The role of bendamustine in the management of plasma cell myeloma

In this issue of Leukemia and Lymphoma , Musto and colleagues report on 78 patients with myeloma who received bendamustine as part of a nationwide compassionate-use program. Th e overall response rate, using bendamustine combined primarily with either lenalidomide or bortezomib, was 29% in a heavily pretreated population. Th e response rate in patients who received bendamustine in the absence of a novel agent was only 10%. Although the numbers were small, the response rate appeared to be better when bendamustine was combined with lenalidomide, but this did not translate to improved survival, which was seen in the group that received bendamustine and bortezomib [1]. Bendamustine is a bifunctional hybrid alkylating agent (Figure 1) used in the treatment of chronic lymphatic leukemia and lymphomas, fi rst synthesized in 1963 by Ozegowski and Krebs [2]. In the United States, it has Food and Drug Administration (FDA) approval for its use in indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with a rituximab-containing regimen, and chronic lymphocytic leukemia (CLL). It is eliminated primarily through the kidneys, and is not FDA approved in the USA for use with a creatinine clearance below 40 mL/min. A phase 1 trial of 31 patients with myeloma, progressing after high-dose therapy, was reported. Patients received 100 mg/m 2 of bendamustine on days 1 and 2, with an overall response rate of 55% and a median progression-free survival of 26 weeks [3]. In a phase 3 myeloma trial, bendamustine – prednisone produced a higher complete response rate (32% vs. 13%) and a more rapid response than melphalan – prednisone. Th e duration of response was signifi cantly longer with bendamustine – prednisone, and the patients receiving bendamustine had a higher quality of life and less pain. Th is phase 3 trial in untreated patients suff ers from the fact that novel agents were not used, and the comparator arm of melphalan and prednisone as a single agent would no longer be considered standard of care [4]. Multiple recent trials combining bendamustine with either immunomodulatory drugs or proteasome inhibitors have recently been published, and support consideration of bendamustine for the treatment of relapsed disease. Th e drug can be used safely in patients with myeloma cast nephropathy and renal impairment. A trial in which the effi cacy of bendamustine was evaluated in patients with varying degrees of renal impairment has been reported. Bendamustine 60 mg/m 2 per day for 2 days combined with bortezomib in a schedule of 1.3 mg/m 2 on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 resulted in a 67% response rate with an additional 17% having a minor response, for a clinical benefi t rate of 83%. Th e median progression-free survival and overall survival were 10 and 25 months, respectively. Results were better for those patients with an estimated glomerular fi ltration rate (eGFR) 15 mL/min [5]. In a trial of 49 patients with newly diagnosed plasma cell myeloma, receiving bendamustine 60 mg/m 2 on days 1 and 2, bortezomib 1.3 mg/m 2 on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 every 21 days, 82% of patients responded at a median of one cycle; in this case, the outcomes were not statistically better than for patients with renal insuffi ciency at presentation, suggesting that bendamustine – bortezomib can eliminate the adverse prognostic impact of cast nephropathy [6].