(PA-226) MYC Copy Number Variation Detected by FISH Indicates a Similarly Poor Prognosis to MYC Rearrangement in Newly Diagnosed Multiple Myeloma

Cytogenetic abnormality is one of the imperative prognostic factors of multiple myeloma (MM), and help to outline double-hit high-risk patients. Mainstream risk stratification systems included t(4;14), t(14;16), t(14;20), del(17p), gain(1q) and/or del(1p) as high-risk factors. MYC rearrangement detected by FISH is also a confirmed adverse prognostic factor in MM. However, MYC is not under consideration when defining double-hit MM. Another interesting issue is whether MYC copy number variation indicates inferior outcome, as both rearrangement and amplification may result in MYC overexpression. To answer these questions, we conducted an analysis of a prospective observational cohort.

Methods:

This study was carried out based on the MM database of the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199). 227 newly diagnosed MM patients were enrolled from January 1, 2014 to January 31, 2021. Patients received BCD or VRD induction therapy. Transplant-eligible patients accepted first-line autologous stem cell transplantation. All patients were treated by lenalidomide-based maintenance therapy for at least two years. FISH panel included del(13q), del(17p), del(1p), 1q21 gain/amp, IgH rearrangement, with its translocation partners [t(4;14), t(11;14), t(14;16), and t(14;20)], and MYC (8q24.1) break-apart probe.

Results:

The median follow-up time was 31.2 months. 18.9% of patients had MYC structural variation (SV) and 19.8% of patients had MYC copy number variation (CNV). Only three patients had both MYC abnormalities. Patients with either MYC SV or CNV intended to have higher level of bone marrow plasma cells, and were more likely to had anemia and LDH elevation. Compared to patients without MYC SV or CNV, patients with SV or CNV had a higher incidence rate of del(17p) (4.7%, 15.6% vs. 3.5%) and gain(1q) (60.5%, 71.1% vs. 34.5%). Patients with SV or CNV had an inferior PFS (24.7, 24.2 months) and OS (30.6, 32.7 months), compared to patients without any (PFS 31.1 months, OS 38.2 months). By adding MYC abnormalities on double-hit model [t(4;14), t(14;16), t(14;20), del(17p), gain(1q), del(1p)], concordance index for PFS and OS was increased (0.580 vs. 0.563, 0.608 vs. 0.575).

Conclusions:

Our findings suggest that MYC CNV also exerted an adverse effect on survival as SV did. It may be better if we considered MYC abnormalities (including SV and CNV) as high-risk factors to define double-hit MM. The conclusion should be verified in larger prospective cohort.