Combination of Bendamustine, Lenalidomide, and Dexamethasone In Patients with Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of a Phase I Clinical Trial

Lenalidomide is an analog of thalidomide that has significant clinical activity in combination with dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. This multicenter phase I trial is the first to investigate the combination of bendamustine, lenalidomide, and dexamethasone. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM.

Patients aged ≥18 years with confirmed, measurable symptomatic MM that was refractory to or progressed after 1 or more prior therapies were treated with bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau or best response, as determined by the International Myeloma Working Group uniform response criteria, was reached. Study drug doses were escalated through 3 levels (Table 1) in a 3+3 dose-escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level is associated with DLTs in ≥2 patients. After determining the MTD, an expansion cohort of 12 additional patients at the MTD will be treated to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy as evidenced by objective response, time to disease progression, and overall survival.

Twenty-six patients with a median age of 63 years (range, 38 to 81 years) were enrolled. The mean number of prior therapies was 3 (range, 2–7); 81% of the patients had prior lenalidomide, 48% had prior thalidomide, and 29% had both. The MTD was identified at dose level 2: 75 mg/m² bendamustine and 10 mg lenalidomide. Four DLTs were recorded: at dose level 2 (n = 6), 1 patient with grade 4 neutropenia; at dose level 3 (n = 6), 2 patients with grade 4 neutropenia and another with delayed platelet recovery from grade 3 thrombocytopenia. Currently 9 patients have been enrolled in the expansion cohort. Twenty-one of 26 patients received at least 2 cycles and were included in the response assessment. A partial response (PR) or better was observed in 63% (n = 12) of the patients, including 16% (n = 3) achieving a very good PR (VGPR). In addition to these 12 patients, another 3 (15%) had a minor response (25%-49% reduction in M-protein). Stable disease was observed in 32% (n = 6), and only 5% (n = 1) had disease progression. The median time to next treatment was 8.1 months (range, 1.9–27.3 months). Other grade 3/4 adverse events occurring after the first cycles of treatment included prolonged QTc in 1 patient.

This is the first phase I trial testing the combination of bendamustine, lenalidomide, and dexamethasone for relapsed and refractory MM. This regimen is well tolerated even in older patients up to 81 years. With a PR/VGPR rate of 63%, this combination is a highly active regimen even in heavily pretreated MM patients, and its side effect profile makes it an attractive treatment option for MM patients especially with pre-existing therapy-related peripheral sensory neuropathy. Final data on response and overall survival will be available at the time of presentation.

Lentzsch:Celgene Corp: Research Funding. Roodman:Amgen, Novartis, Celgene, Acceleron: Consultancy. Zonder:Amgen, Celgene, Cephalon: Consultancy; Millennium: Research Funding; Millennium: CME only, no promotional work.