In 2005, Spanish Myeloma Group (GEM/Pethema) activated a two-stage, randomized trial including 260 elderly untreated myeloma patients. In the first stage, patients received induction therapy based mainly on a once per week dosing of bortezomib in combination with prednisone plus either melphalan (VMP) or thalidomide (VTP). The results of this first stage were already published (Mateos et al. Lancet Oncology 2010) and among all the 260 patients included in the trial, VMP and VTP as induction regimens yielded similar overall responses rate (80% and 81%, respectively). Patients completing the six induction cycles, in absence of disease progression or toxicity, moved to the second stage, in which each of the arms were equally randomly assigned to maintenance therapy with bortezomib plus prednisone (VP) or bortezomib plus thalidomide (VT). Maintenance consisted of one conventional cycle of bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) every 3 months, plus either oral prednisone 50 mg every other day or oral thalidomide 50 mg daily, for up to 3 years. We report the results of this second stage of the trial comparing VT with VP for up to three years as maintenance following induction with VMP or VTP.
178 out of 260 patients were randomized to receive VT or VP. Concerning baseline characteristics, both groups were well balanced, including the response status at the moment of randomization to maintenance (23% of patients were in CR in VT arm and 20% in VP arm). Median follow-up after randomization to maintenance therapy was 34 months (8-54). Overall, maintenance therapy resulted in an improvement of the depth of response and the IF-CR rate was increased from 24% after induction up to 42%. Although no significant differences were observed between VT and VP, the IF-CR rate was slightly higher for VT versus VP (46% versus 39%). For all patients receiving maintenance therapy, the median progression free survival (PFS) from initiation of treatment was 35 months (95% CI 29-39) and the median overall survival (OS) 60 months (95%C CI 51-69). From the randomization to maintenance therapy, the median PFS was 30 months (95% CI 21–39) for patients receiving VT and 24 months (95% CI 15–33) for those receiving VP (p=0·1). The slight benefit of VT versus VP as maintenance was independent of the type of induction therapy (VMP or VTP) (p=0·9). No differences in overall survival from this timepoint for VT and VP arms were observed (HR 1·4, 95% CI 0·8–2·4). Concerning safety profile, grade 3 or higher hematological toxicity was recorded only as neutropenia in one patient (1%) in each arm and grade 1-2 occurred in less than 5% of patients (3% and 2% of patients in VT arm developped neutropenia and thrombocytopenia, respectively; and 1% of anemia in VP arm). Concerning non-hematological toxicity, although more of the side effects were of grade 1-2 in both arms, their incidence was superior for VT as compared with VP arm (p=0·0001). Of note, seven patients (7%) in VT arm developped cardiac events, consisting on bradycardia (2 pts), tachycardia (2 pts), heart attack (2 pts) and cardiac failure (1 pt), while only one patient in VP arm. Gastrointestinal toxicity, as constipation or paralitic ileus, was reported in 11 patients (11%) in VT and 3 patients (3%) in VP arm. Grade 3-4 peripheral neuropathy was observed in 9 patients (9%) in VT and 3 (3%) in VP arm.
In summary, VT or VP as maintenance therapy resulted in a substantial increase in complete response rate, from 24% after induction to 42%, which can not be attributed to thalidomide or prednisone single agents but to their combination with bortezomib. In terms of CR, PFS and OS, although no significant differences between VT and VP were observed, a trend to better outcome for VT patients was observed, with a PFS that is one of the longest so far reported for elderly MM patients (39 months from diagnosis). However, VT arm was also associated with a higher incidence of non-hematological toxicity. These regimens, including bortezomib-based induction schemes that use weekly dosing of bortezomib, followed by bortezomib-maintenance schemes represent a platform for further optimisation of the treatment for elderly patients with multiple myeloma through use of lenalidomide instead of thalidomide by reducing adverse events and potentially improving the efficacy.