Phase II Trial of Initial Safety and Toxicity Prior to the Phase III Trial of Lenalidomide Versus Observation Alone in Patients with Asymptomatic High-Risk Smoldering Multiple Myeloma (E3A06): A Trial Coordinated by the Eastern Cooperative Oncology Group (2012)

Abstract Abstract 4079 The treatment and natural history of asymptomatic or smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated significant benefit, likely as a consequence of limited therapeutic options as well lack of attention to the vast heterogeneity contained within the diagnosis of smoldering myeloma. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression to myeloma in a short time. Recently the PETHEMA group has conducted a randomized clinical trial testing lenalidomide and dexamethasone vs observation among high risk smoldering patients and has demonstrated a clear benefit in terms of progression free survival and hints towards improvement in overall survival favoring early intervention. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II trial testing the safety and efficacy of single agent lenalidomide with the intent of broadening to a randomized phase III trial if toxicity was acceptable. We report here on the safety portion of the phase II trial. The phase II group of patients received lenalidomide at a dose of 25 mg days 1–21 every 28 days to evaluate the early toxicity and tolerance of this dosing. The dose of lenalidomide could be adjusted based on toxicity using a defined dose-modification guideline in the protocol. The primary endpoint for the safety study was the rate of any treatment-related grade 4–5 non-hematologic toxicity plus grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events) observed within 6 cycles of treatment. The goal was to enroll 34 patients; if 9 or more patients experience toxicity as defined, then the study would not continue. In terms of eligibility, patients were to be diagnosed with asymptomatic high-risk smoldering multiple myeloma (SMM) within the past 12 months, as confirmed by both of the following: bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells and an abnormal serum free light chain ratio (<0.125 or >8.0) by serum FLC assay. Further, patients must have measurable levels of monoclonal protein (M-protein): >=1g/dL on serum protein electrophoresis or >=200 mg of monoclonal protein on a 24 hour urine protein electrophoresis. Patients must have no lytic lesions on skeletal surveys and no hypercalcemia. Among the 36 patients enrolled in the phase II study, 56% were female, and 44% were 65 years and older. Treatment and toxicity data at a minimum through cycle 6 is complete as of August 2, 2102. The last patient enrolled completed cycle 6 treatment on June 7, 2012. The median treatment duration of the entire cohort is 9 cycles (range 1–18 cycles), with 86% of patients completing at least 6 cycles of treatment. Ten patients are off treatment for the following reasons: disease progression (n=1), AE/complication (n=5), death (n=1) and patient withdrawal/refusal (n=3); 5 of the 10 patients ended treatment before completing 6 cycles. Of 36 patients assessed for toxicity, 8 patients [22.2%, 90% CI: (11.6%-36.5%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher. Separately, 6 patients experienced unrelated non-hematologic toxicity of grade 3 or higher. Three patients [8.3%, 90% CI: (2.3%-20.2%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis (treatment-related grade 4–5 non-hematologic toxicity or grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events). Based upon this analysis of the study, the phase II portion of the trial met the prespecified safety benchmark established to allow for phase III expansion, and accrual to the phase III portion of this study will begin. Efficacy data will be presented at the time of presentation. Disclosures: Lonial: Novartis: Consultancy; Millennium: Consultancy; Onyx: Consultancy; BMS: Consultancy; Celgene Corp: Consultancy; Merck: Consultancy. Off Label Use: Lenalidomide is not approved for treatment of smoldering MM. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy; Binding site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Celgene : Research Funding; Onyx: Research Funding; prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties. Dhodapkar:Celgene: Research Funding; KHK: Research Funding.