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 

 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 

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; 

 < 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 (

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.

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Andrew Ip, MD, discusses alternative splicing of the TNFRSF17 gene, which encodes BCMA, in patients with lymphoma or multiple myeloma.

Andrew Ip, MD, discusses the implications of using next-generation sequencing alongside machine learning in the diagnosis of hematologic malignancies.

Dr Ip on the Implications of NGS Plus Machine Learning for Diagnosing Hematologic Malignancies

Andrew Ip, MD, medical oncologist, John Theurer Cancer Center, Hackensack University Medical Center, discusses findings from a study assessing the feasibility of replacing flow cytometry analysis with next-generation sequencing (NGS) alongside machine learning to detect and diagnose hematologic malignancies, highlighting the clinical implications of this research.

, results from the study showed that the use of NGS to quantify RNA levels from 30 CD markers in combination with a machine learning algorithm may serve as a reliable and accurate screening method for differential diagnosis across various hematologic conditions. The study reported an area under the curve (AUC) consistently exceeding 90%, indicating a strong true positive rate with a 2% chance of false positivity. Notably, the data from this study were obtained from peripheral blood test samples.

The utilization of liquid biopsies has gained traction in recent years due to its ability to provide comprehensive information about cancer without the need for invasive tissue biopsies, Ip begins. This approach has been promising in hematologic malignancies, where NGS technologies can detect specific genetic alterations associated with various blood cancers, he notes.

Findings from this study build upon prior research, including a study published in the 

, which explored the feasibility of detecting acute myeloid leukemia (AML) using whole-exome sequencing, Ip states. The study found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or myelodysplastic syndrome, he reports.

Based on this study, Ip and his colleagues at the Genomics Testing Cooperative used a more targeted NGS panel focused on RNA and DNA mutations to assess the utility of NGS-based liquid biopsies across different hematologic conditions beyond AML, Ip says.

This research suggests that liquid biopsies using NGS and machine learning could improve the diagnosis and monitoring of hematologic neoplasms, Ip explains. By providing potentially more accurate, powerful, and automated methods of disease detection, this approach could enhance patient care, facilitate earlier interventions, and potentially reduce the need for more invasive diagnostic procedures like bone marrow biopsies or lymph node biopsies, Ip expands. Further research and validation will be needed to potentially integrate these technologies into routine clinical practice and optimize their utility across different hematologic cancers, Ip concludes.

Dr Ip on the Importance of NGS Testing in Hematologic Malignancies

Andrew Ip, MD, medical oncologist, John Theurer Cancer Center, Hackensack University Medical Center, discusses findings from a study on the use of next-generation sequencing (NGS) of flow cytometry CD markers and machine learning as a replacement to flow cytometry analysis for the diagnosis of hematologic neoplasms.

The focus of this study extended beyond the utilization of NGS CD1300 RNA and NGS CD300 DNA mutations, Ip begins. Collaboratively, investigators incorporated more conventional flow cytometry CD markers, a traditional method for detecting hematologic neoplasms, into the testing approach, he states. This involved the use of 30 CD markers in combination with the NGS platform from the genomics testing cooperative, Ip elucidates. The synergy of these 2 testing modalities significantly enhanced the power, sensitivity, specificity, and accuracy of the overall diagnostic process, he explains.

, Ip and other investigators presented data on this investigative approach. Ip presented results from a substantial dataset that necessitate the application of machine learning techniques and big data analyses in the diagnosis of hematologic malignancies. The primary outcome reported was the area under the curve (AUC), a metric that elucidates the true positive rate vs the false positive rate, Ip explains.

The true positive rate reflects the reliability of a positive test result, gauging the likelihood of it being a genuine positive or a potential false positive, Ip continues. In this study, across various hematologic conditions, such as acute myeloid leukemia, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, and lymphomas, the AUC consistently exceeded 90%, he elucidates. In some instances, the AUC approached 98%, Ip notes. These findings indicate that a positive test result with a 90% confidence level corresponds with only a 2% chance of false positivity, he states. Such a high true positive rate signifies that the combination of NGS quantification and machine learning techniques denotes a potent screening modality, Ip concludes.

Andrew Ip, MD, discusses findings from a study on the use of next-generation sequencing of flow cytometry CD markers and machine learning as a replacement to flow cytometry analysis for the diagnosis of hematologic neoplasms.

Andrew Ip, MD, Hematologic Oncology, John Theurer Cancer Center, Hackensack University Medical Center, discusses carboplatin (Paraplatin), pemetrexed (Alimta), and pembrolizumab (Keytruda) as first-line therapy in recurrent/metastatic non–small cell lung cancer. 

In an ongoing analysis, investigators studied 523 patients treated at Hackensack University Medical Center and Memorial Sloan Kettering Cancer Center to determine outcomes with carboplatin, pemetrexed, and pembrolizumab, Ip says. At the time of analysis, the median overall survival for patients was 11 months, Ip adds. However, this is a stark contrast to what was expected based on a previous report of a 17-month overall survival benefit with the triplet, Ip concludes.

Andrew Ip, MD, discusses carboplatin, pemetrexed, and pembrolizumab as first-line therapy in recurrent/metastatic non–small cell lung cancer.  


Dr. Ip on the Utility of Carboplatin, Pemetrexed, and Pembrolizumab in Lung Adenocarcinoma

Andrew Ip, MD, chief, Outcomes and Value Care Division, member, Division of Lymphoma, John Theurer Cancer Center, Hackensack Meridian Health, discusses the use of targeted next-generation sequencing (NGS) in detecting chromosomal structural abnormalities in patients with myeloid neoplasms.

In a study of the reliability of targeted cell-free DNA (cfDNA) NGS in predicting chromosomal abnormalities in patients with myeloid neoplasms, Ip and colleagues found that liquid biopsy with targeted NGS is an accurate way to detect chromosomal structural abnormalities in myeloid neoplasms when compared with samples from bone marrow biopsies. When classified by prognostic classes, the investigators observed a 100% concordance in cytogenetic abnormalities between cfDNA NGS data and cytogenetic data.

This study looked at copy number variation, or cytogenetic differences, in the blood samples, with the goal of risk stratifying patients to understand whether peripheral blood tests can replace more invasive testing, Ip says. Findings showed that cfDNA-targeted NGS was sensitive enough to identify myeloid neoplasms and lymphoid neoplasms in many patients, Ip explains.

An important limitation of DNA mutation testing is that it doesn’t detect some rare isolated chromosomal abnormalities, Ip notes. In this study, for instance, deletion 5q, a mutation that does not appear on a broad NGS panel, was not detected with cfDNA-targeted NGS, Ip says. However, most patients being tested for myelodysplastic syndrome will have a molecular mutation profile that NGS testing can detect, Ip concludes.

Andrew Ip, MD, discusses the use of targeted next-generation sequencing in detecting chromosomal structural abnormalities in patients with myeloid neoplasms.

Andrew Ip, MD

Articles

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

Dr Ip on the Implications of NGS Plus Machine Learning for Diagnosing Hematologic Malignancies

Dr Ip on the Importance of NGS Testing in Hematologic Malignancies

Dr. Ip on the Utility of Carboplatin, Pemetrexed, and Pembrolizumab in Lung Adenocarcinoma

Dr. Ip on Next-Generation Sequencing in Myeloid Neoplasms