Myeloma-related disorder (MRD) is an uncommon disease in cats, for which there is no established standard of care. In this retrospective study, we evaluated presentation, response to treatment, and toxicity in cats with MRD receiving systemic treatment. Previously reported prognostic factors were evaluated for their impact on survival in cats receiving chemotherapy. Of fifteen cases identified, thirteen received melphalan or cyclophosphamide +/- corticosteroids as first-line therapy. Chlorambucil was commonly used as rescue therapy in cats with progressive disease, or in cases of chemotherapy-related toxicity with first line agents. Overall response rates were 71% and 83% for melphalan- and cyclophosphamide-treated cats, respectively. Discontinuation of melphalan due to toxicity was common. Survival times for cats initially treated with melphalan or cyclophosphamide were not significantly different (median 252 and 394 days, respectively), and no statistically significant prognostic factors were identified. This study suggests that the combination of cyclophosphamide and corticosteroids is well tolerated and may be considered as first-line therapy for cats with systemic MRD.