Efficacy and safety of fotemustine for the treatment of relapsed and refractory multiple myeloma patients

To the editor: Multiple Myeloma (MM) is highly sensitive to alkylating agent, particularly to melphalan. Despite the emerging role of new biological agents (thalidomide, lenalidomide, bortezomib), melphalan still remains a milestone in the treatment of MM (1). It is effective in conjunction with autologous stem cells support (2), as well as conventional dose therapy with prednisone with or without new drugs [melphalan, prednisone, revlimid (MPR), melphalan, prednisone, thalidomide (MPT), velcade, melphalan, prednisone (VMP)] (3). Although the outcome has significantly improved in the last decade MM remains incurable. Thus it is important to identify new compounds active against the plasmacell clone. Fotemustine (Muphoran , Servier; Thissen Laboratoires, Braine L’alleud, Belgium) (4), a cytotoxic alkylating agent belonging to the nitrosoureas family, has been successfully used as single agent or in combination for the treatment of neoplasm such as metastatic melanoma and brain tumours. Only one phase II study has been reported in relapsed or refractory MM (5). Here we report our experience with single agent fotemustine used on a compassionate basis in five heavily pre-treated MM patients (two males, three females, and age range 41–64). All patients had a poor performance status and compromised haematological conditions. Two patients had chronic renal failure. All patients had received at least five prior lines of therapy, including thalidomide and bortezomib. We adopted the schedule reported by Dumonet et al. that consists of an induction with two doses of fotemustine 100 mg ⁄m delivered intravenously 1 wk apart. This was followed by a dose of fotemustine 100 mg ⁄m every 3 wks until progression or unacceptable toxicity, to a maximum of 16 administrations. No hospitalisation was required for treatment administration. Table 1 reports the most relevant clinical data and the therapeutic history of each patient. Table 2 summarised haematological characteristics, the type and the incidence of adverse events, and the outcome of treatment according to European group for blood and bone marrow transplant (EMBT) uniform response criteria (6). Two of five patients completed the 16 scheduled doses achieving a partial response (PR). One is in partial remission and the other in progression after 17 and 18 months, respectively, from starting fotemustine. Three patients did not complete the programme: two patients died of progressive disease after 9 months and 4 months of therapy, one patient died of encephalitis while in partial remission after 12 months of therapy. No dose reduction was needed, even in the two patients with renal impairment. Most common grade 4 National cancer institute (NCI) haematological toxicity was thrombocytopenia (20 episodes), followed by neutropenia (six episodes) and anaemia (three episodes). Infection was the most common extraematological toxicity: three episodes of NCI grade 3 infection without neutropenia, one grade 4 febrile neutropenia, one herpes zoster reactivation, a fatal encephalitis. In particular, regarding the adverse event encephalitis, no infectious agent could be identified despite cerebrospinal co-cultures both for bacterial and mycotic agents and polymerase chain reaction for brain tropic viruses were made; no abnormalities were detected in peripheral blood lymphocytes count. In conclusion, fotemustine as a single agent appears manageable and safe for the treatment of heavily pretreated relapsed or refractory MM patients. PR was the best response