Retinoid s ap pear to h ave anti-p roliferative ef fect s on mu ltiple myeloma lines. All trans retinoic acid (ATRA) given at high dose according to an intermittent schedule has better pharmacokinetically sustained levels. We studied 10 patients with relapsed/refractory MMwho were treated with ATRA and interferon (IFN). We failed to demonstrate that this combination has clinically significant activity. Interleukin-6 (IL-6) receptor was not downregulated by ATRA in the patients we studied. Significant hematologic and neurotoxicity were encountered. This regimen of intermittent ATRA and IFN is ineffective and poorly tolerated.

Multiple myeloma is a fatal, progressive neoplasm characterized by growth and accumulation of malignant plasma cells. IL-6 has been shown to regulate growth of myeloma cells3, 6, 2, 7 and hence IL-6 signaling pathways are potential targets for new therapies. Sidell et al. 11 identi fied the anti-proliferative a ction of a ll trans retinoic acid (AT RA) on am yelom a cell line Af-10, as a result of down regulation of IL-6 receptor (IL-6R) and subsequent inhibition of IL-6 mediated autocrine growth. Ogata et al. 1 0 demonstrated dose-dependent growth inhibition of freshly isolated myeloma cells by ATRA. Pharmacokinetic studies have revealed a rapid and sustained decrease in plasma drug concentrations when ATRA is administered on a continuous daily schedule. 1 2 An intermittent schedule of ATRA administration results in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment with a continuous schedule. 1 0, 1 2, 1 I nterferon-α (IFN-α), retinoids, and steroids have been noted to have in vitro anti proliferative synergistic effects on different cancer cell lines, including myeloma. 1 3 We therefore initiated a phase II trial to 1) evaluate the biological and clinical roles of high intermittent dose ATRA in refractory multiple m yeloma patients, and 2) determine whether there is a role for IFN-α in combination with ATRA in the management of this disease.