Previous literature suggests that cytogenetics may be used for risk-adapted therapy in patients with relapsed/refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone. However, the significance of each abnormality is still unclear, and chromosome 1 abnormalities have yet to be studied in this population. We therefore evaluated genetic risk factors including chromosome 1q gain and 1p loss by cIg-FISH in 143 patients with relapsed/refractory MM treated with lenalidomide and dexamethasone, and correlated the genomic aberrations with patient clinical outcomes. Patients had a median of two (range 1-7) previous therapies in this cohort. A total of 119 out of 143 (83%) patients had an objective response, with median time to progression (TTP) and overall survival (OS) of 11 and 28 months, respectively. Patients with del(1p21) or del(17p) (p53) deletions had a significantly shorter TTP. OS was shorter in patients with 1p21 or 17p deletions, but did not reach statistical significance. Prior bortezomib or thalidomide treatment was associated with shorter TTP and OS. Multivariate analysis identified del(17p), del(1p21), and prior bortezomib or thalidomide therapy as independent risk factors for shorter TTP. Our data suggest that chromosome 17p and 1p21 deletions adversely impact the outcome of lenalidomide and dexamethasone treated patients with relapsed/refractory MM. Improved therapeutic strategies are required for these patients.