Multiple myeloma has an incurable relapsing and remitting course despite advances made with new therapies. Preclinical data and early phase trials of the broad histone deacetylase (HDAC) inhibitors vorinostat and panobinostat in multiple myeloma suggested promising antitumour activity with in-vitro synergy with bortezomib, and also activity with immunomodulatory drugs such as lenalidomide. However, as single agents in relapsed refractory disease, the HDAC inhibitors have only shown modest activity at best. In The Lancet Oncology, researchers report the results of an RCT evaluating the use of the combination of vorinostat and bortezomib in patients with relapsed multiple myeloma that had previously responded to treatment (1-3 regimens).
In the study, subjects received 21 day cycles of bortezomib (1.3mg/m2 IV on days 1, 4, 8, and 11) in combination with oral vorinostat 400mg (n=317) or matching placebo (n=320) once-daily on days 1—14. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population, which was 7.63 months (95% CI, 6.87—8.40) in the vorinostat group and 6.83 months (5.67—7.73) in the placebo group (hazard ratio, 0.77, 95% CI, 0.64—0.94; p=0.0100). Median follow-up for overall survival was 14.2 months and did not differ between groups. Overall 312 (99%) patients in the vorinostat group and 315 (98%) patients in the placebo group had adverse events (300 [95%] adverse events in vorinostat group and 282 [88%] in control group were related to treatment). The most common grade 3—4 adverse events were thrombocytopenia (143 [45%] in vorinostat group vs 77 [24%] in placebo group), neutropenia (89 [28%] v. 80 [25%]), and anaemia (53 [17%] vs. 40 [13%]).
The researchers note that the clinical relevance of the small (0.8 months) difference in PFS between the two groups is not clear and suggest that this might be due to the non-durability of the responses, or possibly due to the toxicty of the combination, thus different treatment schedules of bortezomib and vorinostat need to be evaluated.
An accompanying commentary notes that bortezomib alone was used as the control arm in the study whereas in clinical practice, it is invariably given in combination with dexamethasone and other drugs—although at the time the study was started the benefit of this combination was less well established. In addition, dose reductions were common and might partly explain the lower thanexpected improvement in PFS. Furthermore, the median age of patients in the trial was 62 years, which is young for a myeloma population and because dose reductions were frequent, revised dosing schedules will be needed for clinical application (especially in a more representative elderly population). The author highlights that “as different HDAC inhibitors show different patterns of inhibitory activity, improved understanding of HDAC biology in multiple myeloma is key to making improvements in effective targeting of HDAC enzymes relevant to myeloma pathogenesis and to reduce toxicity.”
In April 2011, orphan designation was granted by the European Commission for vorinostat for the treatment of multiple myeloma. In May 2012, NICE was informed by the manufacturer that it was no longer pursuing a licensing application for vorinostat in combination with bortezomib for the treatment of multiple myeloma in people who have received at least one prior therapy, therefore the appraisal was suspended.