Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p

Abstract

In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For all analyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P ‫؍‬ .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P ‫؍‬ .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P ‫؍‬ .28) or OS (P ‫؍‬ .12) was seen in arm B. In conclusion, the adverse impact of del (17p13)

Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value

“…3 However, another study from Germany showed that 1q21 gains with at least four copies were only detected in 16 of 344 (4.7%) newly diagnosed MM patients. 11 Our results demonstrated that the frequency of newly diagnosed MM harboring at least four copies of 1q21 are comparable with those from Arkanas, but the frequency in relapsed MM appeared to be lower in our study. We further observed that the incidence of 1q21 gains always increases at relapse, but that there was no significant change in copy numbers or the proportion of cells with extra copies of 1q21.…”

“…A German group found that the clinical course of patients with more than three copies of 1q21 was characterized by a remarkably short PFS and OS, whereas exactly three copies of 1q21 were associated with only a marginal effect on outcome. 11 However, the Arkansas group reported that patients with more than three copies of 1q21 at diagnosis had similar 5-year event-free survival (EFS) and OS compared with those with three copies of 1q21. 3 Our data are in agreement with the conclusion of the Arkansas group that although 1q21 gains were linked to significantly inferior clinical outcomes of patients receiving bortezomibbased therapy, the copy number variation showed no additional prognostic value.…”

“…However, to our knowledge, the prevalence of 1q21 gains with more than three copies and the impact of copy number variation on the survival of MM have been only mentioned in two studies, with apparently conflicting results. 3,11 According to the study from Arkansas, 1q21 gains with at least four copies were detected in 88 of 479 (18%) newly diagnosed MM and 20 of 45 (44%) relapsed/refractory MM. 3 However, another study from Germany showed that 1q21 gains with at least four copies were only detected in 16 of 344 (4.7%) newly diagnosed MM patients.…”

“…9 However, in studies from Neben et al,del(17p) remains the most important genetic prognostic factor in MM even if the proportion of plasma cells involved is just over 10%. 10,11 It is unclear whether the prognostic impact of 1q21 gains would be different if we split the patients according to the percentage of plasma cells involved.…”

Heterogeneity of outcome with single-agent carfilzomib: all relapsed/refractory myelomas are not created equal

“…The HOVON-65/GMMG-HD4 phase III trial randomized patients to receive either vincristine-adriamycin-dexamethasone (VAD) or bortezomib-adriamycin-dexamethasone (PAD) as induction followed by thalidomide maintenance in the VAD arm, and bortezomib maintenance in the PAD arm. 9 The 3-year OS for patients with t(4;14) was superior in the bortezomib arm (82% vs 55%, P ¼ 0.0003), similar trends were observed for deletion 7p (83% vs 33%, Po0.0001). Similar trends have been reported by the Arkansas team in the Total Therapy (TT) program, where the poor risk associated with MS molecular subgroup of patients (comprising FGFR3 gene and/or MMSET gene overexpression) that was observed in TT2 trial (no bortezomib) was overcome by inclusion of bortezomib in TT3A 10 and TT3B 11 trials (Figure 1).…”