For this week’s Article of the Week we have chosen an article which is particularly relevant to the results of the recent VCAT study which is currently being prepared for publication. It features a study recently published in the British Journal of Haematology comparing the use of bortezomib consolidation therapy with observation only in patients with myeloma-related bone disease who had a partial response or better after high-dose chaemotherapy and autologous stem-cell transplantation (ASCT).
Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study was designed around the hypothesis that bortezomib consolidation therapy would be superior to observation alone for myeloma-related bone disease. Previous studies have demonstrated that in addition to a direct anti-myeloma activity, bortezomib has been shown in previous studies to also inhibit osteoclastogenesis and stimulate osteoblast activity.
The study included 104 patients from 18 sites across eight European countries. These were all adult patients with MM who had achieved a partial response or better after frontline high-dose chaemotherapy and ASCT. Patients were stratified by age (<65 vs. 65 or older) and history of bisphosphonate use (yes/no) and were then randomised to receive either four cycles of intravenous bortezomib (days 1, 8, 15 and 22) or observation alone. Concomitant bisphosphonate use was permitted as medically indicated. Patients were followed up for 18 months after the end of treatment (EOT). The primary endpoint was the change in bone mineral density from baseline to EOT. Secondary endpoints included change from baseline to other endpoints, change from baseline in bone biomarkers, skeletal-related events, disease status/myeloma response, progression free survival (PFS), overall survival (OS) and safety.
In terms of change in BMD from baseline, the study found that both the bortezomib and observation groups had increases in BMD from baseline. However, there was no meaningful difference found between arms in relation to magnitude of response. Additionally, no significant difference was found between groups in subgroup analyses according to stratification factors. In terms of bone biomarkers, the serum levels of each biomarker decreased from baseline to EOT in both groups. The magnitude of this varied between different biomarkers but did not demonstrate a meaningful difference between the bortezomib and the observation only groups. In terms of skeletal-related events there were no meaningful differences observed between bortezomib and observation only groups.
In measuring myeloma response, the study found that relative to response rates at screening, bortezomib consolidation appeared to improve depth of response in some patients and also to reduce the rate of progressive disease. At EOT rates of very good partial response or more were 80% in the bortezomib arm and only 68% in the observation alone arm. There was also longer PFS in the bortezomib arm (median 44.9 months compared with 21.8 months in observation arm). There was no statistically significant difference in OS between the arms, however the follow up period for the study was not long enough to achieve median overall survival for either group.
Finally, in terms of safety the overall incidence of treatment emergent adverse effects (TEAEs) was higher in the bortezomib arm (as was expected). The largest differences were seen in rates of diarrhoea (37% vs. 0%), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0%) and vomiting (16% vs. 0%). Serious (grade III or IV) adverse events were rare in both arms with no significant difference found. 4 patients ceased bortezomib due to TEAEs and the one patient who died during bortezomib therapy was determined to have died from an cause unrelated to treatment.
There were a number of possible confounding factors recognised by the authors in this study, most notably the use of bortezomib based induction therapy in a large proportion of patients (which may have led to persistent bortezomib effect during the study period). Additionally the prior/con-comitant use of bisphosphonates in a substantial proportion of the study population may have been a confounding factor. It may be also be difficult to generalise this study to myeloma patients in a clinical setting as the population was limited to those who had achieved a partial response or better prior to ASCT. However, in conclusion this study suggests that post high-dose chaemotherapy and ASCT, bortezomib consolidation therapy had no obvious effect on bone mineral density in patients with myeloma related bone disease compared with observation alone. However, there was a benefit demonstrated in increased progression free survival and the bortezomib therapy was very well tolerated.
Download the full article here.