Antonio Palumbo, MD, Sara Bringhen, MD, Davide Rossi, MD, Valeria Magarotto, MD, Francesco Di Raimondo, MD, Roberto Ria, MD, Massimo Offidani, MD, Chiara Nozzoli, MD, Francesca Patriarca, Vincenzo Callea, MD, Giulia Benevolo, MD, Roberto Marasca, MD, Tommasina Guglielmelli, MD, Manuela Rizzo, MD, Mariella Grasso, MD, Maria Teresa Petrucci, MD, Paola Omedè, PhD, Gianluca Gaidano, MD and Mario Boccadoro, MD

Background:  In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4  drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR).

Methods: Newly diagnosed myeloma patients (N=393) older than 65 years, from 58 centers in Italy, were randomly assigned to receive VMPT (N=193) or VMP (N=200). Initially, patients were treated with nine 6-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1-4 and days 1,8,22,29 in cycles 5-9; melphalan 9 mg/m2 days 1-4; prednisone 60 mg/m2 days 1-4 and thalidomide 50 mg days 1-42, followed by bortezomib 1.3 mg/m2 every 15 days and thalidomide 50 mg/day as maintenance) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (bortezomib 1.3 mg/m2 days 1,8,15,22 in cycles 1-9). Primary end-point was progression-free survival (PFS).

Results: Patient characteristics were similar in both groups: median age was 71 years, 23% of patients were aged > 75 years. Patients who received at least 1 cycle were evaluated: 152 patients for VMPT (62 received bortezomib bi-weekly infusion and 90 weekly infusion) and 152 patients for VMP (62 received bortezomib bi-weekly infusion and 90 weekly infusion). Data were analyzed in intention-to-treat. The very good partial response (VGPR) rate was higher in the VMPT group (55% versus 42%, p=0.02), including a CR rate of 31% in the VMPT group and 16% in the VMP group (p=0.003). In the subgroup treated with weekly infusion of bortezomib, VGPR was 59% for VMPT and 37% for VMP (p=0.004), including 28% CR for VMPT and 10% for VMP (p=0.004). Subgroup analyses did not show any statistical difference between responses and either age, B2-microglobulin or chromosomal abnormalities, such as del13, t(4;14), t(14;16) and del17. After a median follow-up of 13.6 months, the 2-year PFS was 83.9% in the VMPT group and 75.7% in the VMP group (HR=0.73, 95% CI 0.38-1.42, p=0.35). In patients who received weekly infusion of bortezomib, the 2-year PFS was 86.8% in the VMPT group and 78.1% in the VMP group (HR=0.65, 95% CI 0.24-1.8, p=0.41). In patients who achieved CR after induction, the 2-year PFS was 100% for VMPT and 79% for VMP (p=0.02). The 3-year overall survival (OS) was 89.5% in the VMPT group and 88.7% in the VMP group (HR=1.02, 95% CI 0.43-2.46, p=0.96). The incidence of grade 3-4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%), infections (14% vs 10%), and gastrointestinal complications (7% vs 8%), respectively. The weekly infusion of bortezomib significantly decreased the incidence of grade 3-4 peripheral neuropathy (9% for VMPT and 3% for VMP).

Conclusion: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. The weekly infusion of bortezomib significantly reduced the incidence of grade 3-4 peripheral neuropathy without influencing outcome.

Table. Complete responses, progression-free survival and peripheral neuropathy in all patients and in those who received weekly infusion of bortezomib

	VMPT group (n=152)		VMP group (n=152)
	All patients (n=152)	Subgroup with bortezomib weekly infusion (n=90)	All patients (n=152)	Subgroup with bortezomib weekly infusion (n=90)
CR rate (%)	31	28	16	10
2-year PFS (%)	84	87	76	78
Grade 3-4 peripheral neuropathy (%)	18	9	12	3