Myeloma Resistance and is Well Tolerated in Patients with Relapse Multiple Immunomodulatory Derivative of Thalidomide CC-5013 Overcomes Drug

AbstractThalidomide (Thal) can overcome drug resistance in multiple myeloma (MM), but is associated with somnolence, constipation, and neuropathy. In previous in vitro studies, we have shown that the potent Immunomodulatory Derivative of Thalidomide (IMiD) CC-5013 induces apoptosis or growth arrest even in resistant MM cell lines and patient cells; decreases binding of MM cells to bone marrow stromal cells (BMSCs); inhibits the production in the BM milieu of cytokines (IL-6, VEGF, TNF- ) mediating growth and survival of MM cells; blocks angiogenesis; and stimulates host anti-MM NK cell immunity. Moreover, CC-5013 also inhibits tumor growth, decreases angiogenesis, and prolongs host survival in a human plasmacytoma mouse model. In the present study, we carried out a phase I CC-5013 dose escalation (5 mg/d, 10 mg/d, 25 mg/d and 50 mg/d) study in 27 patients (median age 57, range 40-71y) with relapsed and refractory relapsed MM. They received a median of 3 (range 2-6) prior regimens, including autologous stem cell transplantation and Thal in 15 and 16 patients, respectively. In 24 evaluable patients, no DLT was observed in patients treated at any dose level within the first 28d; however, grade 3 myelosuppression developed after d28 in all 13 patients treated with 50mg/d CC-5013. In 12 patients, dose reduction to 25mg/d was well tolerated and therefore considered the maximal tolerated dose (MTD). Importantly no significant somnolence, constipation, or neuropathy has been seen in any cohort. Best responses of > 25% reduction in paraprotein occurred in 17 of 24 (71%) patients (90%CI: 52%, 85%), including 11 (46%) patients who had received prior Thal. Stable disease (< 25% reduction in paraprotein) was observed in an additional 2 (8%) patients. Therefore, 17 of 24 (71%) patients (90%CI: 52%, 85%) demonstrated benefit from treatment,. Our study therefore provides the basis for the evaluation of CC-5013, either alone or in combination, to treat patients with MM at earlier stages of disease.From bloodjournal.hematologylibrary.org by guest on May 30, 2013. For personal use only.