Vorinostat Plus Bortezomib for the Treatment of Relapsed/Refractory Multiple Myeloma: Early Clinical Experience

Abstract

Bortezomib, a proteasome inhibitor, is extremely effective for the treatment of multiple myeloma (MM). However, nearly all patients will eventually become refractory to bortezomib. Vorinostat is a potent inhibitor of histone deacetylase enzymes, and has been shown to affect growth of various cell lines, including MM, in a variety of in vitro non-clinical studies. Furthermore, the combination of bortezomib and vorinostat has demonstrated synergy in several in vitro and murine models. Subsequently, 2 multicenter, open-label, Phase I clinical trials have been conducted to investigate the combination of vorinostat with bortezomib in patients with MM. In the first trial, 34 patients with relapsed/refractory MM were enrolled. Patients received escalating doses of vorinostat (200 mg bid or 300–400 mg daily for 14 days) and bortezomib (0.7, 0.9, 1.1, or 1.3 mg/m2 on days 1, 4, 8, and 11); cycles were repeated every 21 days for ≤8 cycles or until progressive disease (PD) or intolerable toxicity. In the event of PD, oral dexamethasone (20 mg on days 1–4 and 17–20) could be added to the bortezomib plus vorinostat combination. The highest dose level of vorinostat was 400 mg daily for 14 days and bortezomib 1.3 mg/m2. The maximum tolerated dose (MTD) was not determined because ≥2 dose-limiting toxicities (DLTs) did not occur at any dose level. The most common drug-related adverse events were nausea (61.8%), diarrhea (58.8%), thrombocytopenia (50%), and vomiting (50%). Two patients experienced a DLT; grade 3 transient AST elevation was experienced by 1 patient receiving 400 mg vorinostat daily and 0.9 mg/m2 bortezomib, and grade 4 thrombocytopenia was experienced by 1 patient receiving 400 mg vorinostat daily and 1.3 mg/m2 bortezomib. Among 34 evaluable patients, the best response to vorinostat plus bortezomib was a partial response (PR) in 9 (26%) patients, minimal response (MR) in 7 (21%) patients, and stable disease (SD) in 18 (53%) patients. Mean duration of SD was 89 days, range 9–369 days. Of the 13 evaluable patients who had previously been treated with bortezomib, 5 achieved a PR, 1 had a MR, and 7 had SD. The effect of adding dexamethasone will also be analyzed and presented. The second trial enrolled 23 patients who received vorinostat (100–500 mg on days 4–11) and bortezomib (1–1.3 mg/m2 on days 1, 4, 8, and 11). Dexamethasone was added at cycle 2 for 6 patients who achieved less than a PR, and at cycle 4 for 5 patients with PD and at cycle 6 for 2 patients with PD. There was no upgrade in response for any patients who received additional dexamethasone. Two patients in the vorinostat 500 mg group experienced DLT (fatigue and prolonged QTc); MTD was identified as vorinostat 400 mg plus bortezomib 1.3 mg/m2. The main toxicities in this trial were hematologic (anemia, neutropenia, and thrombocytopenia). Twenty-one patients were evaluable for response (2 achieved very good PR, 7 PR, 10 SD, 2 progressive PD). Of the 9 patients who were refractory to bortezomib, 3 had PR, 4 had SD, 1 had PD, and 1 was non-evaluable. Co-administration of bortezomib did not alter the pharmacokinetics of vorinostat. In conclusion, these data suggest that the combination of vorinostat plus bortezomib is active for treatment of MM, even among some patients with prior exposure to bortezomib.

Vorinostat enhances the antimyeloma effects of melphalan and bortezomib

“…In support of these effective combination therapies, the activity of vorinostat combined with bortezomib has previously been demonstrated in preclinical and clinical studies (29–33), and shown to enhance the antimyeloma activity of other anticancer agents including tumor necrosis factor‐related apoptosis‐inducing ligand, and interferon α2b (34, 35). Furthermore, other HDAC inhibitors have also shown the ability to enhance the activity of bortezomib and melphalan in chemoresistant myeloma cells.…”

The Synergistic Effects of DNA-Targeted Chemotherapeutics and Histone Deacetylase Inhibitors As Therapeutic Strategies for Cancer Treatment

“…[97]. In addition, earlyphase clinical trials of vorinostat in patients suffering from multiple myeloma demonstrated an increase in its antitumor effects in combinations with bortezomib [98][99][100]. Mitochondrial damage, stimulations of JNK and caspases or enhanced oxidative stress were increased in cells exposed to proteasome and HDAC inhibitors used in combination.…”

Future Directions of Next-Generation Novel Therapies, Combination Approaches, and the Development of Personalized Medicine in Myeloma

“…33,94 The transcriptional and protein homeostasis effects of HDAC inhibitors could conceivably cooperate to enhance the anti-MM activity of bortezomib, including clinical responses even in bortezomib-refractory patients. 28,91 The combination of elotuzumab with lenalidomide was made based on the notion that the immunostimulatory effect of lenalidomide would enhance the antibodydependent cellular cytotoxicity triggered by elotuzumab.…”