Bortezomib (BOR) and High Dose Melphalan (HDM) as Conditioning Regimen Before Autologous Stem Cell Transplantation (ASCT) for De Novo Multiple Myeloma (MM): Final Results of the IFM Phase II Study VEL/MEL

Introduction: ASCT is recommended for young patients (pts) with newly diagnosed MM. The achievement of Complete Response (CR) or at least Very Good Partial Response (VGPR) is the main prognostic factor for survival after ASCT. However, only 40–50% of patients achieve CR and VGPR with current HDM regimen. BOR has demonstrated significant activity in relapsed/refractory pts, a synergistic effect with Melphalan (MEL) and a lack of prolonged hematological toxicity. The combination of BOR and HDM is therefore a logical approach to attempt to improve CR+VGPR rates after ASCT.

Methods: In July 2007, the IFM initiated an open-label, multicenter, phase II study. Fifty-seven pts with symptomatic de novo MM were enrolled to receive BOR and HDM as conditioning regimen before ASCT. The choice of induction therapy was not specified in the protocol, and was made on an individual-patient basis by the treating clinician. BOR (1 mg/m²) was delivered on days −6, −3, +1, +4 and MEL (200 mg/m²) on day −2. Peripheral blood stem cells (median 4 × 10⁶ CD34/kg, range 2–12) were infused on day 0. The primary endpoint was the CR+VGPR rates at 3 months post ASCT. The secondary endpoint was the safety profile of this regimen. Baseline characteristics of the pts were: median age = 58; ISS= 1 in 30, 2 in 15 and 3 in 12 cases; chromosome 13q deletion in 27 of 52 assessable; chromosome 17p del in 3 and t(4;14) translocation in 6. Twenty-nine pts received VAD induction therapy while 18 received a BOR-Dexamethasone (DEX) based regimen. Seven pts needed more than 2 lines of therapy to achieve response before ASCT and 3 pts had already received a first course of HDM. Overall response rates before ASCT were: CR=2, VGPR=6, partial response (PR)= 33 and stable disease (SD)=16.

Results: All pts but one were assessed for response at 3 months after ASCT. Twenty pts (36%) achieved a CR and 17 (30%) a VGPR. One patient was non-responder. Among the 3 pts receiving a tandem ASCT, no CR or VGPR was observed after BOR+HDM. In the VAD induction group, 12 pts (43%) achieved CR and 7 (25%) VGPR. In the BOR-DEX based induction group, 7 pts (39%) achieved CR and 6 (33%) VGPR. All results are summarized in table 1. From the standpoint of safety, BOR did not increase hematological toxicity. Median duration of neutropenia (< 0.5 × 10⁹/l) and thrombocytopenia (< 50 × 10⁹/l) was 7 (range 1–15) and 8 (range 3–31) days respectively. Grade 3/4 extra-hematological toxicities were limited: mucositis in 22 cases (39%), peripheral neuropathy in 1 case. Other toxicities included: erythroderma in 30%, headache in 20%, hallucinations in 9% and grade 2 peripheral neuropathy in 3 cases (preexisting ASCT). Five serious adverse events were reported: 1 pulmonary embolism, 1 seizure, 1 acute cholecystis and 2 pneumonias. No toxic death was observed.

Conclusions: These results suggest that BOR (1 mg/m²) and HDM is a safe and highly effective conditioning regimen in frontline MM pts with almost 70% achieving CR and VGPR. This compares favorably to the updated results of the IFM 2005/01 trial (comparing BOR-DEX versus VAD as induction prior to ASCT in de novo MM pts) reported in last ASH meeting (Harousseau et al.). A matched case-control study will be conducted between our cohort and the pts of the IFM 2005/01 trial.

Table 1: