Objective? Chronic myelomonocytic leukemia (CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms that have an inherent risk of progressing to acute myeloid leukemia (AML). Methods? This study presents a case of confirmed CMML combined with M protein, in which the molecular changes upon progression to AML and under decitabine (DAC) plus bortezomib therapy were reported by tracking variant allele frequency (VAF) of mutations in a series of bone marrow samples. Results? First, variable sensitivity of clones was observed during DAC treatment, and incomplete mutation clearance may be associated with low overall response rate and unsustained response. Secondly, DAC cannot prevent the new genetic alterations and accumulation of genetic progression on treatment, leading to acute transformation. Finally, autoimmunity was found to have acted as an important pathogenetic factor, increasing the additive mutations that further drive the clonal evolution in CMML. Conclusion? Overall, changes in mutations and clonal architecture during CMML progression or treatment are predictive of an early evaluation of therapeutic strategies in CMML.