Abstract
Introduction Multiple myeloma is a malignant plasma cell dyscrasia traditionally managed with high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT). In cases of relapsed or refractory disease, treatment historically relied on cytotoxic agents. However, recent advancements in immunotherapy, including monoclonal antibodies and chimeric antigen receptor (CAR) T-cell therapies, have demonstrated promising clinical outcomes. Both anti-CD38 monoclonal antibodies (e.g., daratumumab) and anti-B-cell maturation antigen (BCMA) CAR T-cell therapies have received FDA approval for the treatment of relapsed/refractory multiple myeloma (RRMM). Nevertheless, emerging evidence has begun to highlight the long-term hematologic complications associated with these novel therapies, possibly including therapy-related myeloid neoplasms.
Case Report We present the case of a female patient diagnosed with IgG multiple myeloma in 2015, initially treated with induction chemotherapy using lenalidomide, bortezomib, and dexamethasone (RVD), followed by autologous HSCT. She subsequently remained in remission on lenalidomide maintenance therapy until 2019, when disease relapse occurred.
The patient underwent multiple lines of salvage therapy. An initial trial of bortezomib was discontinued due to the development of cardiomyopathy. She subsequently progressed on a combination of daratumumab, lenalidomide, and dexamethasone. Further disease progression occurred on a regimen of ixazomib, pomalidomide, and dexamethasone. She then achieved a temporary response to carfilzomib, lenalidomide, and dexamethasone, followed by a second autologous HSCT, but relapsed again after approximately one year of maintenance therapy.
Ultimately, she was treated with dual-domain anti-BCMA CAR T-cell therapy (ddBCMA), achieving a complete response confirmed at 90-day post-infusion restaging.
Approximately seven months following CAR T-cell therapy, the patient developed severe, persistent cytopenias. A bone marrow biopsy revealed no residual plasma cell dyscrasia, with plasma cells comprising <1% of total marrow cellularity. However, the biopsy demonstrated 12% myeloblasts within a hypocellular marrow, consistent with a diagnosis of high-risk therapy-related myeloid neoplasm. Cytogenetic analysis revealed a complex karyotype with abnormalities involving chromosomes 5 and 7. Next-generation sequencing identified a TP53 missense mutation with a variant allele frequency (VAF) of 85%.
Discussion While treatment-related myeloid neoplasms following CD19-directed CAR T-cell therapies for acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) have been increasingly reported, there remains a paucity of data regarding such events following anti-BCMA CAR T-cell therapy for multiple myeloma. In a retrospective study of four cases, Vainstein et al found MDS-associated changes were identified in the pre-treatment bone marrow samples of those patients with secondary myeloid neoplasms, suggesting a possible antecedent clonal hematopoiesis that was selected for during therapy. Another meta-analysis by An et al, which included both CD19- and BCMA-directed CAR T-cell therapy recipients, reported poor overall prognoses in patients developing therapy-related MDS. Although multiple small-scale studies have described comparable findings, current literature remains inconclusive regarding a definitive causal relationship between anti-BCMA CAR T-cell therapy and subsequent development of secondary myeloid malignancies.
Conclusion This case illustrates the development of high-risk therapy-related myeloid neoplasm following ddBCMA CAR T-cell therapy in a patient with refractory multiple myeloma. While this association warrants further investigation, it emphasizes the need for ongoing observation of patients who have received CAR T-cell therapy. Future studies should aim to clarify the potential mechanistic links, including clonal evolution, selective pressures imposed by immunotherapy, and the contribution of prior cytotoxic exposures.
