Peptic ulcer disease (PUD) is a common cause of abdominal pain which can present acutely with gastrointestinal perforation. This report presents an exceptionally rare case of a patient whose presentation of perforated PUD heralded a new diagnosis of both multiple myeloma and sickle cell disease (SCD). Histological analysis of the ulcer tissue, following omental patch repair, did not demonstrate features of extramedullary myeloma or amyloid light chain deposition, two pathologies traditionally thought to drive PUD in this patient group. Instead, we suggest malignant hypercalcaemia stimulating gastric acid secretion, in combination with mucosal ischaemia caused by SCD, may have led to gastric mucosal erosion. This case underscores the diagnostic challenges in managing patients with complex comorbidities and the need to consider atypical causes of PUD in the workup of this patient group.