Differential effects of lenalidomide during plasma cell differentiation.

// Michel Jourdan 1, 2 , Mailys Cren 1 , Peter Schafer 3 , Nicolas Robert 4 , Christophe Duperray 5 , Laure Vincent 6 , Patrice Ceballos 6 , Guillaume Cartron 6, 7 , Jean-Francois Rossi 6, 7 , Jerome Moreaux 2, 4, 7 , Rajesh Chopra 3 , Bernard Klein 2, 4, 7 1 INSERM, U1040, Montpellier, France 2 CNRS UPR1142, Institute of Human Genetics, Montpellier, France 3 Translational Development Department, Celgene Corporation, Summit, NJ, USA 4 CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biological Hematology, Montpellier, France 5 Cytometry IRB, Montpellier Rio Imaging, Montpellier, France 6 CHU Montpellier, Department of Clinical Hematology, Montpellier, France 7 University Montpellier 1, UFR Medicine, Montpellier, France Correspondence to: Jerome Moreaux, email: jerome.moreaux@igh.cnrs.fr Keywords: plasma cell, differentiation, IKZF1, IKZF3, lenalidomide Received: February 05, 2016      Accepted: March 28, 2016      Published: April 4, 2016 ABSTRACT Thalidomide, lenalidomide and pomalidomide have greatly improved the outcome of patients with multiple myeloma. However, their effects on plasma cells, the healthy counterpart of myeloma cells, are unknown. Here, we investigated lenalidomide effects on normal human plasma cell generation using an in vitro model. Lenalidomide inhibited the generation of pre-plasmablasts and early plasma cells, while it moderately affected plasmablast production. It also reduced the expression level of Ikaros, Aiolos, and IRF4 transcription factors, in plasmablasts and early plasma cells. This suggests that their differential sensitivity to lenalidomide is not due to a difference in Ikaros or Aiolos degradation. Lenalidomide also inhibited long-lived plasma cell generation, but did not impair their long-term survival once generated. This last observation is in agreement with the finding that lenalidomide treatment for 3-18 months did not affect the bone marrow healthy plasma cell count in allografted patients with multiple myeloma. Our findings should prompt to investigate whether lenalidomide resistance in patients with multiple myeloma could be associated with the emergence of malignant plasmablasts or long-lived plasma cells that are less sensitive to lenalidomide.