Purpose: Patients with Multiple Myeloma (MM) who relapse after exposure to lenalidomide in the context of their first line therapeutic strategy are becoming a growing and clinically relevant population. We performed a systematic review of available clinical trials evaluating the efficacy, in terms of Progression-Free Survival (PFS), of different therapeutic strategies for the treatment of MM patients at first relapse after front-line use of lenalidomide.

Methods: Publications of interest were searched on the PubMed database. The following search terms were employed: relapsed multiple myeloma, refractory multiple myeloma, first relapse, second line therapy, and lenalidomide-refractory, lenalidomide-exposed.

Results: Triplets including anti-CD38 antibodies, carfilzomib and dexamethasone obtained more significant PFS regardless of the number of prior therapies. Other trials also demonstrated a not negligible benefit with combinations containing pomalidomide, particularly in early lines of therapy. However, the variable amount of Len-Exp/Len-R patients enrolled in these studies and the limited number of those analyzed after progression following front-line lenalidomide, makes it difficult to select an “optimal” choice for the treatment of these MM patients at first relapse. Promising results have been more recently obtained by using combo therapies including belantamab-mafodotin and immunotherapies with CAR-T cells.

Conclusion: In absence of clear-cut data regarding specifically the effects of currently available regimens in MM patients refractory or relapsed after first-line therapies including lenalidomide, novel approaches based on immune-therapies and focused on this specific population of MM patients would warrant further specific investigation.