Patients diagnosed with more than one cancer generally develop the individual tumors sequentially. There are a few cases of co-occurring multiple myeloma and lung cancer reported in the literature. Here, we report two cases of co-occurring multiple myeloma and lung cancer in patients who presented with the chief complaint of pain. The diagnoses of multiple myeloma and lung cancer were supported by hematologic and biochemical investigations, as well as bone marrow and lung histopathologic examination. We provided suitable interventions for both two patients. The patients are still currently undergoing treatment and followed up closely. We first performed a bioinformatic analysis to determine commonly shared genes and pathways in the two types of cancer types. Fortunately, we identified the hub gene mitochondrial trans-2-enoyl-CoA reductase (MECR), which was overexpressed in both tumors. Survival analysis correlated higher MECR expression with poorer overall survival. Signaling pathway analysis suggested possible transduction pathways implicated in the co-occurrence of both tumors. The clinical cases combined with bioinformatic analysis may provide insight for the pathogenesis of synchronous tumors.