The Impact of Maintenance Lenalidomide and Depth of Response on the Mutational Status of the Myeloma Clone from Presentation to Relapse

The use of lenalidomide (len) maintenance has been associated with improved outcomes in both transplant eligible (TE) and non-eligible (TNE) newly diagnosed myeloma patients (NDMM). Despite this an understanding of the impact of maintenance on MM clonal architecture and mutational load has not been assessed. Applying constant treatment pressure may halt cancer cell division, slowing genetic and clonal evolution. We addressed this hypothesis by performing whole exome sequencing (WES) on 70 paired presentation/relapse samples, comparing those who received maintenance len and those being actively observed. We have undertaken a nested case control analysis using patients enrolled to the NCRI Myeloma XI trial for NDMM patients who had completed induction +/- ASCT and been randomised to maintenance with len or observation. WES was performed to a median depth of 125x on 70 presentation/relapse pairs. Of the 70 patients included, 35 (50%) received len maintenance and 35 (50%) observation, with a median age of 66 and 69 respectively. Twenty nine (41%) patients had undergone ASCT. The median time to relapse following maintenance randomisation was 10 months for the len group and 11 months for the observation group. Sixty one patients (87%) achieved a ≥VGPR as their best response prior to relapse. At presentation the median number non-silent mutations was comparable in both the len maintenance and observation groups (37 vs 34, p=0.75). At relapse the median number of mutations in the len group was 34 vs 44 in the observation group (p=0.22). The number of mutations at presentation and relapse for the whole cohort (n=70) was 37 vs 41 respectively (p=0.25). In patients who achieved a CR (n=33, 47%) the number of mutations at presentation was 33 vs 41 at relapse (p=0.05). The mutational load in patients who achieved<=“” div=“”>.