Unveiling Clinical Potential: Exploring Cytogenomic Aberrations through Optical Genomic Mapping in Multiple Myeloma

Introduction: Optical genome mapping (OGM) is a novel DNA-based technology for comprehensive genome-wide analysis of cytogenomic abnormalities. Multiple Myeloma (MM) is characterized by recurrent cytogenetic abnormalities including copy number variants (CNVs) such as hyperdiploidy, gain of 1q, loss of 1p, del(17p), del(13q); as well as structural variants (SVs) such as chromosomal rearrangements involving IgH. This study assessed the use of OGM compared to fluorescence in situ hybridization (FISH) and karyotyping in clinical MM cases.

Methods: Bone marrow aspirate (BMA) samples with >20% plasma cells from MM patients (pts) at a single institute (March 2023 – April 2024) were collected, and subjected to OGM, karyotyping, and FISH analysis for rearrangements of IGH/CCND1, IGH/FGFR3, IGH/MAF, MYC, and numerical changes of CDKN2C/CKS1B, CDKN2A/CEP9, RB1/13q34, and TP53/CEP17. Cytogenomic findings detected by OGM were classified as pathogenic/likely pathogenic, or uncertain clinical significance. Clinical data including staging, extramedullary disease and Line of therapy (LOT) were also collected.

Results: The study cohort included newly diagnosed MM (NDMM, n=10) and relapsed refractory MM (RRMM, n=15). OGM detected all cytogenomic aberrations which were reported by karyotyping and FISH. Furthermore, OGM identified additional cytogenomic abnormalities in 15 (60%) of patients that were not identified by FISH and karyotyping. OGM identified 3 or more CNVs in 7 pts and SVs in 8 pts, and uncharacterized cytogenetic aberrations in 15 patients. Notably del(17p) was detected in 2 pts by FISH but not by OGM, likely due to the small clonal size below OGM’s detection limit (20%). MYC rearrangement (eg MYC::IGH) was detected by both FISH and OGM, however with OGM identifying additional MYC partner genes (IGL, PECAM1, NBEA and TENT5C). Furthermore several abnormalities involving novel genes were exclusively detected by OGM only: PTK2, PVT1, and ARIH2.

Chromoanagenesis was detected only by OGM in 6 pts (n=1 for NDMM; n=5 for RRMM). The NDMM pt with chromoanagenesis achieved only a partial response after induction therapy. RRMM pts with chromoanagenesis demonstrated functionally aggressive clinical features, all required intensive chemotherapy regimens such as hypercytoxan, hyperCVAD, and also novel bispecific antibodies. Chromoanagenesis can present either independently or in combination with known high-risk FISH features.

Conclusion: OGM, as a novel cytogenomic technique, offers broader genomic coverage compared to current FISH probe sets (with limited targets) and much higher genomic resolution and sensitivity compared to karyotyping. OGM may complement classical cytogenetics for the diagnosis and risk stratification in MM. OGM’s ability to detect chromoanagenesis is promising, despite its current limitation in detection sensitivity which could be improved by cell sorting techniques. Chromoanagenesis identified by OGM can potentially serve as a biomarker for complex chromosomal rearrangement and genomic instability, and also for strategizing the subsequent LOTs for more favorable clinical responses. Future prospective studies are warranted.