Final results of the IFM9904 protocol double transplant +- anti-IL6 by ctg14933

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									 Final results of the IFM 99-04 protocol :

double transplant +/- anti-IL6 monoclonal
                antibody
 in high-risk de novo multiple myeloma


   P.Moreau, C.Hullin, F.Garban, T.Facon, M.Attal,
L.Benboubker, G.Marit, J.G.Fuzibet, C.Doyen, L.Voillat,
  C.Berthou, P.Casassus, M.Monconduit, M.Michallet,
  A.Najman, J.J.Sotto, R.Bataille, Hervé Avet-Loiseau,
                   J.L.Harousseau
        Overall survival according to the number of
    unfavorable prognostic factors (β2m ≥ 2.5 mg/L, ∆13)

Survival
   1.0



   0.8
                                                      # factors   O/N   Survival time
                                                                           (month)
   0.6                                                    0       2/22    > 111.
                                                          1       29/55   47.3 ± 4.6
                                                          2       22/33   25.3 ± 3.2
   0.4



   0.2
                P < .0001

   0.0
         0     12    24     36   48   60   72    84        96
                                            time from diagnosis (months)
             Facon et al , Blood 2001
                 de novo MM, < 65 years
                 β2M > 3 mg/L and ∆13


                           VAD x 4

                    Stem cell collection

                           HDM 200



If HLA-sibling available                No donor available
      Mini-allo                        HDM 220 +/- anti-IL6
    Bu-Fluda-ATG

   IFM9903 trial                           IFM9904 trial
        Rationale

HDM220 +/- anti-IL-6 moAb
                     Moreau et al, Br J Haematol 1996;95:527

Melphalan mg/l


14
12
10
                HDM 220
 8
 6
 4              HDM 200

 2       HDM 140

     0    0.5    1         2       3       4      5 Hours
Moreau et al, Bone Marrow Transplant
1999;23:1003

Melphalan 220 mg/m2 + PBSCT in 27 pts
with advanced multiple myeloma

Response rate : 87.5%
Murine anti-IL-6 moAb, B-E8

Klein et al Blood 1991;78:1198
Bataille et al Blood 1995;86:685

  feasible without toxicity
  suppress the proliferation of
myeloma cells in vivo
    BE-8 : anti-iL-6-mAb (Diaclone Research / OPI – France)

    100mg 50mg      50mg    50mg
                                   HDM 220


                                                      ASCT
DXM 40mg     40mg    40mg 40mg                                G-CSF

 Day

       -6    -5      -4       -3       -2      -1       0       7
  Enrollment IFM 9903 or 9904 : 284   patients


IFM 9903 : 64             IFM9904 : 220

       Progression                 VAD
       Infection
       Death                     HDM200
       Refusal
       Violation
                        Randomisation
       54 (24%)
                             166

   Arm A : HDM220          Arm B : HDM220 + anti-IL6 moAb
          85                               81
                          1.0

                          0.9

                          0.8                        Median : 39 months
                          0.7
Probability of Survival




                          0.6

                          0.5

                          0.4

                          0.3

                          0.2

                          0.1

                           0
                            0        12        24        36        48        60




                            Overall survival from diagnosis : 220 patients
                                           Intent-to-treat
                          1.0


                          0.9


                          0.8
                                                  Median 30 months
                          0.7


                          0.6
Probability of Survival




                          0.5


                          0.4


                          0.3


                          0.2


                          0.1


                           0
                            0       12       24        36       48       60




                           Event-free survival from diagnosis : 220 patients
                                            intent-to-treat
Non randomised, n = 54 (24%)
- Toxic death VAD :       6
- Toxic death HDM200 :    2
- Protocol violation :    5
- Refusal :               10
- Progressive disease :   17
- No graft :              1
- Cardiac :               2
- Pulmonary :             2
- Infection :             4
- Other :                 5
                          1.0

                          0.9

                          0.8
                                                     p < .0001
                          0.7
Probability of Survival




                          0.6

                          0.5

                          0.4

                          0.3

                          0.2

                          0.1

                           0
                            0        12       24        36       48       60




                                Overall survival : randomised (166 pts)
                                     vs non randomised (54 pts)
                          1.0

                          0.9

                          0.8
                                                     p < .0001
                          0.7
Probability of Survival




                          0.6

                          0.5

                          0.4

                          0.3

                          0.2

                          0.1

                           0
                            0      12       24      36       48   60




                                EFS randomised (166 patients)
                                vs non randomised (54 patients)
                          1.0


                          0.9


                          0.8
                                                            Median 47 months
                          0.7


                          0.6
Probability of Survival




                          0.5


                          0.4


                          0.3


                          0.2


                          0.1


                           0
                            0    12        24       36       48      60




                                Overall survival : 166 patients
                          1.0


                          0.9


                          0.8
                                                     Median : 33 months
                          0.7


                          0.6
Probability of Survival




                          0.5


                          0.4


                          0.3


                          0.2


                          0.1


                           0
                            0      12         24        36           48   60




                                Event-free survival : 166 patients
                     Arm A             Arm B             p
                     n = 85            n = 81

Age at diagnosis     56 (34-65)         58 (28-65)      0.053
Sex (M/F)              41 / 44            47 / 34       0.28
Isotype (G/A/BJ)      45/23/17           42/24/15       0.93
Stage (I/II/III)        1/9/75           0/10/71        0.98
Beta2mic             4.6 (3-28.5)      4.8 (3-37.2)     0.35
Albumin             9.5 (5.1-14.7)   10.2 (4.7-14.4)    0.14
Platelets           216 (60-462)       204 (84-469)     0.63
Hb                  38 (22.5-54)       37 (16.2-52)     0.62
Ca                 2.42 (1.96-4.5)   2.42 (1.87-4.03)   0.85
CRP                   7 (1-244)         5 (1-137)       0.22
                          1.0
                                                    p = .53
                          0.9


                          0.8


                          0.7


                          0.6
                                                            Arm B
Probability of Survival




                          0.5


                          0.4
                                                  Arm A
                          0.3


                          0.2


                          0.1


                           0
                            0    12       24       36         48    60




                                Survival : arm A vs arm B
                          1.0


                          0.9


                          0.8                          p = .59
                          0.7
Probability of Survival




                          0.6


                          0.5


                          0.4                  Arm B
                          0.3


                          0.2
                                                                       Arm A
                          0.1


                           0
                            0          12      24       36       48     60




                                Event-free survival : arm A vs arm B
                      Response


              VAD   ASCT n°1   Arm A     Arm B
                     HDM       HDM        HDM        p
                      200       220    220 + moAb

CR (%)        4        14        31        35       0.84
VGPR          12       20        19        18       0.93
PR            48       54        46        38       0.46
Stable        20       8         2         5        0.45
Progressive   12       2         1         2        0.96
Death         4        2         1         2        0.96
       Conclusions IFM99-04

- The combination of anti-IL6 moAB +
HDM220 is not superior to HDM220 alone

- The survival rates after tandem transplant
HDM200 / HDM220 in this high-risk group
are « encouraging »
Comparison IFM 99-03 (Dr Sotto/Dr Garban)
             vs IFM 99-04
               Enrollment IFM 9903 or 9904 : 284   patients



          IFM 9903 : 64                IFM9904 : 220



n = 18
Progression
Refusal
Infection


     Miniallo performed : 46         Randomisation : 166
               71%                         76%
IFM99-03 vs 99-04 : Initial characteristics
                         IFM99-03         IFM99-04         p
                           N = 64          N = 220


Age at diagnosis          53 (36-65)       57 (28-65)     0.004
Sex (M/F)                   31/33           115/105        0.69
Beta2-mic               4.1 (3.1-16.6)    5 (3.1-39.4)    0.024
Albumin                   38 (27-60)     37.9 (16.2-59)    0.46
Hemoglobin               97 (52-135)      98 (47-147)      0.79
Ca                       2.4 (1.4-3.9)    2.4 (1.9-5.4)    0.37
t(11;14) Y/No/missing      10/33/21        21/124/75       0.35
t(4;14) Y/No/missing       16/27/21        26/116/78       0.54
                          1.0



                          0.9
                                                              p = .34
                          0.8



                          0.7



                          0.6
                                                                9904
                          0.5
Probability of Survival




                                                  9903
                          0.4



                          0.3



                          0.2



                          0.1



                           0
                            0       12       24          36             48   60



                          SURVIVAL Intent-to-treat : 64 vs 220 patients
                                     IFM9903 vs 9904
                          1.0



                          0.9
                                                             p = .70
                          0.8



                          0.7



                          0.6
                                                 9904
                          0.5
Probability of Survival




                          0.4
                                          9903
                          0.3



                          0.2



                          0.1



                           0
                            0    12         24          36        48       60




                                EFS intent-to treat : 64 vs 220 patients
                                          IFM9903 vs 9904
                          1.0


                          0.9                             p = .49
                          0.8


                          0.7

                                                  9904
                          0.6


                          0.5
Probability of Survival




                          0.4              9903
                          0.3


                          0.2


                          0.1


                           0
                            0   12        24         36             48   60




                                     EFS 166 vs 46 patients
                                       IFM9904 vs 9903
                          1.0


                          0.9
                                                     P = .09
                          0.8


                          0.7



                          0.6
                                                           Tandem auto
                          0.5
Probability of Survival




                          0.4


                          0.3
                                                               9903
                          0.2


                          0.1


                           0
                            0   12          24        36           48    60


                                     Survival 166 vs 46 patients
                                         IFM9904 vs 9903
1.0


0.9


0.8


0.7


0.6


0.5


0.4


0.3


0.2


0.1


 0
  0   10       20   30    40   50




           Chronic GVHd
Conclusion IFM99-03 vs IFM99-04


 In patients with high-risk de novo MM,

 autologous + miniallogeneic SCT
 is not superior to tandem autologous SCT

								
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