Performed
VAD (A1A2) N185 84 11.4 27.6 51.9 93.5
Vel-Dex (B1B2) N197 88 21.3 39.6 71.6 9
5.4
P value 0.0051 0.01 lt 0.0001 NS
CR CR nCR gt VGPR gt PR
14
Response to Second ASCT
36
24
9
7
VAD N 87 (47)
VEL / DEX N 55 (28)
15
Overall SurvivalMedian Follow-Up Time 18 Months
P0.45
VAD
VEL/DEX
days
16
Progression-Free Survival
P0.38
VAD
VEL/DEX
days
17
Toxicities During Induction
Vel-Dex N 239 231 (96.7) 112 (46.9) 27
(11.3) 65 (27.2) 15 (6.3) 2 (0.8)
VAD N 239 218 (91.2) 110 (46) 37 (15.5) 81
(34.9) 12 (5) 7 (2.9)
P value 0.01 0.83 0.18 0.11 0.52 0.09
Any AE, n () Grade ? 3, n () Grade ? 4, n
() SAE, n () AE leading to study drug
discontinuation, n () AE leading to death, n ()
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Hematologic Toxicity
48.1
8.8
38.5
Patients,
12.1
21.8
2.9
16.3
8.8
13.8
4.2
10.9
11.7
1.3
9.2
7.9
10
4.6
4.6
5
2.1
Anemia
Neutropenia
Platelets
Infection
Herpes Zoster
Thrombosis
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Non Hematologic Toxicity
VAD N 239 20.9 8.8 31.4 7.9 2 5.4 8.8
Vel-Dex N 239 28.9 11.7 26.8 18 7.1 5.9
5
Fatigue (all grades) Rash (all grades) GI
symptoms (all grades) Peripheral
Neuropathy Grade 2 Grade 3 Cardiac
Disorders Pneumonia
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Stem Cell Collection
VAD 8.36 1.62 1.7 10.3 11.6
Vel-Dex 6.80 2.04 3.8 22.1 24.2
After 1st mobilization G-CSF alone Median No.
CD34 (x106/kg) Mean No. Apheresis Patients
with lt 2.106/kg Patients with lt
5.106/kg Patients needing a 2nd collection
with Cyclophosphamide G-CSF
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Conclusions (1)

• Vel-Dex significantly improved post-induction
  response rate compared to VAD (evaluable
  population)
• - CRnCR rate 19.3 vs 7.8, p0.004
• - VGPR rate 46.6 vs 19.2, plt0.0001
• Vel-Dex was superior to VAD in all prognostic
  subgroups
• DCEP consolidation did not significantly improve
  the outcome (evaluable population)
• The better response after induction treatment
  with Vel-Dex translated into significantly better
  response rate after ASCT (ITT)
• - CR/nCR rate 35 vs 23.3, p0.0063
• - VGPR rate 63.2 vs 43.8, plt0.0001

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Conclusions (2)

• In the Vel-Dex arm stem cell collection yield was
  2.106 CD34/kg in 96 of patients with G-CSF
  alone
• Vel-Dex regimen was well tolerated (7 grade 3
  PN)
• Vel-Dex could now be considered the standard
  induction treatment prior to ASCT to which other
  regimens including novel agents should be compared

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Acknowledgments

• CHU Nantes
• - Maëlle Ningre Project Manager
• - Tanguy Roman Data Managers
• - Nicolas Pontoizeau
• - JM Nguyen
• - Christelle Volteau Biostatistics
• - Lucie Planche
• - Anne Chiffoleau Pharmacovigilance

IFM - Claire Mathiot - Philippe Moreau - Herve
Avet-Loiseau
Millennium Pharmaceuticals - Iain Webb - Dixie
Esseltine
24
AcknowledgmentsIFM investigators and CR
assistants
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Back up slides
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A1 vs B1Response rate after Induction and after
ASCT
64 34
70 60 50 40 30 20 10 0
37 20
47 23
CR n-CR VGPR

19 9
B1 ? N112
A1 ? N110
27
POST-ASCT RESPONSE(ASCT actually performed)
73 42.5
70 37
70 60 50 40 30 20 10 0
60 32
44 23
CR n-CR VGPR

A2 N91
B2 N103
B2 N94
A1 N94