MYC rearrangement improves the predictive efficacy of the double-hit model in newly diagnosed multiple myeloma

BACKGROUND: MYC rearrangement (MYC-R) is a known adverse prognostic factor in multiple myeloma (MM), yet its role in the double-hit model remains undefined. Meanwhile, the prognostic value of MYC gain/amp has not been clearly characterized. This study aimed to evaluate the prognostic impact of MYC-R and/or gain/amp to assess their potential role in refining risk stratification. PATIENTS AND METHODS: A prospective cohort of 227 patients with newly diagnosed MM (enrolled in the NICHE clinical trial, NCT04645199) received bortezomib-based induction therapy and, if eligible, underwent upfront autologous stem cell transplantation. The FISH panel included del(13q), del(17p), del(1p), 1q21 gain/amp, IgH rearrangement, t(4;14), t(11;14), t(14;16), t(14;20), MYC break-apart probe, and IgH/MYC fusion probe. RESULTS: Median progression-free survival (PFS) was significantly shorter in patients with MYC-R (34.0 months) or MYC gain/amp (34.3 months), compared with those without MYC abnormalities (49.2 months; P = 0.003 and 0.016, respectively). IgH/MYC was notably more common in cases with undefined-partner IgH translocations (16.6%) than those with defined partners (5.7%), and was associated with poorer outcomes. In multivariate analysis, MYC-R remained an independent predictor of PFS (hazard ratio 1.96, P = 0.007) and improved the discriminative performance of the double-hit model by increasing the concordance index for PFS from 0.549 to 0.581. CONCLUSION: Both MYC-R and MYC gain/amp indicate adverse prognosis in newly diagnosed MM. The independent prognostic value of MYC-R supports its integration into routine FISH panels and future refinements of the double-hit risk model.