Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial

Abstract

Renal impairment is frequent in patients with multiple myeloma and is correlated with an inferior prognosis. This analysis evaluates the prognostic role of renal impairment in patients with myeloma treated with bortezomib before and after autologous stem cell transplantation within a prospective randomized phase III trial. Eight hundred and twenty-seven newly diagnosed myeloma patients in the HOVON-65/GMMG-HD4 trial were randomized to receive three cycles of vincristine, adriamycin, dexamethasone (VAD) or bortezomib, adriamycin, dexamethasone (PAD) followed by autologous stem cell transplantation and maintenance with thalidomide 50 mg daily (VAD-arm) or bortezomib 1.3 mg/m(2) every 2 weeks (PAD-arm). Baseline serum creatinine was less than 2 mg/dL (Durie-Salmon-stage A) in 746 patients and 2 mg/dL or higher (stage B) in 81. In myeloma patients with a baseline creatinine ≥ 2 mg/dL the renal response rate was 63% in the VAD-arm and 81% in the PAD-arm (P=0.31). The overall myeloma response rate was 64% in the VAD-arm versus 89% in the PAD-arm with 13% complete responses in the VAD-arm versus 36% in the PAD-arm (P=0.01). Overall survival at 3 years for patients with a baseline creatinine ≥ 2 mg/dL was 34% in the VAD-arm versus 74% in the PAD-arm (P<0.001) with a progression-free survival rate at 3 years of 16% in the VAD-arm versus 48% in the PAD-arm (P=0.004). Overall and progression-free survival rates in the PAD-arm were similar in patients with a baseline creatinine ≥ 2 mg/dL or <2 mg/dL. We conclude that a bortezomib-containing treatment before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in patients with newly diagnosed multiple myeloma. The trial was registered at www.trialregister.nl as NTR213 and at www.controlled-trials.com as ISRCTN 64455289.

Figure 1A.

Percentages of adverse events (AE) during induction therapy cycle 1 according to baseline creatinine (<2 mg/dL or ≥2 mg/dL) and CTCAE grades 1–4 (CTCAE version 3.0).

Figure 1B.

Percentages of events (AE) during first high-dose therapy according to baseline creatinine (<2 mg/dL or ≥2 mg/dL) and CTCAE grades 1–4 (CTCAE version 3.0)

Figure 2.

Myeloma response according to baseline creatinine (intent-to-treat). BLC: baseline creatinine, Ind: response after induction treatment, Best: best response achieved any time on study treatment. BLC <2 mg/dL: n=746, BLC≥2 mg/dL: n=81. *P=0.001 compared to BLC <2 mg/dL; **P<0.001 compared to BLC <2 mg/dL.

Figure 3.

Response in the subgroup of 81 patients with BLC ≥2 mg/dL according to treatment arm (intent-to-treat). BLC: baseline creatinine, Ind=response after induction treatment, Best: best response achieved any time on study treatment. VAD-arm: n=45, PAD-arm: n=36. *P=0.003 compared to VAD-arm; **P=0.01 compared to VAD-arm.

Figure 4.

Progression-free survival (A) and overall survival (B) according to baseline creatinine (BLC) and treatment arm. PAD: bortezomib for induction and maintenance, VAD=VAD for induction and thalidomide for maintenance.