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

The treatment and natural history of smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated benefit, likely as a consequence of lack of attention to the vast heterogeneity contained within the diagnosis. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression in a short time, using different methodology. Recently the PETHEMA group published a randomized clinical trial testing lenalidomide/dexamethasone vs observation among high risk smoldering patients, and demonstrated a clear benefit in terms of progression free and overall survival favoring early intervention. However, the risk criteria utilized a highly sensitive method of flow cytometry, a test not routinely available in the US. It is not clear that the group of patients defined in the PETHEMA study share similar outcomes with those defined as high risk using the ECOG/Mayo criteria. A recent publication demonstrated only 25% overlap for the highest risk smoldering patients when using either the PETHEMA or the ECOG criteria. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II/III trial testing the safety and efficacy of single agent lenalidomide. We report here on the safety and efficacy of the phase II portion of the trial.

The phase II group of patients received lenalidomide alone at a dose of 25 mg days 1-21 every 28 days. 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. Patients were to be diagnosed with 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. Patients must have had measurable levels of monoclonal protein. Patients must have had no lytic lesions on skeletal surveys and no hypercalcemia (i.e. >= 11 mg/dL).

Among the final phase II cohort (n=44 patients), 55% were female, and 43% were 65 years and older. Enrollment began in January 2011 and lasted 2 years with the last patient completing 6 cycles of treatment in August 2013. The median treatment duration of the entire cohort is 13.5 cycles (range 1-30 cycles). Mean percentage lenalidomide dose over the first 6 cycles was 94, 89, 82, 79, 76, 72. With a median follow up of 17 months, 2 patients had progression on therapy. Fifteen patients are off treatment for the following reasons: disease progression (n=2), AE/complication (n=5), death (n=2), patient withdrawal/refusal (n=5), other (n=1); 6 of the 15 patients ended treatment before completing 6 cycles. Of 44 patients assessed for toxicity, 11 patients [25.0%, 95% CI: (13.2%-40.3%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher based on CTCAE v4, with neutropenia and fatigue being the most frequent. This includes 2 fatal deaths (MI and TE). Two patients [4.6%, 95% CI: (0.1%-15.5%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis that included treatment-related grade 4-5 non-hematologic toxicity or any grade 3 toxicity affecting vital organ function (such as cardiac, hepatic, or thromboembolic events) during the first 6 cycles of treatment. Twelve patients achieved partial response or better [33.3%, 95% CI: (15.0%-42.8%)] along with 25 patients reporting stable disease. Lenalidomide has shown promise in the treatment of high-risk smoldering myeloma and based on this analysis, accrual to the phase III portion is ongoing. In the context of the encouraging data from the PETHEMA group, completion of the phase III portion of this study is needed to validate their findings using a different criteria, and using a steroid sparing approach.

This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650, CA32102 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services.