MDR-1 induction during successful alkylating chemotherapy in multiple myeloma

In multiple myeloma (MM) the multiple drug resistance (MDR-1) phenotype is frequently expressed in disease refractory to vincristine and doxorubicin, conferring resistance to these agents by a drug efflux pump, the P-glycoprotein (Pgp). The present study was performed to assess whether MDR-1 expression occurs during initial chemotherapy with alkylating agents and to determine the clinical significance of endogeneous P-glycoprotein. In 41 patients with MM we retrospectively determined MDR-1 expression on cytocentrifuged plasma cells with an immunohistochemical detection method using the JSB-1 monoclonal antibody. MDR-I expression was assessed in samples obtained either in newly diagnosed, untreated disease, during initial chemotherapy or at the moment of relapse after initial response. In 22 of the patients MDR-1 expression was evaluated longitudinally. At diagnosis 9/29 (31%) samples were MDR-1 positive. No relation was found between MDR-1 expression and response to alkylating agents or survival. During initial chemotherapy 15/33 (45%) of samples were MDR-1 positive. Remarkably the frequency of MDR-I expression was significantly higher in patients with responsive disease (12/17, 71%) as compared to both untreated patients (9/29, 31%) and patients with refractory disease (3/16, 19%) (chi-square, p < 0.01 for comparisons). At the moment of relapse 4/13 (31%) samples were MDR-1 positive. In patients studied longitudinally MDR-I expression changed fi om negative before treatment to positive in responsive disease in 3/7 (43%) cases studied. MDR-1 positivity found in responsive disease disappeared in 6/7 (86%) patients when their disease relapsed. In conclusion, our results show a transient induction of MDR-1 expression after successful, alkylating, chemotherapy in MM. This finding agrees with earlier in vitro reports relating MDR-1 as a stress-inducable gene after cytotoxicity caused by non-Pgp transported drugs.