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Abstract Background The presence of minimal residual disease (MRD+) following autologous stem cell transplantation (ASCT) in multiple myeloma represents a poor prognostic factor for progression‐free survival (PFS) and overall survival (OS). Methods At our department, we recommend lenalidomide maintenance for patients who are MRD+ after ASCT, while MRD‐negative (MRD−) patients, after information about the national guidelines, were not advised to follow this regimen. Results Out of the total 228 patients, 175 received ASCT following first‐line induction (MRD− 92 (53%), MRD+ 83 (47%), at 2 months post‐ASCT), while 53 underwent ASCT after second‐line treatment (MRD− 27 (51%), MRD+ 26 (49%), at the same time point). Comparatively, MRD− patients who did not receive maintenance demonstrated better OS than MRD+ patients who received upfront ASCT and maintenance treatment (96% vs. 86%, p = 0.030, at 3 years). However, nonsignificant difference was found in PFS (76% vs. 62%, at 3 years). Furthermore, second‐line ASCT, MRD− non‐maintained patients exhibited significantly better PFS than MRD+ (71% vs. 27%, p > 0.001, at 3 years). However, OS was better but nonsignificant (96% vs. 76%, at 3 years). Fluorescence in situ hybridization (FISH) analysis was performed on 141 out of the 228 patients. Of these, 85 (60%) patients were deemed standard risk (SR), and 56 (40%) were classified as high risk (HR). In the SR cohort, MRD− patients exhibited better PFS and OS than MRD+ patients (71% vs. 59% and 100% vs. 85%, respectively). In the HR cohort, the MRD− patients showed superior PFS but similar OS compared to MRD+ patients (66% vs. 42% and 81% vs. 80%, respectively). Conclusions Our results indicate that being MRD− is a more crucial prognostic factor for the 3‐year PFS and OS than the presence of high‐risk cytogenetic markers or undergoing maintenance treatment. The latter appears insufficient, particularly for MRD+ patients following ASCT in the second‐line setting, suggesting that these patients may require a more intensive treatment approach.