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Influence of Renal Function on Outcome of VAD or Bortezomib, Doxorubicin, Dexamethasone (PAD) Induction Treatment Followed by High-Dose Melphalan (HDM): A Subgroup Analysis From the HOVON-65/GMMG-HD4 Randomized Phase III Trial for Newly Diagnosed Multiple Myeloma
Christof Scheid
GMMG and University Hospital
Cologne, Germany
12.02.10

Christof Scheid1*, Pieter Sonneveld2, Ingo Schmidt-Wolf3*, Bronno van der Holt2*, Thomas Hielscher4*, Laila el Jarari2*, Uta Bertsch5*, Hans Salwender3*, Sonja Zweegman2*, Mathias Hänel3, Edo Vellenga2, Joerg Schubert3*, Igor Wolfgang Blau3*, Asiong Jie2*, Helgi van de Velde6*, Norma Peter3*, Martijn Schaafsma2*, Walter Lindemann3*, Marie Jose Kersten2*, Ulrich Duehrsen3, Michel Delforge7, Katja Weisel3*, Sandra Croockewit2*, Hans Martin3*, Shulamit Wittebol2*, Harry Schouten2, Marinus van Marwijk-Kooy2*, Pierre Wijermans2*, Henk M Lokhorst2* and Hartmut Goldschmidt5

1GMMG and University Hospital, Cologne, Germany
2HOVON, Netherlands
3GMMG, Germany
4German Cancer Research Center, Heidelberg, Germany
5GMMG and University Hospital, Heidelberg, Germany
6Johnson & Johnson, Belgium
7HOVON, Belgium

Introduction: Renal impairment is a frequent complication in patients with multiple myeloma (MM) and is correlated with an inferior prognosis. Bortezomib can be applied independently of renal function and has been shown to improve response and overall survival in patients with relapsed MM. We wanted to investigate the role of renal impairment in the context of a large randomized study comparing a bortezomib-containing induction regimen (PAD) with standard VAD followed by HDM and maintenance with either thalidomide or bortezomib.

Methods: Patients were randomly assigned to 3 cycles of standard VAD (arm A) or PAD (Arm B); PAD was dosed as bortezomib 1.3 mg/m2, days 1,4,8,11, doxorubicin 9 mg/m2, days 1-4, dexamethasone 40 mg, days 1-4, 9-12, 17-20). Patients received one (HOVON) or two (GMMG) cycles of high-dose melphalan (HDM) 200 mg/m2 with ASCT. Maintenance consisted of thalidomide (T): 50 mg daily (arm A) or bortezomib (B): 1.3 mg/m2, 2-weekly (arm B) for 2 years. As of July 2010 data from the first consecutively enrolled  626 patients of the HOVON-65/GMMG-HD4 trial have been analyzed. 613 patients have been evaluable (n=305 in arm A and n=308 in arm B, respectively). For this analysis patients were grouped according to renal function at baseline with creatinine < 2 mg/dl (177 µmol/l, n=553), 2-5 mg/dl (177-442 µmol/l, n=46) or > 5 mg/dl (> 442 µmol/l, n=13). Frequencies were compared by logistic regression, survival data by Cox PH regression. The analysis was intention-to-treat, with PFS censored for patients treated with allo-SCT (n=46).

Results: Data are summarized in tables 1-3. Response rates tended to be lower on patients with renal impairment. The overall response rate (at least PR) after HDM in the VAD arm for patients with a creatinine of 2-5 mg/dl was 48% compared to 83% with creatinine < 2 mg/dl. However in the PAD arm the response rate was 84% vs. 89% respectively (table 1). Progression-free survival (PFS) was significantly influenced by renal function, with 24 months rates of 64%, 50% or 31% for the 3 groups (p=0.006). In patients with creatinine < 2 mg/dl 2yr PFS was 61% (VAD) vs. 67% (PAD), while it was markedly different for creatinine of 2-5 mg/dl: 78% in the PAD arm vs. 30% in the VAD arm (p=0.002) (table 2.). Overall survival at 24 months was 86% for patients with creatinine < 2 mg/dl in both arms. With a creatinine of 2-5 mg/dl it was similar with PAD (89%) but significantly inferior with VAD (44%, p<0.001)(table 3).

Discussion: Experience in patients with relapsed MM suggests those with an impaired renal function may in particular benefit from a bortezomib-containing therapy-regimen. In this subgroup analysis of a large randomized study testing bortezomib both in the induction and maintenance-treatment before and after HDM in newly diagnosed MM we could show that patients with elevated creatinine (2-5 mg/dl) have a markedly inferior response, progression-free and overall survival when receiving VAD and thalidomide-maintenance, while the treatment results in the bortezomib-containing arm were similar to those in patients with creatinine < 2 mg/dl. We conclude that combining HDM with a bortezomib-containing induction- and maintenance regimen is able to overcome the negative prognostic impact of an impaired renal function in patients with newly diagnosed MM.

 

Table 1. Response rate, all in %

Creatinine (mg/dl)

Treatment

at least PR after Ind

at least PR after HDM

VGPR+CR after Ind

VGPR+CR after HDM

CR after Ind

CR after HDM

< 2

(n=553)

VAD

61

83

17

41

2

10

PAD

79

89

43

62

7

22

2-5

(n=46)

VAD

26

48

7

26

0

4

PAD

58

84

26

42

0

16

> 5

(n=13)

VAD

75

75

13

25

0

0

PAD

60

60

20

40

0

0

Table 2. Progression free survival, censored at allo-SCT (all in %)

Creatinine (mg/dl)

Treatment

PFS 12 mo

PFS 24mo

PFS 36mo

PFS 48 mo

<2

(n=553)

VAD

86

61

45

31

PAD

88

67

48

33

2-5

(n=46)

VAD

47

30

13

NR

PAD

89

78

56

47

> 5

(n=13)

VAD

75

25

25

25

PAD

60

40

40

NR

NR = not yet reached

Table 3. Overall survival (all in %)

Creatinine (mg/dl)

Treatment

OS 12 mo

OS 24mo

OS 36mo

OS 48 mo

<2

(n=553)

VAD

93

86

77

70

PAD

93

86

78

73

2-5

(n=46)

VAD

59

44

16

16

PAD

89

89

83

83

> 5

(n=13)

VAD

75

50

50

17

PAD

60

60

60

NR

NR = not yet reached

The HOVON-65/GMMG-HD4-trial was supported by the Dutch Cancer Foundation (EudraCT nr 2004-000944-26), the German Federal Ministry of Education and Research and a grant from Janssen-Cilag-Ortho Biotech. The GMMG study group received further grants to perform this trial by Novartis, AMGEN, Chugai and Roche.


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