Bortezomib (Velcade)-Melphalan-Prednisone (VMP) Versus Velcade- Thalidomide-Prednisone (VTP) in Elderly Untreated Multiple Myeloma Patients: Which Is the Best Partner for Velcade: An Alkylating or An Immunomodulator Agent?
Authors: Mateos Maria-Victoria , Oriol Albert , Martínez Joaquín , Cibeira Ma Teresa , de Paz Raquel , Terol Ma José , García-Laraña José , Bengoechea Enrique , Martínez Rafael , Martin Alejandro , de Arriba Felipe , Palomera Luis , Hernández José , Bello Jose-Luis , Martín María-Luisa , González Yolanda , Blade Joan , Lahuerta Juan José , Miguel J.F San 
Published: October 2019

Abstract
Melphalan – Prednisone (MP) has been the Standard of care for elderly multiple myeloma patients in the past 40 years. However, bortezomib and thalidomide-based combinations have demonstrated to improve the efficacy in terms of both response rate and time to events as compared to MP. In two recent Phase II and phase III trials we have shown (Mateos et al. Blood 2006; San Miguel JF et al. EHA 2008) that the combination VMP is highly effective, but it remains to be elucidated which agent is the optimal partner for bortezomib: an alkylating or an immunomodulatory drug. In order to answer this question in April 2006, Spanish Myeloma Group (PETHEMA/GEM) activated a phase III trial comparing VMP versus VTP in untreated MM patients older than 65 years. Patients in the VMP arm received intravenous bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, 11; 22, 25, 29 and 32) for one 6-week cycle (8 doses per cycle), followed by once weekly (days 1, 8, 15 y 22) for five 5-week cycles (4 doses per cycle) in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Patients in the VTP arm received the same bortezomib and prednisone regimen, but instead of melphalan they received continuous thalidomide at dose of 100 mg daily. For both groups, treatment continued for a maximum of 6 cycles (31 weeks) unless disease progression or unacceptable treatment-related toxicity occurred. The primary endpoint was overall response rate (ORR) after induction therapy and secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), time to and duration of response, and safety. As of July 30, 2008, 246 out of 260 planned patients have been included in the study and 167 are evaluables for response to induction therapy and adverse events (AEs). Efficacy and toxicity analyses were performed on an intention-to-treat basis. 80 patients were randomly assigned to receive VMP and 87 to receive VTP. Regarding baseline characteristics, including cytogenetic abnormalities, no significant differences were observed in both arms. No significant differences were observed in response rate: ≥ PR in 78% of patients in VMP and VTP groups respectively, with a CR rate of 18% vs 23% (p=NS) and CR/nCR of 38% vs 32% (P= NS). Only one patient prgressed under induction treatment in each arm. Median time to first response was similar in both arms (1,6 months) and there were not differences in the median time to achieve CR (4,4 vs 4,9 months). Regarding haematological toxicity, VMP resulted in higher incidence of ≥G3 neutropenia (34% vs 19%; p=0,009) and thrombocytopenia (21% vs 9%; p=0,01); in contrast, 157 related non-hematological AEs occurred in VTP arm vs 133 in VMP arm (p<0,005); and they were ≥G3 in 32% vs 25% (p=0,04). The most relevant toxicities included: ≥G3 cardiac toxicity reported in 7% of patients receiving VTP vs 0% in VMP arm; the incidence of ≥G3 thromboembolic events was 3,4% in VTP arm and <1% in VMP arm; finally, 15% of patients in VTP arm developed ≥G3 peripheral neuropathy and 9% in VMP arm. No significant differences were reported in other non-hematologic toxicities, including infections despite the higher incidence of neutropenia in VMP arm. Treatment discontinuation due to AEs was required in 8 patients in VMP arm and in 16 patients in VTP arm (p=0,08). Five patients in VMP arm and 7 in VTP group died during the induction phase due to AEs. In summary this initial analysis indicates that there are no significant differences in terms of efficacy between VMP and VTP, while the incidence of non-hematological AEs, specially cardiac events, was higher in the VTP arm, resulting in more serious AEs and treatment discontinuations.. These data suggest that thalidomide may not be the partner of choice for combination with bortezomib and other IMIDs such as lenalidomide should be explored. In addition, our data indicate that the modified VMP regimen used in this trial (weekly schedule after cycle 1 and only six cycles) is well tolerated although the CR rate is lower than in the VISTA trial.