MYC rearrangements with immunoglobulin genes as an independent prognostic factor of progression-free survival in newly diagnosed patients

Abstract Introduction: MYC rearrangement (MYC-R), especially those involving the immunoglobulin loci (IGL, IGH, and IGK), are drivers of MM and other malignancies. IGL::MYC has been associated with hyperdiploidy and inferior outcomes. Despite this, MYC is not part of the recommended fluorescence in situ hybridization (FISH) panel at diagnosis. We describe the clinical impact of MYC alterations in newly diagnosed MM (NDMM) and the MYC-R prevalence in systematic MYC assessment by FISH and genomic proximity mapping (GPM). Methods: The Multiple Myeloma Research Foundation CoMMpass (MMRF-NGS cohort) was used to assess the frequency and impact of MYC rearrangements (MYC-R) on progression-free survival (PFS). FISH using a MYC break apart probe was part of the routine FISH panel at our center for MM starting in June 2023 in 133 patients (pts) (WCM-FISH cohort). GPM was performed on CD138+-selected cells from 50 pts who part of a prospective clinical trial of NDMM (NCT01559935 (CarBiRD cohort)) and in 37 pts from the WCM-FISH cohort. MYC-R breakpoints and gain (MYC-g) were identified. PFS was defined as the time from MM diagnosis to progression of disease or death, as determined by the International Myeloma Working Group. High-risk cytogenetics (HR-CG) were defined as any of del17p, t(4;14), t(14;16), or gain1q. Supported by R44CA268681 and WA Care Fund. Results: In the MMRF-NGS cohort, MYC-R was seen in 234/913 pts (25.6%), with most MYC-R having IGH/IGL/IGK (IG::MYC) as a partner in 52% of cases. IG::MYC pts had inferior PFS (25.4 months) when compared to MYC-R with non-IGH/L/K partners (MYC::non-IG) (42.2 months, pairwise p= 0.04) and MYC-negative (neg) (37.9 months, pairwise p= 0.04). There were no differences in PFS between MYC-neg and MYC::non-IG (p = 0.59). In a multivariable model, IG::MYC remained associated with inferior PFS (hazard ratio [HR] 1.39, 1.09-1.7, p = 0.01) after adjusting for age, transplant, triplet vs. duplet induction, and del17p, gain1q, del1p, and del13q status. 24 pts with IG::MYC had sequential samples available, and 22/24 (92%) IG::MYC was present at diagnosis, suggesting IG::MYC-Ris a truncal event and is often present at MM diagnosis. In the WCM-FISH cohort, MYC alterations were present in 44/133 pts with MM (33%). MYC-R was present in 35 pts (26%), while MYC-g was present in 13 (9.8%). Pts with MYC-R had significantly shorter PFS compared to MYC-neg (15.6 vs. 35.7 months, p = 0.017). Other variables associated with PFS included ISS, R-ISS, lactate dehydrogenase, albumin, del17p, and HR-CG. In the multivariable model, only MYC-R was associated with inferior PFS (HR 2.82, 95% CI 1.12-7.06, p = 0.02). When pts were stratified by MYC-R and HR-CG status, pts with MYC -R and no HR-CG had inferior PFS compared to MYC-neg/no HR-CG pts (p = 0.001) and had comparable PFS to HR-CG alone. Most MYC-R cases were not further assessed by standard FISH for, with MYC::IGH being the only partner genes identified (3/35 cases). In the CarBiRD cohort, GPM identified 17/50 (34%) pts with MYC alterations, including 12 pts (24%) with MYC-R. The MYC partner was identified in all cases, with 8 pts having IG::MYC. MYC-R, were associated with inferior PFS when compared to MYC-neg (HR 2.1, 1.06 – 4.4, p = 0.03), mainly driven MYC::IG cases, which had inferior PFS when compared to non-MYC-R pts (HR 4.27, 1.82 – 10.1, p < 0.001). In the pts who had GPM and FISH available (87 pts), GPM identified MYC alteration in 32/87 (37%) of cases, including MYC-R in 27/87 (31%) of pts. 48% of MYC-R involved the IGL, IGK or IGH (6, 4, and 3 cases, respectively). GPM identified the breakpoint in all cases, also identifying complex alterations involving several translocations or inversions in the same patient in addition to inversions of chromosome 8q. GPM detected all cases of t(11;14), t(4;14), MYC-R, and t(14;16) identified by FISH, in addition to 3 pts with t(11;14), t(14;16), and MYC-R that FISH missed due to atypical breakpoints. MYC alterations were associated with a higher rate of del1p, hyperdiploidy, and del17p, while mutually exclusive from t(11;14). Conclusion: MYC-R is common in NDMM and is associated with inferior PFS independent of other genomic variables. MYC FISH should be considered part of the standard risk stratification. MYC partner may have important prognostic implications. GPM provides higher resolution and can locate other recurrent abnormalities in MM, in addition to characterizing complex MYC alterations and breakpoints.