Effect of Expression of Multidrug Resistance Genes on Efficacy the Treatment of Multiple Myeloma By Proteasome Inhibitor

Background: Increased expression of efflux protein, such as P-glycoprotein, multidrug resistance protein, lung resistance protein, breast cancer resistance protein are a major reason for resistance to existing or previously effective therapy multiple myeloma (MM). Effect of the expression of genes of multidrug resistance (MDR) - MDR1, MRP1, LRP, and BCRP on the efficacy of therapy with proteasome inhibitor is currently not well understood.

Aim: Determination of mRNA expression of genes responsible for the development of drug resistance, such as MDR1, MRP1, LRP, BCRP in bone marrow aspirates in patients with newly diagnosed and refractory / relapsed MM before start bortezomib-containing chemotherapy programs.

Materials and methods: We studied bone marrow aspirates of 29 patients (12 men and 17 women) aged 48 to 77 years (median 60 years) with stage 3 MM by classification Durie-Salmon. 14 of studied patients made a group of newly diagnosed MM. 15 patients made a clinically refractory / relapsed group MM. The bone marrow in this group of patients was studied after treatment with alkylating agents at the time of registration of resistance to the given therapy. In the future, all patients were treated by bortezomib - containing chemtheapy regimens. mRNA expression studied genes was determined by semi-quantitative polymerase chain reaction reverse transcription.

Results: In both groups of patients had comparable expression of all studied MDR`s genes. In the group of newly diagnose patients the MDR 1 mRNA expression was detected in 93% (13/14) of the samples, the mRNA of the gene MRP 1 was detected in 79% (11/14). The BCRP mRNA expression was detected in 100% of the investigated samples. The expression of mRNA of the gene LRP was identified in 71% of the studied cases (10/14). In the group of patients after treatment with alkylating agents the expression of mRNA of MDR1 was detected in 87% (13/15) of samples, MRP 1 was detected in 93% (14/15), BCRP was in 100% of cases, and the LRP mRNA was detected in 13/15 (87%) of the samples.Treatment efficacy was assessed by Iinternational Unified Response Criteria for multiple myeloma after the 6 cycles of treatment. Evaluation of treatment efficacy in patients previously non-treated with chemotherapy as well as in the group of clinical resistance patients showed comparable results by the number of objective response rate (57% and 60% respectively).

Conclusions: The expression of MDR genes does not determine the resistance of tumor cells to bortezomib. The proteasome inhibitor bortezomib can overcome the MDR gene activity, attaching it to alkylating drugs increases the sensitivity to them of resistant tumor cells.