Dr Ip on the Impact of BCMA Alternative Splicing in Lymphoma and Multiple Myeloma

Andrew Ip, MD, director, Hematologic Malignancies, John Theurer Cancer Center, discusses findings with alternative splicing of the TNFRSF17 gene, which encodes BCMA. Ip and colleagues conducted a study to explore the potential of the presence of alternative splicing in BCMA transcripts through the sequencing of BCMA RNA in patients with lymphoma or multiple myeloma.

BCMA is a critical target for a variety of therapies, including CAR T cells, bispecific antibodies, and antibody-drug conjugates. This gene, expressed mainly on plasma cells and some B-cell malignancies, consists of 3 exons responsible for different domains of the protein.

The study investigated the presence of alternative splicing in BCMA RNA transcripts from 587 fresh bone marrow samples from patients with lymphoid/plasma cell neoplasms and 260 cell-free RNA (cfRNA) samples from the peripheral blood plasma of patients with lymphoma or multiple myeloma. RNA sequencing was performed using a hybrid capture-targeted RNA panel, with a focus on the TNFRSF17 gene transcript.

Results revealed that 27% of the lymphoid/plasma cell samples exhibited alternative splicing involving the deletion of exon 2 (BCMA∆Ex2), and 6% of cfRNA samples showed BCMA∆Ex2. The median percentage of BCMA∆Ex2 transcripts was 0.7% in cellular samples compared with 9% in cfRNA samples. In cellular samples, there was a significant correlation between overall BCMA levels and BCMA∆Ex2 (R = 0.63; P < 0.0001). However, in cfRNA samples, no correlation was observed between BCMA levels and BCMA∆Ex2 (R = 0.21), although higher BCMA levels corresponded with slightly increased BCMA∆Ex2 levels (P = 0.002).

Importantly, exon 3, typically detected in standard assays, was less frequently observed compared with other exons. Exon 2 was detected approximately 30% more, and exon 1 was detected approximately 20% more. Ip emphasizes that translating these data into clinical practice to better detect response and prognostic markers is a future direction for this research.

The study concluded that BCMA exon 2 skipping, which deletes the transmembrane domain, is prevalent in subsets of patients with multiple myeloma and lymphoma. This alteration could result in a cytoplasmic or secreted form of BCMA, contributing to increased cell turnover and possibly indicating more aggressive disease.

Ip notes that these findings underscore the need for further research to explore the clinical implications of BCMA exon 2 skipping on the effectiveness of antibody-based therapies and CAR T-cell treatments. Understanding these mechanisms could enhance the development of curative therapies and improve long-term remission rates in both myeloma and lymphoma, Ip concludes.