Randomized trial comparing
MP, MP-Thalidomide and high-dose therapy
using Melphalan 100 mg/m2 for newly diagnosed
myeloma patients aged 65-75 years.
Interim analysis of the IFM 99-06 trial on 340 patients
T. Facon, J.Y. Mary, C. Hulin, L. Benboubker, M. Attal,
B. Pegourie, M. Renaud, J.L. Harousseau, M. Monconduit,
G. Guillerm, L. Voillat, C. Chaleteix, J. Troncy, P. Casassus,
H. Maisonneuve, V. Dorvaux, J. Jaubert, M. Dib, C. Doyen,
on behalf of the Intergroupe Francophone du Myélome
Introduction
· The standard frontline therapy for patients 65 years
of age or older consists of oral melphalan and
prednisone (MP)
· Combination of Thalidomide with MP may provide
increased antitumor benefit and better survival
· Intermediate-dose melphalan (two courses of
melphalan 100 mg/m2) improves survival of MM
patients aged 50-70 (including those aged 65-70)
(Palumbo et al. Blood 2004)
IFM 99-06
Newly diagnosed MM 65-75 years
Arm A
Arm B
Arm C
VAD 1
MP 1
Arm A
+
VAD 2
MP 2
Thalidomide
400 mg/J
MP 3
Cyclophosphamide 3g/m2
+ G-CSF
+ PBSC harvest
MEL 100 mg/m2
+ PBSC + G-CSF
MP 12
MEL 100 mg/m2
Clodronate for all pts
+ PBSC + G-CSF
Treatment assignment
Randomization with two primary objectives
1. comparison of the overall survival between MP and
MP+Thalidomide
2. comparison of the overall survival between MP and MEL100
For a given total number of inclusions, optimal power for these
two comparisons is obtained through unequal allocation between
arms with approximately 50% more inclusions in the MP arm
than in the MP+Thalidomide and intensive arm
Randomization stratified by center using permutation blocks of
length 7 with
3 MP, 2 MP+Thalidomide, 2 intensive
Interim analyses
· In the IFM 99-06 protocol, 2 interim analyses
according to Peto's rule1 were planned after 40 and
70% of inclusions and at least 5 months of follow-up
· These 2 interim analyses were reviewed by a Data
Safety Monitoring Board, independent from IFM,
consisting of 3 international experts :
Pr.M. Boccadoro/Torino ; Dr.R. Schots/Pr.Van Camp-
Brussels ; Dr.S.Chevret Biostatistics/Paris- StLouis
1Peto et al., Br.J.Cancer, 1976, 34:585-612
Second interim analysis
Date of point July 1, 2004
Total analyzed = 340 (350 for toxicity)
MP = 153
MP-T = 95
MEL100 = 92
Median follow-up time = 28 months
IFM 99-06 - Clinical features of patients
(n=340)(%)
Age > 70
41
M-component type
IgG
63
IgA
24
BJ
11
Other
2
2m 6 mg/L
27
13
48
Calcium 105 mg/L
21
Albumin < 35 g/L
27
Creatinine 15mg/L
21
MEL 100 treatment - Patient Flow (1)
Cyclo. 3g/m2
VAD x2
MEL 100
MEL 100
92
14
12
6
death
3
1
0
complications
4
3
2
progression
7
5
2
insufficient SC
-
3
1
refusal
-
-
1
35 %
MEL 100 treatment - Patient Flow (2)
MM patients aged 65-75 years
77/92 pts received the cyclophosphamide (84%)
60/92 pts received the two programmed MEL 100 (65%)
(6 additional pts received only the first MEL 100)
No toxic death among 126 MEL100 courses
Hematological toxicity / Infection : MP vs MP-T
Toxicity
MP
MP- T*
(grade 3/4)
(n=153)
(n=99)
(% of patients)
Neutropenia
32
41
Thrombocytopenia
14
9
Anemia
18
14
Infection
11
17
Infection-related death
2
2
* 36 patients (36%) had peripheral neuropathy
Incidence of DVT in the IFM 99-06 trial
(% of patients)
Patients with a previous history of DVT were excluded from the trial
MP
MP-T
MEL 100
5
12
6.5
(8/153)
(12/99)
(6/92)
No toxic death related to DVT
In the MP-T arm, DVT between day 3 and month 13, median 3 months
Response to treatment in the IFM 99-06 trial
% of patients (at 12 months)
Category of response
MP
MP-T
MEL100
Complete response
3
14
18
90%
8
51
39
50%
34
84
71
Conclusions
· Results of the MP arm are as expected
· Neurotoxicity and DVT are concerns in the
MP-T arm
· MEL100 is feasible in approximately 2/3 of
patients aged 65-75 years
· MP-T and MEL response rates are similar
Data Safety Monitoring Board Conclusions
· Observed adverse events are as expected in
each arm
· No excessive number of toxic deaths is
observed in any arm
· Overall survival data do not support stopping
patient recruitment in any arm
· A third interim analysis is recommended (date
of point April 15, 2005)
Document Outline