Safety and Efficacy of the Combination of Bortezomib with the Deacetylase Inhibitor Romidepsin in Patients with Relapsed or Refractory Multiple Myeloma: Preliminary Results of a Phase I Trial.

INTRODUCTION. There is substantial pre-clinical data demonstrating single agent and synergistic activity of the proteasome inhibitor (PI) bortezomib and deacetylase inhibitors (DACi) in multiple myeloma (MM). This is the first clinical trial combining these two classes of drugs.

METHODS. This is an ongoing open label single-centre single-arm phase I/II dose escalation trial of bortezomib, dexamethasone and romidepsin (depsipeptide) in patients with relapsed or refractory MM. All patients received bortezomib (1.3 mg/m²; d1,4,8,11) with dexamethasone (20mg d1,2,4,5,8,9,11,12). The dose escalation of romidepsin commenced at a dose of 8 mg/m² IV d1, 8, 15 every 28d and involved an initial accelerated dose escalation phase, with intra-patient dose escalation of romidepsin. Response rates were assessed according to M-protein response criteria, with complete responses documented by EMBT criteria.

RESULTS. To date, 8 patients have entered the study with 7 evaluable for response and toxicity. Median number of prior therapies = 2 (range: 2–5). Most patients had previously taken potential neurotoxic medications; vincristine-containing (3), thalidomide (4), bortezomib (1). No dose-limiting toxicities (NCI-CTC v3: defined as platelets <25 × 10⁹/L; Grade 4 neutropenia despite G-CSF support; Grade 3 or 4 nausea, emesis or diarrhoea despite treatment; any other Grade 3 or 4 non-haematological toxicity; > 4 week suspension of treatment due to toxicity) were demonstrated at romidepsin doses of 8mg (n=1) or 10mg (n=3). At doses of 12mg, 3 episodes of Grade 4 thrombocytopenia occurred and one episode of febrile neutropenia. Of note, 2 of the patients with Grade 4 thrombocytopaenia had platelets below 100 × 10⁹/L prior to commencing the combination (at inclusion, patients must have had a platelet count >50 × 10⁹/L). Other drug-related toxicities observed include: Grade 3: fatigue (n=1), neutropaenia (n=1), sepsis (n=1); Grade 2: fatigue (n=1), peripheral neuropathy (n=2), nausea (n=1), diarrhoea (n=1). Two patients required dose reduction of bortezomib due to peripheral neuropathy (these patients were co-administered 12 mg/m² romidepsin). As of August 2007, the median number of cycles delivered was 3; 3 patients have progressed (after Cycle 1 (n=2), and Cycle 4 (n=1). There has been 1 immunofixation negative Complete Response, 3 Partial Responses and 1 Minor Response with an overall response rate of 5/7 (71%). Most patients remain on the combination therapy (n=5/8). The trial continues accruing patients at the doses of romidepsin (10 mg/m²) with bortezomib (1.3 mg/m²).

CONCLUSION. These early results demonstrate efficacy with a promising response rate and some durable responses with acceptable toxicity of a proteasome inhibitor-DACi combination. There are planned regimen scheduling modifications to address the current dose limiting toxicity of transient thrombocytopenia.