The Effect of Statin Use at the Time of Autologous Transplant on Response and Survival in Patients with Multiple Myeloma.

Background : Statins (HMG-CoA reductase inhibitors) prevent the synthesis of mevalonic acid and ultimately this interferes with the isoprenylation of proteins involved in the cell cycle, namely Ras, Rac, and Rho A kinases, sometimes resulting in caspase-3 dependent apoptosis. Lovastatin has been shown to have antimyeloma activity in myeloma cells (van de Donk, Leukemia, 2002) and simvastatin restores chemosensitivity to myeloma cells exhibiting cell adhesion mediated drug resistance (Schmidmaier, Blood, 2004). Simvastatin when added to bortezomib or bendamustine in 6 patients with relapsed myeloma improved responses (Schmidmaier, EJH, 2007). Because autologous hematopoietic stem cell transplantation (HSCT) following high-dose melphalan is a standard treatment and statins may serve as sensitizing agents, we hypothesized that statin use at the time of autologous HSCT may increase the response rate to transplant, improve progression free survival (PFS), and prolong overall survival (OS).

Methods : 146 patients with MM underwent autologous HSCT after melphalan 200mg/m² at Ohio State University between June 1999 and December 2006. We reviewed their records and divided the patients into those that received (n=28) or did not receive (n=118) statins (≥ 20mg/day) for at least one month before and after transplant. Response was assessed according to the International Myeloma Working Group (IMWG) uniform response criteria (Durie BG et al. 2006).

Results : The median age of the study population was 58 years (range 35–74yrs) with 86 male and 58 female patients. The two groups had similar baseline characteristics including age, serum cholesterol, international stage, disease status at the time of transplantation, number of prior therapies, and percentage of patients with high-risk cytogenetics (defined by the presence of t[4;14], t[14;16], deletion 17p, karyotypic del 13, del 13q w/14q32 rearrangement, or any tetrasomy). Stem cell mobilization in patients using statins yielded a mean of 8.3 x 10⁶ CD34+ cells/kg versus 6.5 in patients not taking statins (p=0.4). The rate of complete response (CR) plus very good partial response (VGPR) in patients using statins (43%) was comparable to the CR + VGPR rate (45%) in patients not using statins (p=0.84). However the overall response rate (CR + VGPR + PR) was higher in the statin group (93% vs. 78%; p=0.07). In a subset analysis of patients with high-risk cytogenetics, the overall response rate in the statin group (n=5) was 100% versus 78% for non-statin group (n=14). Median overall survival (OS) for the statin vs. non-statin groups were 25.7 and 22 months respectively (P 0.65), and the progression free survivals were 19.5 and 14.8 months respectively (p=0.97). Three year PFS in the statin versus no statin groups were 32% and 30% respectively. No differences in terms of hepatic toxicity, myositis, infectious complications, and fatal cardiovascular events between groups were noted.

Conclusion: Patients using statins at the time of transplant showed a trend for a better overall response rate (93% vs. 78%; p=0.07) that did not translate to improved PFS or OS.