Combined Histone Deacetylase and Proteasome Inhibitor Therapy in Myeloma

In this study, Harrison and colleagues report the results of a clinical trial that examined the combination of romidepsin, bortezomib, and dexamethasone in patients with relapsed multiple myeloma (MM). Using a novel accelerated dose-escalation trial strategy, they established the maximum tolerated dose in a 28-day cycle to be bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; dexamethasone 20 mg on days of and after bortezomib; and romidepsin 10 mg/m2 on days 1, 8, and 15. Grade > 3 thrombocytopenia and neuropathy occurred in 64 percent and 8 percent of cases, respectively. Remarkably, the overall response rate was 72 percent, with 8 percent complete responses, 28 percent very good partial responses, and 24 percent partial responses. Moreover, time to progression was 7.2 months and median overall survival was 36 months. These data provide the rationale for further evaluation of this regimen.

The proteasome inhibitor bortezomib achieves remarkable frequency and extent of response when used as initial therapy for MM or to treat relapsed/refractory disease. Moreover, based upon preclinical mechanistic studies showing that combination therapies can achieve additive or synergistic cytotoxicity, bortezomib has been combined with other classes of targeted therapies with some of these combinations producing striking clinical efficacy. For example, the combination of bortezomib, lenalidomide, and dexamethasone triggers dual apoptotic signaling in vitro and achieves responses in the majority of patients whose MM is refractory to any of these agents alone. Moreover, near universal response is observed when this combination is used as initial therapy for MM. In vitro studies have shown that perifosine (an inhibitor of Akt and PI3 kinase) blocks bortezomib-induced activation of Akt, suggesting a mechanism by which this drug can increase sensitivity to or overcome clinical resistance to bortezomib. Previous studies have shown that bortezomib down-regulates class I histone deacetylase (HDAC) activity and that the class I HDAC inhibitor romidepsin enhances histone H3 and H4 hyperacetylation induced by bortezomib.¹  Therefore, the remarkable clinical responses to romidepsin, bortezomib, and dexamethasone observed in the present study may be related, at least in part, to greater class I HDAC inhibition. It is also possible that inhibiting class I HDACs is efficacious because such treatment results in reduced expression of cytokine genes that mediate the growth, survival, and drug resistance of MM cells within the bone marrow microenvironment. Importantly, although targeting the proteasome with bortezomib results in multiple sequelae affecting the MM cell directly, the tumor-host interaction in the bone marrow milieu is also affected. The primary effects of proteasome inhibition, however, are a consequence of blocking the degradation of substrate proteins by the proteasome. Proteasome inhibition also triggers compensatory up-regulation of the alternative aggresomal pathway for degradation of ubiquitinated proteins in vitro, and dual blockade of both the proteasome with bortezomib and the aggresome with HDAC inhibitors triggers synergistic MM cytotoxicity.²  Specifically, HDAC 6 (a class II b family member) binds to ubiquitinated proteins on the one hand and to dynein motility complexes on the other to shuttle proteins for degradation via the aggresomal pathway. Importantly, combination therapy either with broad class I, II HDAC inhibitors (e.g., panobinostat, vorinostat), or with an HDAC 6 selective inhibitor (e.g., ACY 1215) blocks bortezomib-induced up-regulation of this alternative aggresomal pathway and mediates synergistic MM cell death in vitro.