Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients

Lenalidomide (Revlimid) is an oral analogue of thalidomide that lacks both the neurotoxic and teratogenic side effects associated with the parent drug and, in laboratory studies, has more potent antitumour and immunomodulatory activity. In vitro studies suggested that its action may be synergistic with a number of conventional chemotherapeutic agents and clinical studies have shown it to be effective when combined with dexamethasone for the treatment of relapsed/refractory myeloma (Richardson et al, 2002, 2006; Dimopoulos et al, 2005; Rajkumar et al, 2005; Weber et al, 2006). Based on the in vitro data, we postulated that the addition of an alkylating agent to lenalidomide and dexamethasone could increase response rates; therefore, we conducted a retrospective analysis to assess the efficacy and toxicity profile when lenalidomide was used in combination with cyclophosphamide and dexamethasone for patients with relapsed refractory disease. Multiply relapsed/refractory patients were given lenalidomide 25 mg p.o. days 1–21, cyclophosphamide 500 mg p.o. days 1, 8, 15 and 21, and dexamethasone 40 mg p.o. days 1–4 and 12–15, of a 28 day cycle for a maximum of 9 cycles. Toxicity profiles and response were assessed every 4 weeks. Twenty-one patients were included with a median age of 59 years (range: 34–76 years). All were heavily pretreated with a median of four previous lines of therapy (range: 1–8): 14 patients had received high-dose melphalan, 21 patients thalidomide, 17 patients bortezomib and two had undergone an allogeneic bone marrow transplantation. The median time from diagnosis to treatment initiation was 54 months (range: 11–122 months). To date, 93 complete courses of therapy have been given to 21 patients with median number of five courses (range: 1–8). The side effect profile was highly predictable with the neutrophil count falling below 0.5 · 10/l in eight patients (38%). By the end of the third cycle of treatment, this required a dose reduction or withdrawal of cyclophosphamide in 10 patients (48%), and a dose reduction of lenalidomide in five patients (24%). Granulocyte colony-stimulating factor was required in 12 patients (57%). Despite this, i.v. antibiotics for neutropenic fever were only required in six patients (29%). In contrast to other immunomodulatory drugs, the side effect profile of the combination was highly tolerable with no patient experiencing sedation, constipation or worsening of peripheral neuropathy. Deep vein thrombosis occurred in three patients (14%) with a heavy myeloma load, which is similar to the rates seen with the lenalidomide and dexamethasone combination (Dimopoulos et al, 2005; Weber et al, 2006). Response to therapy using the European Group for Blood and Marrow Transplantation criteria (Blade et al, 1998) was seen in 15 of 20 assessable patients [one complete response (CR), three very good partial response (PR), nine PR and two minimal response], resulting an overall response rate (CR + PR) of 65%. The median time to response was prompt at 31 days (range: 15– 68), which is in contrast to what would be expected with a VAD (dexamethasone, doxorubicin, vincristine)-type regimen in this setting. This prompt response resulted in no difference in response rates between those patients who required a dose reduction in therapy compared with those who tolerated fulldose treatment as all patients received full-dose therapy for their first treatment course. To date, only two patients have discontinued therapy because of a failure to respond to therapy; however, one unusual case discontinued therapy as a consequence of hepato-toxicity although the relationship to lenalidamide remains uncertain. With a median follow-up of 8 months (range: 4–15), there were no treatment-related deaths, but five patients have died from progressive/relapsed myeloma with the median time to progression of 171 days. In summary, the combination of RCD is effective in heavily pretreated myeloma patients and has manageable toxicities. The toxicity profile of RCD seems better than with similar combinations using melphalan based on the currently available datasets. The observed overall response rate of 65% appears superior to lenalidomide alone (17–23%) or in combination with dexamethasone (48–51%) (Dimopoulos et al, 2005; Richardson et al, 2006; Weber et al, 2006). In view of the frequent yet tolerable neutropenia, we would suggest that further studies using this combination should be carried out with less frequent cyclophosphamide dosing, which may be optimal especially in the elderly population.