Immunomodulatory analogs of thalidomide: an emerging new therapy in myeloma.

Abstract

In this issue of the Journal of Clinical Oncology (JCO), Schey et al present the results of a phase I study of the immunomodulatory thalidomide analog CC-4047 in relapsed, and relapsed refractory multiple myeloma (MM). This important work represents a next step in a series of studies for the development of new agents in the treatment of relapsed MM, which remains incurable, despite advances such as highdose therapy and stem-cell transplantation (SCT). Since the encouraging results of the thalidomide trial led by Singhal et al in advanced relapsed and refractory MM, thalidomide has been established as an effective therapy for the treatment of MM in the relapsed and upfront settings. However, the efficacy of thalidomide has been significantly limited by adverse effects, which include sedation, neuropathy, constipation, and deep vein thrombosis. This toxicity profile seems both dose-related and duration-related, especially post-SCT, spurring the development of thalidomide-derived immunomodulatory analogs known as immunomodulatory drugs (IMiDs), which have the potential of improved potency and reduced toxicity. CC-4047 is one of two small-molecule 4-amino derivatives currently under study in patients with MM. Studies demonstrate that both thalidomide and IMiDs not only act to inhibit angiogenesis, but also act directly to induce both apoptosis and growth arrest in resistant myeloma cells. They also block both the adhesion of myeloma cells to bone marrow stromal cells and the related protection against apoptosis, and block the increased secretion of myeloma cell growth, survival, and migratory factors such as interleukin-6, tumor necrosis factor alpha (TNF), and vascular endothelial growth factor, triggered by the binding of myeloma cells to bone marrow stromal cells. In addition, they expand natural killer cell and T-cell numbers, and improve function against human myeloma cells and enhance their susceptibility to antibody-dependent cellmediated cytotoxicity in vivo (Fig 1). By modifying thalidomide structure through the addition of an amino group at the 4 position of the phthaloyl ring (to generate CC-4047) and with the further removal of a carbonyl on the ring to form CC-5013, such analogs are up to 50,000 times more potent at inhibiting TNFthan the thalidomide parent compound in vitro and are markedly more stable. On the basis of this promising preclinical data, the first phase I study of the thalidomide analog CC-5013 was carried out in 2001, when a dose range of 5 to 50 mg/d was tested in 25 patients with relapsed and refractory MM. Patients in this study had received a median of three prior regimens, including autologous SCT and prior thalidomide in approximately twothirds of the patients. Importantly, no dose-limiting toxicity was observed at any dose level within the first 28 days, but grade 3 myelosuppression developed after 28 days in all 13 patients treated at the highest dose level of 50 mg/d. In 12 of these patients, dose reduction to 25 mg/d was well tolerated and was considered the maximum-tolerated dose. No significant constipation or neuropathy was seen in any cohort, and encouragingly, responses were seen in 17 (71%) of 24 assessable patients, including 11 patients (46%) who had received prior thalidomide. A second study by Zangari et al in 15 patients with advanced MM confirmed a maximum-tolerated dose of 25 mg/d. These studies provided the basis for the further evaluation of CC-5013, either alone or in combination with dexamethasone, to treat patients with MM at first relapse, or for relapsed refractory MM. Results of these studies have been encouraging, with impressive response rates and acceptable tolerability. A series of phase II trials with CC-5013 have been completed, and a multicenter, parallel group, controlled phase III randomized double-blind study of CC-5013 plus dexamethasone compared with dexamethasone alone in previously treated patients with MM has just completed accrual. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 16 AUGUST 15 2004