Patients with multiple myeloma (MM) who are not fit to undergo stem-cell transplantation (SCT), typically receive melphalan (Alkeran) plus prednisone in combination with either thalidomide (Thalomid) or bortezomib (Velcade). Recent studies are exploring the clinical benefit of the 4-drug induction regimen of melphalan, prednisone, bortezomib, and thalidomide, followed by maintenance with bortezomib plus thalidomide (VMPT-VT). In a recent phase 3 clinical trial, a total of 511 patients with newly diagnosed MM who were not candidates for SCT were randomized to receive VMPT-VT (N = 254) or bortezomib, melphalan, and prednisone (VMP; N = 257). The patients’ median age was 71 years, and 27% of the patients were aged >75 years (Palumbo A, et al. J Clin Oncol. 2014;32:634-640).
After a median follow-up of 54 months, the progression-free survival (PFS) was 35.3 months with VMPT-VT and 24.8 months with VMP (hazard ratio [HR], 0.58; P <.001). Of note, the overall survival (OS) rates were significantly prolonged with VMPT-VT compared with VMP; the 5-year OS rates were 61% with VMPT-VT and 51% with VMP (HR, 0.7; P = .01). A multivariable analysis revealed that treatment with VMPT-VT, age <75 years, female sex, and disease stages I and II were associated with significantly longer OS. In addition, the difference between median PFS and time to next therapy was approximately 1 year with VMPT-VT, but only 3 months with VMP. The investigators suggested that the significant tumor reduction and ongoing treatment with maintenance therapy delayed disease progression in patients receiving VMPT-VT.
The most common adverse events (AEs) were hematologic and included grade 3 or 4 neutropenia and grade 3 or 4 thrombocytopenia; neutropenia was reported in 38% of patients in the VMPT-VT arm and in 28% of patients in the VMP arm, whereas grade 3 or 4 thrombocytopenia was reported in 22% of patients in the VMPT-VT arm and in 20% of patients in the VMP arm. The most common nonhematologic AEs in both treatment arms included infections, cardiologic events, and peripheral neuropathy. Overall, 28% of patients in the VMPT-VT arm and 16% of patients in the VMP arm discontinued treatment and required dose reduction because of AEs.
The researchers concluded that the VMPT-VT regimen was superior to the VMP regimen in terms of PFS, OS, and time to next therapy in patients with newly diagnosed MM who are not eligible for SCT. Although these follow-up results are encouraging, an important question remains whether the clinical benefit observed with VMPT-VT is attributed to the 4-drug induction combination or to maintenance treatment with bortezomib and thalidomide. In addition, the investigators believe that these results provide the foundation for newer, less-toxic combinations of immunomodulatory agents and proteasome inhibitors.
