Clonal evolution drives tumor progression, chemoresistance and relapse in cancer. Little is known about clonal selection induced by therapeutic pressure in multiple myeloma. To address this issue, we performed large targeted sequencing of bone marrow plasma cells in 43 multiple myeloma patients at diagnosis and at relapse from exactly the same intensive treatment. The most frequently mutated genes at diagnosis were KRAS (35%), NRAS (28%), DIS3 (16%), BRAF, and LRP1B (12% each). At relapse, the mutational burden was unchanged. Many of the mutations were present at the subclonal level at both time points, including driver ones. According to patients and mutations, we observed different scenarios: selection of a very rare subclone present at diagnosis, appearance, or disappearance of mutations, but also stability. Our data highlight that chemoresistance and relapse could be induced by newly acquired mutations in myeloma drivers but also by (sub)clonal mutations preexisting to the treatment. Importantly, no specific mutation or rearrangement was observed at relapse, demonstrating that intensive treatment has a nonspecific effect on clonal selection in multiple myeloma. Finally, we identified 22 cases of biallelic event, including a double event deletion 17p/TP53mut.