In the backdrop of rapidly changing relapsed/refractory (RR) multiple myeloma (MM) treatment schema that mainly evolves around immunotherapies, it is easy to disregard more traditional drugs. Finding the best partner for pomalidomide, a potent third-generation immunomodulatory drug, is an important agenda we face as a community and cyclophosphamide addition has been used for outcomes augmentation. We carried out this real-world study to identify patients who will show durable response to pomalidomide and those who will benefit from cyclophosphamide addition. A total of 103 patients (57 in pomalidomide-dexamethasone [Pd] group versus 46 in pomalidomide-cyclophosphamide-dexamethasone [PCd]) were studied. They were previously treated with bortezomib (98.1%) or lenalidomide (100%) and previous lines of therapy were median 3 lines. Significantly better overall response rate (ORR) was seen in the PCd (75.6%) than Pd (41.7%) group (p = 0.001), but no differences in survival outcomes. Subgroup analysis revealed that high-risk myeloma features, poor response to lenalidomide or bortezomib had superior ORRs when cyclophosphamide was added. Also, long-term responders for pomalidomide were associated with excellent response to previous IMiD treatments. Pomalidomide-based therapy was discontinued in five patients due to intolerance or adverse events, but there was no mortality during treatment. In conclusion, we showed that pomalidomide-based treatment is still relevant and can ensure durable response in RRMM setting, especially for patients who responded well to previous lenalidomide. Addition of cyclophosphamide to Pd is associated with better ORR, and can be positively considered in fit patients with high-risk MM, extramedullary disease, and less-than-satisfactory response to previous lenalidomide treatment.