Abstract

Abstract 2396

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 μ mol/l, n=553), 2–5 mg/dl (177-442 μ mol/l, n=46) or > 5 mg/dl (> 442 μ mol/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 13. 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).

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 10 
 PAD 79 89 43 62 22 
2-5 (n=46) VAD 26 48 26 
 PAD 58 84 26 42 16 
>5(n=13) VAD 75 75 13 25 
 PAD 60 60 20 40 
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 10 
 PAD 79 89 43 62 22 
2-5 (n=46) VAD 26 48 26 
 PAD 58 84 26 42 16 
>5(n=13) VAD 75 75 13 25 
 PAD 60 60 20 40 
Table 2.

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

Creatinine (mg/dl) Treatment PFS 12mo PFS 24mo PFS 36mo PFS 48mo 
<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 
Creatinine (mg/dl) Treatment PFS 12mo PFS 24mo PFS 36mo PFS 48mo 
<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) 59 44 16 16 
 PAD 89 89 83 83 
>5 (n=13) VAD 75 50 50 17 
 PAD 60 60 60 NR 
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) 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

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.

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.

Disclosures:

Scheid: Ortho Biotech: Honoraria. Off Label Use: Bortezomib in newly diagnosed myeloma. Sonneveld: Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees. Schmidt-Wolf: Janssen Cilag:; Celgene: Membership on an entity's Board of Directors or advisory committees. van de Velde: Johnson & Johnson: Employment. Duehrsen: Ortho Biotech: Honoraria. Delforge: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Weisel: Ortho Biotech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Goldschmidt: Ortho Biotech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.