Traitement du mylome du sujet jeune Pr P'Moreau, Nantes

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Traitement du myélome du sujet jeunePr
P.Moreau, Nantes
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Alexanian JAMA 19692081680

• M 0.25 mg/kg/d x 4
• P 2 mg/kg/d x 4
• / 6 weeks

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J Clin Oncol 1998163832

• 27 randomized studies
• 6633 pts
• MP vs combination chemotherapy
• Survival MP vs CCT identical

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McElwain, PowlesLancet 19849 patients with
MM140 mg/m2 melphalan IV alone 9 responses?
proof of principle dose / response
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High dose melphalan alone - High response
rate- Prolonged neutropenia 20 30 days-
Morbidity and mortality? autologous stem cell
support
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IFM 90
200 patients lt 65 ans HDM 140 TBI
/ ABMT
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N Engl J Med 1996 Attal et al
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The New England Journal of Medicine
20033481875-1883
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The New England Journal of Medicine
20033481875-1883
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IFM 95 TRIAL DESIGN
de novo MM lt 65 y
VAD x 3 SC collection if no
progression R
HDM 140 TBI 8g
HDM 200 N 140
N 142
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IFM 95 RESULTS
HDM 200 is at least as effective

• No significant difference in response rate and
• EFS
• Better overall survival
• Better salvage after relapse

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Moreau et al, Blood 2002
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Moreau et al, Blood 2002
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Moreau et al, Blood 2002
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IFM 95 CONCLUSIONS

• HDM 200 should be prefered to HDM 140 TBI

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HIGH-DOSE THERAPY LONG-TERM RESULTS
125 patients treated between 85 and 95 (min. F-up
6 yr) for de novo MM
1.0
TD 3 CR 23 12 yr OS 25
0.9
0.8
0.7
0.6
0.5
Probability of Survival
0.4
0.3
0.2
0.1
0
0
1000
2000
3000
4000
5000 days
Moreau Leukemia 2002
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IFM 94
Randomisation single versus double VAD VAD VAD V
AD
Mel (140) Mel (140) TBI
Mel (140) TBI
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IFM 94 TRIAL FEASIBILITY
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IFM 94 EFS
Médiane 30 mois
P lt 0.03
B
A
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IFM 94 Overall survival
P lt 0.01
B
A
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IFM 94 OS if response to 1stgraft lt90
P lt 0.001
B
A
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IFM 94 OS if response to 1st graft gt 90
P 0.7
B
A
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IFM 94 CONCLUSIONS (1)
1 - Double transplantation significantly
improves OS of MM patients and could be
recommended for patients lt 65 years
Attal et al N Engl J Med 2003
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IFM 94 CONCLUSIONS
2 - Double transplantation should be
recommended for patients failing to achieve
VGPR or CR after the 1st transplant.
Attal et al , N Engl J Med 2003
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SINGLE vs DOUBLE ASCT RANDOMIZED STUDIES
IFM 94 (NEJM 03) MAG 95 (Sydney
05) Bologna (Sydney 05) GMMG (Sydney
05) Hovon (Sydney 05)
Nb of pts 399 227 220 261 303
Age lt 61 lt 56 lt 61 lt 66 lt 66
Results EFS and OS EFS and OS
EFS EFS CR and EFS
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IFM 99-02

• - Patients lt 65 years
• - 0 or 1 adverse prognostic factors (chr 13, b2
  M)

VAD VAD VAD
SC collection
HDM 140 AT HDM 200 AT
Pamidronate Thalidomide
Control
Pamidronate
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IFM 9902 Patient flow (0 - 1 Factor)
Inclusions 780
Exclusions 183 (23)
Randomizations 597 (77)
Arm A 200
Arm B 196
Arm C 201
Arm B 196
Arm C 201
Arm A 200
Attal, Blood 2006
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IFM 99 02 Response Rate 90.


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IFM 99 02 Event-Free-Survival.

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IFM 99 02 EFS from Diagnosis

Arm C

P lt 0.01
P lt 0.003
Arm B
Arm A


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Median EFS in different subgroups.
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IFM 99 02 EFS According to del 13
Del 13 -
Del 13
Thal
Thal

Thal - (n 391)
NS
P 0.001
Thal -
Thal -
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IFM 99 02 EFS According to Response at Random
Response at Random 90
Response at Random lt 90
Thal
Thal
Thal - (n 391)
Thal -
NS
P lt 0.0003
Thal -
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IFM 99 02 Risk of Bone Events



Arm A
Arm B
P 0.1
Arm C
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IFM 99 02 Overall Survival according to
Pamidronate (Arm A versus B)


Arm A
Arm B
NS
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IFM 99 02 Overall Survival according to Thal
(Arm B versus Arm C).

Arm C

Arm B
P lt 0.01
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IFM 99 02 The Thalidomide Arm.

• The most common toxicities were neuropathy
  (68), fatigue (34), constipation (20),
  neutropenia (7), and cardiac (4).
• The incidence of DVT was not increased in the
  Thal arm (4).
• 39 of patients had to discontinue Thal for
  drug-related AE.
• Neuropathy was the main reason for
  discontinuation.
• Median duration of Thal 15 m (1-51).
• Mean dosage of Thal 200 mg / d (50-400).

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IFM 99 02 Conclusions

• After HDT, Maintenance Therapy with THAL
• Is Feasible,
• Improves the Complete Response Rate,
• Prolongs the Duration of Response,
• Improves the Overall Survival.
• Finally, Thalidomide should be recommended as
  maintenance therapy after HDT for patients
  without del 13 and failing to achieve VGPR after
  HDT .

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Survie tous protocoles 99
Médiane 35 mois
EFS
Médiane non atteinte à 5,5 ans
OS
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Incidences
Del(13) (965 pts) 48 t(1114) (760 pts)
21 t(414) (727 pts) 14 Ploidy (658 pts)
40 c-myc (576 pts) 13 Del(17p) (526 pts)
11 1q gains (365 pts) 35
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t(414)
No t(414) 616 pts
EFS
t(414) 100 pts
p10-12
t(414)14 716 pts
No t(414) 616 pts
OS
t(414) 100 pts
p2.10-8
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Del(17p)
No del(17p) 474 pts
EFS
p1.10-7
Del(17p) 58 pts
Del(17p)11 532 pts
No del(17p) 474 pts
OS
Del(17p) 58 pts
p3.10-7
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Multiparametric analysis
Prognostic parameters del(13), t(414),
del(17p), 1q gains, b2mgt3/4 Hblt10, albuminelt30 or
35, plateletslt130
Independent prognostic parameters
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Cytogenetic b2m model
OS
No t(414), no del(17p), b2mlt4, no del(13)
155 pts No t(414), no del(17p), b2mlt4,
del(13) 110 pts No t(414), no
del(17p), b2mgt4, no del(13) 74 pts No
t(414), no del(17p), b2mgt4, del(13)
69 pts t(414) or del(17p)gt60, b2mlt4
63 pts t(414) or del(17p)gt60,
b2mgt4 42 pts
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lt 65 years, de novo
Induction therapy
ASCT
Maintenance
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lt 65 years, de novo
Induction therapy
ASCT
Maintenance
Melphalan 200 mg/m2
Melphalan 200 mg/m2
VAD
Thalidomide
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lt 65 years, de novo
Induction therapy
ASCT
Maintenance
Melphalan 200 mg/m2
Melphalan 200 mg/m2
VAD
Thalidomide
Revlimid
IFM 2005-02 prospective randomized Maintenance
trial, using revlimid
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lt 65 years, de novo
Induction therapy
ASCT
Maintenance
Melphalan 200 mg/m2
Melphalan 200 mg/m2
VAD
Thalidomide
Revlimid IFM 2005-02
Velcade
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The Vel-Mel regimen

• Mel CSP G-CSF
• V V V V

-6 -3 -2 0 1 4 7
V Velcade 1mg/m2/d Mel Melphalan 200mg/m2
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The Vel-Mel Regimen Patients

• N 25
• Median Age 56 y (39-67)
• Status of disease
• Response lt 75 to VAD 18
• Response lt 90 to Mel 200 7

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The Vel-Mel Regimen Results

• PN lt 500/mm3 7 d (5-10)
• Plat lt 20000/mm3 1.5 d (0-7)
• Severe Mucositis 20
• Response Rate
• CR 31 !!
• VGPR 46
• CR / VGPR 77

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lt 65 years, de novo
Induction therapy
ASCT
Maintenance
Melphalan 200 mg/m2
Melphalan 200 mg/m2
VAD
Thalidomide
Revlimid IFM 2005-02
Thalidomide-Dex
Velcade
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Cavo et alBlood 200510635-39
Retrospective analysis Thal-Dex 100 pts vs VAD
100 pts First-line therapy before
ASCT Pair-matched age, stage and beta2-mic
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Cavo et alBlood 200510635-39
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Cavo et alBlood 200510635-39
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lt 65 years, de novo
Induction therapy
ASCT
Maintenance
Melphalan 200 mg/m2
Melphalan 200 mg/m2
VAD
Thalidomide
Revlimid IFM 2005-02
Thalidomide-Dex Velcade-Dex
Velcade
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IFM 2005-01
Patients wiht newly diagnosed MM lt 65 y.o.
R
B2 Vel/Dex Vel/Dex Vel/Dex Vel/Dex DCEP DCE
P 1st ASCT
A2 Vel/Dex Vel/Dex Vel/Dex Vel/Dex 1st ASCT
A1 VAD VAD VAD VAD 1st ASCT
B1 VAD VAD VAD VAD DCEP DCEP 1st ASCT
INDUCTION
CONSOL.
2nd ASCT if lt 90 reduction of the M-component
within 3 months
SC collection
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lt 65 years, de novo
Induction therapy
ASCT
Maintenance
Melphalan 200 mg/m2
Melphalan 200 mg/m2
VAD
Thalidomide
Revlimid IFM 2005-02
Thalidomide-Dex Velcade-Dex (IFM 2005-01)
Velcade-Thal-Dex (VTD) Rev-dex
Velcade
Mel220 KGF
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RajkumarBlood 2005 aug 23 online
Revimid / dexamethasone 1st line Phase II 34
patients Rev 25 ? 15 ? 10 ? 5 mg day 1 to
21 Dex 40 mg D1-4, 9-12, 17-20 At least 4
cycles 31/34 response 91 2 CR 11 VGPR
(38) 18 PR
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RajkumarBlood 2005 aug 23 online
1 toxic death, infection No DVT, 1 pulmonary
embolism Prophylaxis aspirin once-daily 80
mg 12 grade 4 neutropenia 6 grade 4
anemia 0 grade 4 thrombocytopenia Stem cell
collection OK
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MP vs MPT vs HDT ??? the IFM99-06 trial(Facon
et al ASH 2005/ASCO 2006)prospective,
randomized, 436 patients
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IFM 99-06Newly diagnosed MM 65-75 years
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PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT
Proportion
O/N Survival time median se
(month) MP 67/191 17.1  1.4 MPThal 26/124 27.6
3.6 Int. 38/121 19.0 1.2
Time from inclusion (month)
191 132 96 69 39 22 9 4 2 0 MP 124 102 82 63 47
31 22 11 4 0 MPThal 121 88 69 50 27 18 8 5 3 3 I
nt.
at risk
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OVERALL SURVIVAL ACCORDING TO TREATMENT
Proportion
O/N Survival time medianse month MP 86/191 30.
3 5.5 MPThal 34/124 not reached at
56. Int. 52/121 38.6 4.7
Time from inclusion (month)
191 150 120 97 69 49 34 22 13 6 MP 124 105 88
73 61 47 35 22 9 1 MPThal 121 95 77 68 52 44 28
17 11 6 Int.
at risk
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Other combinations ?? MP-V? MP-R
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Phase I/II MP-velcade/ de novo MM, 65 - 85
yearsMV. Mateos et al. ASH 2005

• 4 cycles / 6 weeks

day 1 2 3 4 8 11
22 25 29 32 3342



Bortezomib
Melphalan 9 mg/m2
Prednisone 60 mg/m2

• 5 cycles / 5 weeks

day 1 2 3 4 8 15
22 2335

Bortezomib
Melphalan 9 mg/m2
Prednisone 60 mg/m2
Treatment duration 49 weeks
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MP-V / response rate (n53)
Hernandez, Br J H, 2004
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MP-V / best response (n53)
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Palumbo et al, Abs 785oral session, 2005 dec
13thPhase I/IIMP revlimid24 pts (4
cohorts / 6 pts)median age 72 (61-77)0.18
mg/kg melphalan 5 or 10 mg Revlimid0.25
5 or 10 mg RevlimidResponse rate
approximately 70
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MPT, MPR, MPV, Rev-dex ? RC élevé, bonne
surviecomparer autogreffe à ttt conventionnel
incluant les nouvelles drogues
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VTD ? melphalan 200 vel ASCT ?
RevlimidvsVTD ? MPV ? Revlimid
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