In-room magnetic resonance imaging (MRI) allows the acquisition of fast 2D cine-MRI centered in the tumor for advanced motion management in radiotherapy. To achieve 3D information during treatment, patient-specific motion models can be considered the most viable solution. However, conventional global motion models are built using a single motion surrogate, independently from the anatomical location. In this work, we present a novel motion model based on regions of interest (ROIs) established on 4D computed tomography (4DCT) and 2D cine-MRI, aiming at accurately compensating for changes during treatment. In the planning phase, a motion model is built on a 4DCT dataset, through 3D deformable image registration (DIR). ROIs are then defined and correlated with motion fields derived by 2D DIR between CT slices centered in the tumor. In the treatment phase, the model is applied to in-room cine-MRI data to compensate for organ motion in a multi-modal framework, aiming at estimating a time-resolved 3DCT. The method is validated on a digital phantom and tested on two lung patients. Analysis is performed by considering different anatomical planes (coronal, sagittal and a combination of the two) and evaluating the performance of the method on tumor and diaphragm. For the phantom study, the ROI-based model results in a uniform median error on both diaphragm and tumor below 1.5 mm. For what concerns patients, median errors on both diaphragm and tumor are around 2 mm (maximum patient resolution), confirming the capability of the method to regionally compensate for motion. A novel ROI-based motion model is proposed as an integral part of an envisioned clinical MRI-guided workflow aiming at enhanced image guidance compared to conventional strategies.