Yes. You set the spatial filter's geometry to whatever geometry will select the features you want. If you want to select features on one layer using the geometries of multiple features from another layer then you need to create a geometry that is the union of those feature geometries. This can be done using ITopologicalOperator. The most efficient method would be to use the ConstructUnion method, which requires an IEnumGeometry object. You can get this from IEnumGeometryBind.