Clinical Outcomes According to Genomic Abnormalities in 566 Newly Diagnosed Multiple Myeloma Patients Treated with Bortezomib-Based Regimens.

Bortezomib was initially reported to overcome the poor prognosis related to the presence of del(13q) in patients with advanced refractory/relapsed multiple myeloma (MM). However, more recent evaluations of genomic aberrations in MM provided demonstration that only t(4;14) and del(17p) retained prognostic value for both EFS and OS, thus identifying a subgroup of patients at high risk of progression or death. The combination of bortezomib with melphalan and prednisone, actually licensed as first-line therapy for MM patients who are not eligible for autologous stem-cell transplantation (ASCT), showed comparable activities in terms of time to progression and OS among patients with or without high-risk cytogenetic profiles. However, the number of high-risk patients analyzed was very limited, due to the low frequency of these genomic abnormalities. To more carefully assess the role of bortezomib in patients with high-risk cytogenetics [(e.g. carrying t(4;14) and/or del(17p)], we performed a post-hoc analysis of two phase 3 studies of first-line bortezomib-based regimens for the treatment of a large series of MM patients. Both studies are actually conducted by the Italian Myeloma Network GIMEMA.

The activity of three different bortezomib-based regimens in terms of achievement of best high-quality response (immunofixation negative CR) and PFS was analyzed. Regimens evaluated were bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP) and bortezomib-melphalan-prednisone-thalidomide (VMPT). VTD was followed by ASCT. Treatment details are as follows: VTD (Bortezomib, 1.3 mg/m² twice-weekly, every 21/d cycle; Thalidomide, 200 mg/d; Dexamethasone, 320 mg/cycle); VMP (Bortezomib 1.3 mg/m² on d 1, 8, 15 and 22, every 35/d cycle; Melphalan, 9 mg/m² on d 1 through 4, every cycle; Prednisone, 60 mg/m² on d 1–4 of each cycle); VMPT (VMP, as previously described; Thalidomide, 50 mg/d). A total of 566 patients for whom results of interphase FISH analysis at diagnosis were available for the presence or absence of del(13q) and/or t(4;14) and/or del(17p), were included in the present study. Three cytogenetic subgroups of patients were identified, including those without genomic abnormalities (group 1; n=257), those with del(13q) alone (group 2; n=162) and those who carried t(4;14) and/or del(17p) with or without del(13q) (group 3; n=147). For the purpose of the present analysis, clinical outcomes (e.g. CR rate and PFS) of patients treated with the 3 bortezomib-based regimens were compared according to the presence or absence of different genomic aberrations (e.g. group 1 vs 3 and group 2 vs 3).

Overall, the frequency of patients belonging to group 1 (no abnormalities), group 2 [del(13q) alone] and group 3 [t(4;14)±del(17p)] was 45%, 29% and 26%, respectively. Comparable rates of genomic aberrations were detected in patients treated with the 3 bortezomib-based regimens [no genetic abnormalities: 46% in VTD vs 48% in VMP vs 42% in VMPT; del(13q) alone: 30% in VTD vs 28% in VMP vs 28% in VMPT; t(4;14)±del(17p): 24% in VTD vs 24% in VMP vs 30% in VMPT]. No statistically significant difference in terms of CR rate was detected by comparing patients in group 3 with those in group 1 (38% vs 31.5%, respectively; P=0.1) and in group 2 (48%, P=0.07). The 2-year projected PFS was 63% for patients with high-risk cytogenetics vs 71% for those with del(13q) alone (P=0.1) vs 75% for patients without cytogenetic abnormalities (P=0.01). The finding that in the high-risk cytogenetic subgroup the VMP regimen comprising once-weekly standard-dose bortezomib effected the lowest rate of CR and PFS may explain, at least in part, the longer PFS for the subgroup without cytogenetic abnormalities. Indeed, after exclusion from the analysis of the VMP regimen, no statistically significant difference in terms of PFS was seen among VTD- and VMPT-treated patients according to the presence of high-risk cytogenetics or the absence of genomic abnormalities (P=0.09).

These results, based on a post-hoc analysis of patients with different age and treatment exposure, should be cautiously interpreted, although consistencies exist between them and previous reports on the activity of bortezomib in MM with high-risk cytogenetic abnormalities. Further analyses of large series of homogeneously treated patients are needed before firm conclusions can be drawn about the ability of bortezomib-based regimens to overcome the adverse prognosis related to t(4;14) and/or del(17p).

Cavo:Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Boccadoro:Ortho Biotech, Janssen-Cilag: Honoraria, Speakers Bureau. Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau.