There is uncertainty regarding the usefulness of CDK4/6-inhibitor-based therapy for hormone receptor positive (HR+), human epidermal grow factor receptor 2 negative (HER2-), metastatic breast cancer (MBC), when CDK4/6 inhibitor treatment had previously failed. Furthermore, a biomarker for abemaciclib resistance has not been identified. Herein, we reported outcomes for an HR+/HER2- MBC patient diagnosed with multiple myeloma and treated with abemaciclib and exemestane, who had cancer progression after treatment with palbociclib and fulvestrant. Thalidomide was used in conjunction with all treatments. The patient had a good response to abemaciclib and exemestane, with progression-free survival much longer than previously reported. PIK3CA and TP53 mutations were identified after cancer progression following abemaciclib treatment. It is unclear whether thalidomide increased the effectiveness of abemaciclib. Whether benefit can be derived by the use of PI3K inhibitors, after cancer progression, requires further investigation, and this may be best accomplished by the use of next-generation sequencing.