Fluvastatin-Zometa (FluZom) as A Possible Therapeutic Approach to Plasma Cell Disorders.

Despite significant improvement in the outlook for newly diagnosed patients with multiple myeloma (MM) the disease remains incurable. Novel therapeutic approaches are therefore required. We have previously demonstrated in vitro that both the third generation nitrogen-containing bisphosphonate zometa and the HMG-CoA reductase inhibitor fluvastatin have anti-proliferative and apoptosis-inducing effects against human myeloma cell lines (HMCL). Furthermore, isobologram analyses with the 2 compounds have demonstrated synergistic activity against HMCL. Based on this we have undertaken a pilot study of fluvastatin and zometa (FluZom) in a group of patients with progressive plasma cell disorders (PCD). A 16-week treatment phase was planned with patients commencing fluvastatin 40mgdaily on day 1 escalating to 80mg daily from day 15 to day 112. Zometa 4mg IV over 15 minutes was given on days 29, 57, 85 and 112. Any patient demonstrating any response, based on conventional criteria, or stable disease (SD) by day 112 remained on treatment until further progression (PD). PD prior to day 112 mandated treatment withdrawal. Eleven patients were enrolled on trial - progressive MM (n = 9), smouldering myeloma (SMM) progressing to MM (n = 1) and progressive POEMS disease with multisystem involvement (n = 1). All except the SMM patient were heavily pretreated - median 3 (range, 0 – 6) prior treatment regimens, 7 with prior ASCT and 4 with prior radiotherapy. Median age was 61 years (range, 44 – 74). Six patients completed 16 weeks of therapy, 5 progressed prior. Of the former, 4 (36%) demonstrated SD and continued on therapy to a total of 20, 23 (patient no. 2), 28 (patient no.1) and 45 weeks. No patient demonstrated a disease response based on standard criteria. Patients no.’s 1 and 2 were pancytopenic prior to therapy and demonstrated normalisation of haemoglobin (no. 1), platelets (no. 1) or total leucocytes (no.’s 1 and 2). Two patients, neither of whom achieved SD but who completed 16 weeks of therapy, had a plasma cell labelling index (PCLI) undertaken pre and post therapy, both showed a reduction in the PCLI following therapy - 5.4% to 3.6% and 2.6% to 1.3%, respectively. Therapy was well tolerated with 3 patients developing transient elevation of liver transaminases. We conclude that FluZom while not producing disease response as judged by conventional criteria did nonetheless exhibit beneficial biological activity in a minority of this cohort of progressive PCD patients. Further evaluation in patients with early and/or untreated disease is warranted.