Bortezomib/Cyclophosphamide/Dexamethasone Versus Lenalidomide/Cyclophosphamide/Dexamethasone in Multiple Myeloma Patients at First Relapse: Final Results of a Phase III Study

Introduction. Bortezomib (Bort) and lenalidomide (Len) are standard treatments for relapsed MM, but, so far, a comparative trial between them has never been conducted. We designed a multicenter, open label, phase III study to compare bortezomib/cyclophosphamide/dexamethasone and lenalidomide/cyclophosphamide/dexamethasone in a fixed duration design protocol. The combination of Bort and Len with chemotherapy was devised to improve efficacy and to allow a fixed duration treatment in patients not heavily pretreated.

Methods. The primary endpoint was the achievement of very good partial remission (VGPR) or better at six weeks after 9 cycles. The study enrolled patients at first relapse with measurable disease. Patients could have received Bort or Len in their first line, but they should have obtained at least a PR longer than one year, and previous Bort or Len maintenance was an exclusion criteria. Enrollment started on April 2011, and was ended on April 2015. Patients were assigned 1:1 to sc Bort 1.3 mg/ms on days 1, 8, 15, 22, oral dexamethasone (Dex) 20 mg on days 1-2, 8-9, 15-16, 22-23, iv cyclophosphamide (Cyclo) 500 mg/ms on day 1 and 8 in a 35 days cycle (VCD) or to Len 15 mg from day 1 to 21, oral Dex 20 mg on days 1-2, 8-9, 15-16, 22-23, iv Cyclo 500 mg/ms on day 1 and 8 in a 28 days cycle (RCD). Nine courses of therapy without maintenance were planned. Efficacy and safety were assessed at each cycle using the IMWG response criteria for efficacy assessment (Durie et al. Leukemia 2006), and CTCAE v4.0 for safety.

Results. One hundred fifty-seven patients were enrolled, 155 were randomized, 77 were assigned to the VCD, and 80 to the RCD arm, respectively. Both arms were well balanced according to the baseline characteristics. Median age was 65 years (range 41-79), and 63 years (range 46-76) for VCD and RCD, respectively. ISS stage was grade I in 36 and 33, grade II in 20 and 28, and grade III in 16 and 15 patients in the VCD and RCD arms, respectively. Previous treatment included Bort in 35 and 42, Len in 7 and 7, Bort- and Len-free chemotherapy in 32 and 29, thalidomide in 35 and 31, and autologous stem cell transplantation in 58 and 63 patients in the VCD and RCD arms, respectively. The primary endpoint, represented by achievement of VGPR or better at 6 weeks after 9 courses, was met by 12 (16%) and 16 (20%) patients in the VCD and RCD arms, respectively (p=0.70). Median progression-free survival (PFS) was 16.3 (range 13.3 - 22.4) and 20.2 (range 14.7 - 26.8) months (p=0.70), and median overall survival (OS) was 31.1 and 36.2 months (p=0.83), in the VCD and RCD arms, respectively. In subgroup analysis, patients that were Bort and Len naïve at enrollment had a PFS of 20.0 (range 12.2 - 31.8) and 20.2 months (range 12.0 - 29.9) (p=0.44), and a median OS of 31.1, and 22.5 months (p=0.72), for the VCD and RCD arms, respectively. Patients that were Bort exposed, but Len naïve at enrollment, had a PFS of 15.6 (range 9.9 - 22.4) and 19.5 months (range 11.1 - 28.6) (p=0.35), and a median OS of 29.2, and 34.7 months (p=0.62), for the VCD and RCD arms, respectively. Adverse events were consistent with the well-established safety profile of Bort and Len, and grade III and IV toxicities were not significantly different between the 2 arms.

Conclusions. This is the first head-to-head study comparing fixed duration therapy of Bort and Len in first relapse patients. We show that both drugs are equally effective, in terms of depth of response, PFS, and OS. Despite drug-specific toxicity profiles, incidence of grade III and IV toxicities were not different between the 2 arms.