High Response Rates with the Combination of Bortezomib, Dexamethasone and the Pan-Histone Deacetylase Inhibitor Romidepsin in Patients with Relapsed or Refractory Multiple Myeloma in a Phase I/II Clinical Trial

INTRODUCTION: Proteasome inhibitors (PI) and histone deacetylase inhibitors (HDACi) have demonstrated synergistic pre-clinical activity in multiple myeloma (MM). The goals of this study were to evaluate this combination regimen’s clinical activity and adverse events, including thrombocytopenia (TCP) since both drug classes may cause transient TCP. We performed an open label, single-centre, single-arm, phase I/II, dose-escalation trial of bortezomib, dexamethasone and romidepsin (depsipeptide) in relapsed or refractory MM. This is the first clinical trial to combine these 3 agents.

METHODS. All patients (pts) received bortezomib (1.3mg/m² d1, 4, 8, 11) with dexamethasone (20mg d1, 2, 4, 5, 8, 9, 11, 12). Romidepsin commenced at 8 mg/m² IV d1, 8, and 15 every 28 days with a planned accelerated intra-patient dose escalation to 10, 12 and 14 mg/m² (n=10). After CR + 2 cycles or a maximum of 8 cycles, pts with SD or better commenced maintenance (Mx) therapy, romidepsin at the MTD on days 1 and 8 of a 28 day cycle until PD. An additional 15 pts were treated at the MTD in a phase II expansion. Response was assessed after every 2 cycles according to IMWG criteria (with minimal Response (MR) defined as ≥25% but <50% reduction in M protein). Toxicities were assessed using NCI-CTCAE version 3.

RESULTS: In total, 25 pts have been enrolled of which 18 have completed more than 2 cycles and are evaluable for response. The median number of prior regimens was 2 (2–5). Most pts were treated previously with autologous stem cell transplantation (n=11) and neurotoxic regimens; VAD (n=10), thalidomide (n=12), bortezomib (n=6) and lenalidomide (n=4). The median number of treatment cycles delivered was 4 (1–8); Mx cycles 6 (3–15). 10 patients entered the Phase 1 study. No DLTs occurred at 8mg/m² (n=1) or 10mg/m² (n=6) of romidepsin. At 12mg/m² (n=3), TCP (Grade 4, n=3), febrile neutropenia (n=1), peripheral neuropathy (PN) (n=1) and constipation (n=1) DLTs were observed. Of note, 2 pts with Grade 4 TCP had platelets 50–100×10⁹/L before commencing therapy. The MTD for this regimen was determined as romidepsin (10mg/m²) with bortezomib (1.3mg/m²). Other drug-related toxicities observed included: Grade 3: fatigue (n=2), neutropaenia (n=1), sepsis (n=2), PN (n=1); Grade 2: PN (n=6), nausea (n=1). Five pts required bortezomib dose reductions because of PN (n=4). Two pts required a romidepsin dose reduction because of fatigue (n=1) and abnormal LFTs (n=1). The overall response rate (ORR) is 12/18 (67%) (4 CR/nCR, 4 VGPR, 4 PR) with an additional 5 (28%) patients achieving an MR. To date, 7 patients have entered the romi Mx phase. Pt numbers 1, 2, 6, 7, 9, 10 and 11 been on Mx for 15, 3, 12, 8, 7, 4, and 5 months respectively. Four pts have progressed after C1 (n=2), C4 (n=1) and C8+3Mx (n=1). Of note, 3 pts have entered this trial having progressed on a separate trial examining bortezomib maintenance therapy (study protocol PMCC 05/69). These 3 pts were receiving 2 weekly bortezomib and progressing. On the introduction of bortezomib/dexamethasone/romidepsin, the M band has fallen in all assessable pts [41 to 26 (C2); 16 to 11 (C2); 1 pt has not completed C1].

CONCLUSION. This combination of a bortezomib and dexamethasone with romidepsin is well tolerated, with similar TCP compared to single agent bortezomib and romidepsin and demonstrates substantial efficacy in a heavily pre-treated group of patients. The high response rate (OR 67% + 28% MR), impressive depth of response (44% CR + VGPR), durable responses and the observation of a drop in M band in pts progressing on bortezomib as their immediate prior therapy, all indicate that romidepsin has synergistic activity with bortezomib-dexamethasone.