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

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.

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).

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).

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.

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.