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Background Lenalidomide refractoriness constitutes an adverse factor of survival in MM as Lenalidomide relapsing/resistant patients were reported to respond difficultly to next treatment line. Lenalidomide is widely administered in doublet, triplet, or quadruplet schemas as first line treatment or relapse and is the only approved drug for maintenance treatment in MM. Almost all MM patients will become at some time point Len refractory. Len resistance definitions and cautious evaluation is still lacking. Aims To update a previous study from our group (ref) assessing Len-dex treated MM patients’ outcomes according to elapsed time until relapse under treatment. Methods 186 patients were studied. 158 Len-Dex treated at any line and 18 receiving maintenance after ASCT, after informed consent was obtained initially. They were separated into 5 groups, including patients (1) with no response within two months (defined as primary resistant MM - PRMM) in the first, (2) progressing under treatment within 6 months from Len initiation in the 2nd (referred as very resistant MM - VRMM), (3) presenting progression under treatment within 7-12 months (Resistant MM - ResMM), (4) initially sensitive (ISMMP), progressing under treatment after more than 12 months and less than 4 years and (5) long-lasting response presenting eventually relapse (RALR) after more than 4 years from Len initiation. Statistical analysis was performed by conventional methods with the SPSS 21 software. Results Of the 158 len-dex-treated, 16 were PRMM, 23 VRMM, 25 ResMM, 70 ISMMP, 24 RALR. Median overall survival after Len (LenOS) was 3 months (as it was in the former analysis) for PRMM patients with 2,4,4, 3,1,2 being in 1st, 2nd, 3rd and > 4th line treatment. Only 5 PRMM patients received next treatment line after len and managed a further time to next treatment of 9 months. VRMM shared a slight increase of one month in survival after Len, 7 months LenOS vs 6 months in the former analysis, while median LenOS in ISMMM was the same (39 months). RALR patients improved their median LenOS to 87 months compared to 64 observed in previous data. The difference observed may be interpreted by the new agents available for MM treatment. LenOS was significantly different between all groups (p Conclusions We confirmed our results that outcomes are very poor for PRMM and VRMM that constitute a minority of patients that probably cannot be rescued at present. Therapeutical efforts and innovation are mandatory for ResMM and ISMMP. Improved outcomes observed in RALR patients are encouraging in the era of novel agents and monoclonal antibodies availability.