Abstract
In the recent years the treatment of patients with multiple myeloma (MM) has changed because of the introduction of new agents, mainly thalidomide (THAL) and its derivatives and bortezomib, an inhibitor of the 20S proteasome. Lovastatin (LOV) and other inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, have been demonstrated to exibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines including our own experiments. This observation induced us to administer LOV in combination with THAL and dexamethasone (DEX). We report here our preliminary experiences with THAL and LOV therapy in patients with refractory and relapsed MM. We have treated 81 patients with THAL+DEX regimen (TD) or THAL+DEX+LOV regimen (TLD). Patients received drugs orally in 28 day cycles. THAL was given from day 1 to day 28 each cycle and it was started at a initial dose of 100 mg daily increased to 300 mg daily. DEX was administered at a dose of 40 mg daily in days 1–4 each cycle. LOV was administered at a dose of 2 mg/kg in days 1–5 and 8–12 and at a dose of 0.5 mg/kg in days 15–28 each cycle. TLD regimen was administered to 43 patients and TD regimen to 38 patients. Patients characteristics before treatment were as follows: the median age 61.2 years; 61% of patients IgG, 26% IgA, 7% light chain and 6% other; 76% of patients were light chain kappa and 24% lambda; median serum M-protein level was 4.2 g/dl, bone marrow plasma cells 47%, hemoglobin 10.1 g/dl, platelets 197 G/l, beta-2-microglobulin 4.2 mg/ml, albumin 3.9 g/dl and LDH 292 IU. The median follow-up was 29 month. A clinical response, defined as a reduction of M-protein level by 50% or more, was observed in 67.8% of patients in TD group and in 88.0% in TLD group. CR i NCR was observed in 35.0% and 62.7% respectively. In 11 TLD (25.5%.) and 4 TD (10.5%) patients successful stem cell harvest was performed and mean amount of collected CD34+ cells was 8.2*106/kg. Successful autologous transplantation was performed in 8 patients from this group. Overall survival in TLD group (median 23.0 months) was significantly longer than in TD group (median 18.0 months). Similarly event free survival was longer in TLD (median 7.0 months) group than in TD group (4.5 months). We observed significant negative correlation between response and bone marrow infiltration (p=0.008), M-protein level (p=0.0004) and positive correlation between response and albumin level (p=0.005). Short time to reduction of M-protein by 50% was connected with better response. Common side effects as somnolence, fatigue and constipation were observed in about 45% of patients in TLD and TD groups. In 2 TLD and in 3 TD patients we diagnosed deep vein thrombosis. In 2 TLD patients sinus bradycardia was observed. Our results suggest that addition of LOV to THAL and DEX improves response rate in patients with refactory and relapsed MM. Moreover it is possible to harvest stem cells and perform autologous stem cells graft in patients treated with such regimen. A future prospective randomised study is needed to confirm the value of LOV or other HMG-CoA reductase inhibitors in the treatment of MM patients.
Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency
