Lenalidomide (Revlimid) combined with continuous oral cyclophosphamide (endoxan) and prednisone (REP) is effective in lenalidomide/dexamethasone‐refractory myeloma

Lenalidomide (Revlimid ) has significant activity in multiple myeloma through induction of apoptosis, targeting the bone marrow microenvironment, and stimulation of Tand Natural Killer-cell mediated immune responses. Laboratory studies showed that lenalidomide also enhanced the efficacy of various anti-myeloma agents including cyclophosphamide and dexamethasone (Hideshima et al, 2000; Blansfield et al, 2008; van der Spek et al, 2009). Previously, we showed that continuous low-dose oral cyclophosphamide (endoxan) in combination with prednisone had remarkable activity in relapsed multiple myeloma (de Weerdt et al, 2001). To further improve the efficacy of this oral regimen, we undertook a retrospective analysis to evaluate the combination of lenalidomide with continuous low-dose oral cyclophosphamide and prednisone (REP) in 14 lenalidomide/dexamethasone-refractory myeloma patients. The REP regimen consisted of lenalidomide (10 mg; 21 d, followed by 1 week rest), combined with continuous low-dose oral cyclophosphamide (100 mg) and prednisone. Prednisone was started at 20 mg daily and tapered to 10 mg within 8 weeks after start of therapy. This treatment was continued in responding patients and in case of stable disease until disease progression. All patients received aspirin (100 mg daily) as thromboprophylaxis and cotrimoxazol (480 mg daily) as infection prophylaxis. We treated five male and nine female patients with a median age of 65Æ9 years (range: 39Æ6–81Æ2 years). All patients were heavily pre-treated and had received a median of 6 (range: 4–8) previous lines of anti-myeloma therapy including autologous stem cell transplantation in 10 patients (71Æ4%) and allogeneic stem cell transplantation in seven patients (50%). Thalidomide was previously administered to 13 patients (92Æ9%), bortezomib to 13 patients (92Æ9%), and all patients had received alkylating agents, and also lenalidomide plus dexamethasone. In 12 patients REP chemotherapy was started because of progressive disease during treatment with the combination of full dose lenalidomide (25 mg, days 1–21 of a 28 day cycle) and dexamethasone (40 mg, days 1–4 and 15–18) and in two patients because of lenalidomide/dexamethasone-refractory disease and subsequent failure to treatment with oral cyclophosphamide combined with prednisone. Median time from diagnosis to the first REP cycle was 6Æ5 years (range: 3Æ8– 15Æ1 years). A total of 121 cycles of REP were administered with a median number of eight courses (range: 2–18). Response to therapy using the European Group for Blood and Marrow Transplantation criteria (Bladé et al, 1998) was seen in nine patients (64Æ3%), including two patients (14Æ3%) with a complete response (CR), three (21Æ4%) with a very good partial response, two (14Æ3%) with a partial response (PR), and two (14Æ3%) with a minor response (MR) (Table I). Three patients (21Æ4%) had stable disease and two (14Æ3%) patients had progressive disease. Interestingly, in two patients who progressed during treatment with lenalidomide and dexamethasone, treatment with the REP regimen resulted in a CR. Five of 12 patients who obtained response or stable disease progressed. One patient died of progressive disease. With a median follow-up period of surviving patients of 12Æ8 months (range, 4Æ7–19Æ9 months), median progression-free survival was 12Æ2 months and overall survival at 1 year was 92Æ9%. Toxic effects were graded according to the National Cancer Institute’s Common Toxicity Criteria (CTC), version 3 (http:// ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/ctcaev3.pdf). Four patients experienced CTC grade 3 neutropenia during a total of nine courses and two patients had grade 4 neutropenia during two courses. Pegylated granulocyte colony-stimulating factor was administered in three patients during five cycles for grade 3 neutropenia and on a pre-emptive basis during 11 cycles in two patients who suffered neutropenia during previous therapy with lenalidomide/dexamethasone. CTC grade 3 anaemia occurred in two patients (total of six courses) and grade 3 thrombocytopenia in three patients (total of seven courses). During therapy one patient had a grade 2 upper respiratory tract infection, one patient a grade 2 urinary tract infection, and three patients had grade three infections (all pneumonia). Other CTC grade 3 events were deep venous thrombosis (DVT) in two patients (one patient developed a DVT after stopping aspirin) and nonspecific colitis in one patient. Only one patient experienced (grade 1) bladder irritation, which resolved after dose reduction of cyclophosphamide. One patient permanently stopped treatment because of nonspecific colitis, after which he developed progressive disease. In eight patients, cyclophosphamide dose was reduced to 50%, in seven because of haematological toxicity and in one patient because of bladder irritation. Sedation, worsening of polyneuropathy, Correspondence