An Open-Label Phase 1/2 Trial of Bendamustine Combined with Bortezomib for Patients with Relapsed/Refractory Multiple Myeloma

Multiple myeloma (MM) is an aggressive and incurable disorder with an eventual fatal outcome bringing urgency to the identification of effective treatments for patients who have exhausted standard chemotherapy. New agents, such as lenalidomide and bortezomib have led to a rapid increase in therapeutic options as single agents and in combination with other agents. However, despite this progress nearly all patients will relapse and require additional therapeutic options. Bendamustine is a unique chemotherapeutic agent that combines an alkylating group with a purine-like benzimidazole ring that is approved in the US for the treatment of CLL and refractory indolent B-cell NHL. Bendamustine is approved in Europe for the treatment of MM. Bortezomib is a proteasome inhibitor (PI) that is approved for the treatment of MM and the combination of this PI with alkylating agents including melphalan and cyclophosphamide has proven highly effective in the treatment of MM. Thus, the combination of bortezomib with bendamustine which also possesses alkylating agent properties may enable patients that were previously treated with bortezomib to have additional therapeutic options. In addition, this combination may allow use of lower doses of bortezomib to be used potentially reducing the incidence of peripheral neuropathy as has been observed in other combinations involving bortezomib with other alkylating agents. This study is being conducted to assess the safety and efficacy of bendamustine in combination with bortezomib for the treatment of relapsed/refractory MM.

This open-label, Phase 1/2 study, will enroll up to 40 patients (pts), age ≥18 years, with measurable MM that has relapsed following or is refractory to at least 1 previous treatment. Patients received bendamustine infused intravenously over 1 hour on days 1 & 4 in 3-dose cohorts of 50, 70, or 90 mg/m² and bortezomib on days 1, 4, 8, & 11 at a fixed dose of 1.0 mg/m² for up to eight 28-day cycles. Three pts were initially enrolled at each dose cohort. Up to 5 pts were allowed to enroll in each initial cohort if they were all in screening prior to the 3^rd pt being enrolled. After the first 3 pts completed cycle 1 of each dose, the cohort was assessed for dose-limiting toxicities (DLT). In this study, a DLT was defined as any study drug related grade 3 or grade 4 non-hematologic toxicity, grade 4 hematologic toxicity, grade 3 thrombocytopenia with grade 3 or 4 hemorrhage, grade 3 febrile neutropenia, grade 3 or grade 4 nausea and vomiting refractory to anti-emetic therapy, or any drug-related deaths. A standard 3+3 approach was used for determining the MTD. The MTD cohort will be expanded so that up to 40 total pts are enrolled.

Twenty-five pts with a median age of 62 (44-91) have been enrolled on the study and received at least 1 dose of study drug, and 52% of the pts are male. Patients had received a median of 4 (1-17) prior therapies. Notably, 80% (20/25) of pts had received at least one prior bortezomib-containing regimen. For the Phase 1 portion, 5 pts were enrolled into the 50 mg/m² cohort, 4 pts were enrolled into the 70 mg/m² cohort and 5 pts were enrolled into the 90 mg/m² cohort. No DLTs were observed in the phase 1 portion of the study. The maximum dose (90 mg/m²) was well tolerated. Patients are currently enrolling into the Phase 2 portion of the study and receiving this dose of bendamustine in the combination treatment. To date, the most common grade 3 or 4 adverse events, occurring in more than 10% of pts, were neutropenia (36%), anemia, (24%), thrombocytopenia (24%), and renal failure (12%). A worsening of baseline peripheral neuropathy was reported in 20% of pts. Two (8%) pts were reported to have grade 1, treatment emergent peripheral neuropathy. To date, nearly one-third (8/25) of pts have achieved an MR or PR. To date, 16 pts have been enrolled at the 90 mg/m² dose of bendamustine and 5 (31%) have achieved an MR or PR.

The combination of bendamustine 90 mg/m² on days 1 and 4 and bortezomib 1.0 mg/m² on days 1, 4, 8, & 11 appears to be safe and effective in this heavily pre-treated patient population. The phase 2 portion of this study is ongoing.

Berenson:Cephalon: Consultancy, Research Funding; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Bendamustine is approved for CLL and refractory NHL. It is being studied in combiantion with bortezomib for multiple myeloma. Siegel:Cephalon: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Marmatech: Research Funding; Medivation: Research Funding; Caremark/CVS: Consultancy. Swift:Millennium: Speakers Bureau. Ehrman:Cephalon Inc.: Employment. Bensen-Kennedy:Cephalon Inc.: Employment.