Characterization of Atypical t(11;14) CCND1/IGH Translocations in Multiple Myeloma

Purpose:

Multiple myeloma (MM) is a plasma cell malignancy characterized by a collection of cytogenetic abnormalities that drive clinical presentation, response to treatment, and prognosis. The most common immunoglobulin heavy chain (IGH) translocation found in MM, t(11;14), results in CCND1 overexpression. Although t(11;14) is considered a standard risk cytogenetic abnormality, heterogeneity in patient outcomes and response to therapy within the t(11;14) group has been reported. In contrast to t(11;14) mantle cell lymphoma, where most cases (73%) have a typical, balanced t(11;14) rearrangement, only 47% of t(11;14) MM have a typical, balanced t(11;14) FISH pattern; the remaining 53% of MM are characterized by an atypical t(11;14) FISH result (Dalland, Genes Chromosomes Cancer, 2021). Here, we compared the genetic characteristics of typical vs. atypical t(11;14) MM and the association with other genomic abnormalities, CCND1 expression, IGH breakpoint location and patient outcomes.

Methods:

We performed a retrospective study of newly diagnosed t(11;14) MM patients seen at Mayo Clinic (N=411) or enrolled in the MMRF CoMMpass trial (N=167). The t(11;14) FISH results of the Mayo Clinic samples were segmented into two groups: typical CCND1/IGH signal pattern (n=179, 3 red, 3 green, 2 fusion signals) and atypical CCND1/IGH signal pattern (n=232, any FISH pattern deviating from typical). The CoMMpass cases had both RNAseq and long-insert WGS data and were analyzed to detect gene expression, structural and copy number variants and IGH breakpoint locations. These data were used to classify the t(11;14) as typical (n=63) or atypical (n=104) and whether there was a single t(11;14) fusion (n=107) or a gain of the t(11;14) fusion (n=60), and whether these cases were associated with changes in gene expression or breakpoint location. Differences between the groups were measured using χ² and Wilcoxon tests. Survival curves were estimated using Kaplan Meier and compared using the Log-Rank test. Statistical significance was determined at p<0.05.

Results:

Of the Mayo t(11;14) cohort, 232/411 (56%) had an atypical t(11;14) FISH pattern and 179/411 (44%) had a typical t(11;14) FISH pattern. Although an atypical t(11;14) FISH pattern was not significantly associated with monosomy 17/17p deletion, MYC rearrangements, 1q gain or ISS stage III, it was significantly associated with the presence of any trisomy in comparison to typical t(11;14) cases (40/222=18% vs.12/166=7%, p=0.002). Atypical t(11;14) cases had an increase in CCND1 gene expression compared to typical t(11;14) cases (median 375.0 RPKM vs. 266.4 RPKM, p<0.0001) and cases with a gain of the t(11;14) fusion were associated with even greater CCND1 expression compared to cases with a single t(11;14) fusion (median 459.4 RPKM vs. 263.2 RPKM, p<0.0001). We next evaluated whether the t(11:14) FISH pattern was associated with differences in IGH breakpoint locations. Nearly 80.0% of atypical t(11;14) cases had a breakpoint within the constant region of the IGH locus commonly reported for MM, while only 61.0% of the typical cases had constant region breakpoints (p=0.035); the remaining cases had breakpoints involving the VDJ region. We next evaluated the impact of atypical t(11;14) FISH on OS. In Mayo cases, OS was significantly shorter in patients with atypical FISH patterns compared to typical t(11;14) FISH patterns (6.9 years [95% CI: 5.1-7.8] vs. 9.0 years [95% CI: 7.0-11.6], p=0.019). Although atypical t(11;14) was associated with increased risk of death (RR 1.45, p=0.021), this finding was not retained in a multivariate model including high risk abnormalities such as age, ISS stage, 17p deletion and 1q gain demonstrating atypical t(11;14) is not an independent predictor of poor outcome when treated with standard therapies.

Conclusions:

Atypical t(11;14) FISH in MM is found in approximately half of t(11;14) cases, is associated with trisomies, higher CCND1 expression and is more likely to have a breakpoint involving the constant region of the IGH locus. The enrichment of VDJ breakpoints within typical t(11;14) MM is consistent with enrichment of VDJ IGH breakpoints in MCL, which are mostly characterized by typical t(11;14) FISH patterns. While not an independent predictor of outcome with standard therapies, it remains to be evaluated whether patients with typical or atypical t(11;14) have a differential response to novel agents, such as venetoclax.