(PA-275) Genomic Profiling of Multiple Myeloma via Optical Genome Mapping: An Exploratory Analysis of Response and Progression in Newly Diagnosed and Relapsed Disease

Multiple myeloma (MM) is characterized by genomic complexity and risk-stratified by cytogenetic abnormalities. Optical genome mapping (OGM) provides a high resolution genome wide platform capable of detecting both structural variants (SV) and copy number variants (CNV) beyond the scope of conventional cytogenetics. It may uncover novel cytogenomic complexity with potential prognostic and therapeutic relevance.

Methods:   

Two cohorts of patients from two major cancer centers in the US underwent OGM detection. Clinical data was collected including clinical features such as Extramedullary disease (EMD), plasma cell leukemia (PCL), Line of therapy (LOT) and treatment regimens before/after OGM, response to therapy after OGM.  CNV burden and SVs such as chromoanagenesis and MYC rearrangements were assessed from OGM data. Associations between genomic findings and clinical outcomes were performed using Fisher’s exact test for response status and log-rank test for OS.

Results:   

This study included a total of 83 patients, 46 newly diagnosed MM (NDMM) and 37 relapsed refractory MM (RRMM).

In the NDMM cohort (median follow up from diagnosis was 15.2 mo [95% CI, 13.9 – 17.4]) induction regimens varied (78% D-VRd, 13% DRd, others D-CyBorD or KRd). 13.6% exhibited chromoanagenesis, 30.4% harbored MYC rearrangements. One-year OS rate in chromoanagenesis-positive patients is lower compared with patients without chromoanagenesis (0.8 [95% CI, 0.52, 1.0] vs. 0.94 [95% CI, 0.87, 1.0]), however, this difference in OS was not significant (p-value=0.245).

In the RRMM cohort (median follow up 81.2 mo [95% CI, 59.8 – 169]), patients had a median of 3 prior LOT (range 1-12) before OGM.  Post-OGM 94.6% received additional therapy, including CAR-T (n=6), bispecifics (n=13), Dara-based triplet or quadruplet (n=7), hypercytoxan (n=3). Chromoanagenesis was identified in 31.4% of RRMM, and MYC rearrangements in 32.4%.

Chromoanagenesis was significantly more common in patients with RRMM compared with NDMM (p=0.08). It is also more common in patients with EMD /PCL, occurring in 7 of 15 cases (47%), compared to only 14 of 68 patients (21%) without (p = 0.05). Interestingly, high-risk cytogenetic features by conventional cytogenetics—were observed in 75% of EMD/PCL cases and 60% of non-EMD/PCL cases, a difference that was not statistically significant (p = 0.39).

Conclusions:   

Cytogenomic aberrations, such as chromoanagenesis detected by OGM, may be associated with inferior survival, aggressive clinical features such as EMD and PCL, and clonal evolution acquired during disease progression from NDMM to RRMM. These findings suggest that cytogenomic profiling may enhance the current prognostic tools for risk stratification in NDMM. Prospective validation in larger cohorts is warranted to support the integration of cytogenomic data into clinical decision-making.