(PA-250) Systematic Assessment of MYC by Fluorescence in situ Hybridization in Multiple Myeloma Identifies a High-Risk Population Independent of Other Risk Factors

MYC testing is not routinely performed in multiple myeloma (MM) despite being recognized as a prognostic biomarker. We present the impact of systematic MYC testing for alterations on outcomes in patients (pts) with MM and its relation to clinical features and cytogenetics.

Methods: A total 133 pts who underwent bone marrow biopsy and had a diagnosis of MM (147 total samples) were systematically assessed for MYC alterations using fluorescence in situ hybridization (FISH) testing over a 24-month period. 126 were assessable for progression-free survival (PFS), and 92 were newly diagnosed with MM (NDMM). MYC alterations were classified as rearrangements (MYC-R) or gains. Clinical characteristics, cytogenetic alterations, and outcomes were compared across MYC status. PFS was defined as time from diagnosis to death or progression/relapse of disease as defined by the International Myeloma Working Group criteria.

Results:

MYC alterations were present in 44 of 133 MM pts (33%).  MYC-R was present in 35 pts (26%), while MYC gain was present in 13 pts (9.8%). Most MYC-R partners were not identified on standard of care FISH, with MYC::IGH being present in 7/35 cases.

Compared to non-altered MYC (MYC-negative) cases, those with MYC-R were older (median 75 vs. 67 years, p = 0.005), and more likely to present with international staging system III (56% vs. 29%, p = 0.008) and hypoalbuminemia (68% vs. 42%, p = 0.01). MYC-R cases had higher rates of del(17p): 23% vs. 6.7% (p = 0.02), t(4;14): 23% vs. 9% (p = 0.07), and lower rates of t(11;14): 17% vs 37%, p = 0.03). MYC-R was associated with higher rates of high-risk cytogenetics (HR-CG - del(17p), t(4:14), t(14;16)); 46% vs 19%, p = 0.003), HR-CG plus gain(1q) (74% vs 55%, p = 0.04), and HR-CG plus gain(1q) or del(1p), 80% vs 56%, p = 0.01).
Pts with MYC-R had significantly shorter PFS compared to MYC-negative (15.6 vs. 35.7 months, p = 0.017). Other variables associated with PFS included ISS, R-ISS, LDH, albumin, del(17p), and HR-CG. In multivariable model, only MYC-R was associated with inferior PFS (HR 2.82, 95% CI 1.12-7.06, p = 0.027). Additionally, when patients were stratified by MYC-R and HR-CG status, patients with MYC-R and no HR-CG had inferior PFS compared to MYC-negative/no HR-CG patients (p = 0.001) and similar to when there was the presence of HR-CG.

Conclusions:

MYC-R is a common (27% of cases) alteration that is associated with co-occurrence of other HR-CG alterations, advanced clinical presentation, and significantly inferior PFS, even in the absence of other HR-CG features. Importantly, the presence of MYC-R was associated with inferior PFS regardless of HR-CG status, ECOG, or R-ISS at diagnosis, suggesting it is an independent predictor. These findings highlight the prognostic relevance of MYC rearrangement and support its utility as a risk stratification biomarker that can be widely incorporated into current FISH panels.