Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of B-cell malignancies, achieving deep and durable remissions in patients with B-cell acute lymphoblastic leukemia (B-ALL).¹ Despite remarkable therapeutic successes, rare but clinically significant secondary hematologic malignancies have been reported during CAR-T cell therapy, often driven by lineage switching or clonal selection.² Moreover, CAR-T cell therapy drives profound remodeling of the immune microenvironment, and the sustained inflammatory signaling may promote clonal evolution and influence disease progression.³ High-resolution approaches, such as single-cell RNA sequencing (scRNA-seq) and single-cell B-cell receptor sequencing (scBCR-seq), enable characterization of transcriptional programs, clonal identity, and temporal dynamics to dissect CAR-T cell therapy-induced clonal evolution and immune remodeling.⁴

Here, we report a case of B-ALL with B-cell receptor (BCR) heterogeneity at diagnosis that evolved into smoldering multiple myeloma (SMM) following CD19-targeted CAR-T therapy. The co-occurrence of B-ALL and SMM is exceptionally rare, as it requires malignant clones at distinct stages of B-cell development. This case provides a unique opportunity to dissect how CAR-T cell therapy drives B-lineage clonal evolution and reshapes the immune microenvironment. To this end, bone marrow mononuclear cells (BMMNC) were collected at multiple time points and subjected to longitudinal scRNA-seq and scBCR-seq to track dynamic changes in malignant and immune cell populations, thereby elucidating the mechanisms of clonal evolution and immune remodeling following CAR-T cell therapy. The patient gave informed consent and was enrolled in a clinical trial registered at clinicaltrials.gov (Identifier: NCT00123456).