The Spanish Myeloma Group (PETHEMA/GEM) conducted a randomized phase III trial comparing induction with thalidomide/dexamethasone (TD) vs. bortezomib/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). The induction part of the study has been recently published and the maintenance results are reported here.
The primary end-point was progression-free survival (PFS) and the secondary end-points were increase of response rate, overall survival (OS) and safety.
The maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV: 89; T: 87, alfa2-IFN: 90). Response and survival were evaluated on an intention-to-treat basis. Responses, relapses and progressions (EBMT criteria) were monitored by an external contract research organization and centrally reassessed.
Patient's characteristics at diagnosis such as age, M-protein type, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization for maintenance after ASCT was CR: 51%, nCR: 12%, PR: 34%, MR 2% and SD: 1% and was well balanced in the three groups. The CR rate with maintenance was improved by 19% with TV, 15% with T and 17% with alfa2-IFN (p=NS). After a median follow-up of 34.9 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (figure 1, p=0.0009). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to progressions was not significantly diferent among the three arms (35% vs 24% vs 20%, p=NS). The discontinuation rate due to toxicity was higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p=0.17). Patients with high-risk cytogenetics [t(4;14), t(14;16) and/or del 17p] had a trend towards a shorter PFS (p=0.1) and a significantly shorter OS (p=0.03). The incorporation of bortezomib was not able to overcome the poor impact of high-risk cytogenetics.
The addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with single agent alfa2-IFN with no increased toxicity. However, the addition of bortezomib did not overcome the poor impact of high-risk cytogenetics.
Rosiñol:Janssen, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Granell:Janssen: Honoraria; Celgene: Honoraria. de Arriba:Jansen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria; Onix: Honoraria; Novartis: Honoraria. Bladé:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.
Asterisk with author names denotes non-ASH members.