Objective: Lenalidomide is an immunomodulatory agent with proven efficacy in the treatment of multiple myeloma. In large global clinical studies, lenalidomide plus dexamethasone has demonstrated significant improvements in the overall response rate and overall survival in patients with relapsed and/or refractory multiple myeloma, compared with a placebo and dexamethasone. This is the first study to report lenalidomide plus low-dose dexamethasone administered in Thai patients. Methods: The aim of this phase II, single-center, single-arm study was to evaluate the efficacy and safety of lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. The primary endpoint was the overall response rate at the fourth treatment cycle. Secondary endpoints included depth of response, time to response, and adverse events. Results: In total, 15 patients with a median age of 61 years old (range 23–74 years old) who had received at least one prior anti-myeloma therapy were enrolled in the study and administered 4-week cycles of lenalidomide 25 mg/day (days 1–21) and dexamethasone 40 mg/week. Patients continued in the study until the occurrence of disease progression or serious adverse events. The overall response rate was 86% and 73.3% at the fourth and from all treatment cycles, respectively (median number of treatment cycles, 10.25), and the median dose for patients aged >60 years old was 15 mg/day. The overall response rate at the fourth cycle in patients who had received prior novel agents (bortezomib and/or thalidomide) was 81.82% compared with 100% in those who had received prior conventional therapy (p = 0.15). The most common adverse events reported were anemia and neutropenia, which were both manageable. Conclusion: Lenalidomide and low-dose dexamethasone was highly effective in Thai patients with relapsed and/or refractory multiple myeloma, with a manageable adverse event profile. These findings suggest that lenalidomide 15 mg/day is a safe and effective dose for Thai patients aged ≥60 years old.