Treatment of Multiple Myeloma with All-Trans Retinoic Acid Alone and in Combination with Chemotherapy: a Phase I/II Trial

Abstract

All-trans retinoic acid (ATRA) is a derivative of vitamin A. ATRA inhibits the growth of human myeloma cell lines and freshly isolated myeloma cells in vitro mainly by down-regulating interleukin-6 receptor. Clinically, however, ATRA alone has not been efficacious and adverse events, notably hypercalcemia, have been common. In the present study 10 patients with stable multiple myeloma after conventional chemotherapy received ATRA alone for 2 months, followed by a combination of ATRA and the chemotherapy regimen during which no further reduction of the paraprotein had occurred. The purpose of the combination therapy was to sensitize the myeloma cells with ATRA to chemotherapy by blocking the growth-promoting effect of IL-6. Although ATRA was well tolerated, ATRA alone lacked clinical efficacy. The combination therapy resulted minimal responses in 4 patients and relatively long progression-free survival in 4 patients was achieved. In 3 of these responding patients serum concentrations of interleukin-6 and/or soluble interleukin-6 receptor were elevated prior to the study. The bone marrow cells of responding patients were sensitive to ATRA in vitro. These results show that ATRA alone is not effective to treat multiple myeloma. There may be some beneficial effect of ATRA in combination chemotherapy in selected patients who have activated IL-6 signaling.