Salvage Therapy with Intravenous Liposomal Adryamicin (A), Bortezomib (B), Cyclophosphamide (C), and Dexamethasone (D) (ABCD) in Previously Treated Myeloma Patients

Abstract

Background: Bortezomib is one of the most active drugs for the treatment of multiple myeloma and there are evidences that its activity is highly increased when it is used in combination with other drugs. We have already reported the activity of Bortezomib in combination with intravenous Melphalan (5 mg/m2) and Dexamethasone (BMD) in relapsed/refractory myeloma patients (ASH 2007, #2728). However, this scheme resulted in an elevated percentage of haematologic toxicity that prompted us to test the combination of Bortezomib with other less myelotoxic but active drugs such as Cyclophosphamide, and a liposomal Adryamicin.Methods: Bortezomib was given at dosage 1.3 mg/m2, and Dexamethasone 40 mg i.v. on days 1, 4, 8, 15 plus liposomal Adryamicin 20 mg i.v. on days 1 and 15, and Cyclophosphamide 100 mg per os for 15 days (1à15). An antibiotic and antiviral prophilaxis was guaranted to all patients with Bactrim and Acyclovir, and EPO and G-CSF were used as recommended. So far, 17 previously treated patients have been enrolled in this study, 4 males and 13 females. Median age was 63 (range 51–78), 7/17 patients were IIIA stage according to Durie and Salmon classification and 3/17 had extra-medullary disease. Five patients were resistant to previous therapies and 10 were relapsed. All patients had been already treated with a median of 2 previous lines of treatment (range 1–6). Four patients were in relapse within 12 months of stem-cell transplantation and 12 patients had already received Bortezomib alone or in combination. Six patients had been already treated with BMD (three were refractory, one in partial remission, and two relapsed)Results: After a median follow up of 5 months (range 1–8) 15/17 were valuable for response since they have received at least 2 cycles of therapy. 6/15 (40%) patients were considered responder: 3 patients had a very good partial remission (M-protein ≤ 90%), 3 patients a partial remission (M-protein >50%), 1 progressed, and 8 were in stable disease according to International Myeloma Working Group Criteria. Side effects were predictable and manageable; the most common grade 3/4 adverse events included hematologic toxicity (thrombocytopenia [18%], neutropenia [6%], anemia [6%]), paresthesia grade 2 in 3 patients and nausea and vomiting grade 3 in only one patient. So far, 1 patient has stopped treatment for progression disease, and only one for toxicity (infectious disease grade III), in both cases after 2courses. In table 1 the comparison of efficacy and toxicity between ABCD and BMD after 3 cycles is reported. ABCD seems to be as effective as BMD (considering that 1/3 of patients had been already treated with BMD) but with higher tolerability.Conclusion: The combination of liposomal Adryamicin, Bortezomib, Cyclophosphamide, and Dexamethasone (ABCD) is effective and well tolerated treatment even for heavily pretreated patients with poor prognostic features. The dosage of some drugs could be increased in order to maximize the overall response rate.BMD%ABCD%p - valueTOXICITY#evaluable cycles15210057100witheld or deferred cycles2516240,03Hematological toxicity grade 3–453358*140,005Extrahematol toxicity grade 3–4858*140,05of pts w RBC transf1611120,07of pts w PLT transf128120,2of pts w G-CSF4127120,0001stop Tx for toxicity64120,28stop Tx for progression10,6120,89RESPONSETot pts3410015100PD39170,74SD15448530,78PR7203200,69VGPR6183200,81CR39000,57* only 1 patient grade 4