We studied all patients at our institution with a diagnosis of multiple myeloma (MM), from 1 January 2004 to 1 July 2009, who received lenalidomide-dexamethasone (Rd) as initial therapy and had a time to progression of 72 months or longer. Of 240 patients, we identified 33 exceptional responders. Twenty-five patients received primary therapy with Rd and eight patients received Rd induction followed by early stem cell transplantation (SCT). Seven of the eight patients who received SCT did not receive maintenance therapy; one patient received 9 months of lenalidomide post transplant. Fifteen (45%) patients had known clonal plasma cell disorder before the diagnosis of MM. The dominant mode of clinical presentation was with lytic lesions in 28 patients. Of those with informative cytogenetics (n=24), trisomies were present in 19 (79%), including one patient with concurrent trisomies and t(11;14). Overall, 21 of 24 patients (88%) had either trisomies or t(11;14). None of these exceptional responders had high-risk cytogenetic features at baseline. Twenty-five patients (76%) had a complete response (CR), whereas eight patients (24%) achieved the exceptional response state without ever achieving a CR. We identify a cohort of exceptional responders to Rd-based therapy, representing ~10-15% newly diagnosed MM patients with normal renal function.