Reu, Frederic J.

Abstract Abstract 5045 Observation remains the standard approach to patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (AMM) who lack end-organ impairment characteristic of symptomatic MM. Institution of early MM therapy has not been shown to improve survival or alter the natural progression of the disease. Cyclooxygenase-2 (COX2) inhibitors inhibit proliferation and induce apoptosis in drug resistant MM cell lines. 23 asymptomatic adult patients with a serum monoclonal protein >1g/dL, from Cleveland Clinic, Mayo Clinic, or University of Arkansas Medical Center between August 2005 and April 2008 were randomized to either celecoxib or placebo in a double-blind, 1:1 fashion. The primary end point was change in the monoclonal protein concentration after 6 months. Correlative biomarkers, including IL6 and IL-6R, CD4/CD8+ T-cell ratios, and beta-2 microglobulin, were examined before and after treatment. Celecoxib had no significant effect on the median monoclonal protein concentration, which went from a median of 1. 44 to 1. 65 g/dL with placebo and 2. 42 to 2. 24 g/dL with Celecoxib (p=0. 36), or on any of the analyzed correlative markers (all p-values >0. 34). One patient's monoclonal protein concentration increased on placebo, but he did not require treatment for symptomatic MM. There were no adverse events of Grade 2 or higher. Celecoxib was well tolerated in contrast to previous reports when given in higher doses and in combination with thalidomide. Although accrual was limited we conclude that celecoxib has no clinical or immunologic effect on high risk asymptomatic plasma cell disorders. This study does not support using celecoxib for preventing progression to symptomatic MM. Future studies on progression of MGUS to symptomatic MM would require more patients and a longer follow-up period. Disclosures: Off Label Use: Celecoxib for chemoprophylaxis. Hussein:Celgene: Employment. Reu:Celgene: Research Funding.

AbstractCarfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m2 intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m2 for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Abstract Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.