Overexpression of EZH2 in Multiple Myeloma Is Associated with Poor Prognosis Regardless of Treatment with Novel Agents or High-Dose Chemotherapy

Background: EZH2 overexpression has been linked to the development and progression of a variety of cancers. Pawlyn et al (Blood Cancer J, 2017) recently reported that EZH2 overexpression among patients with multiple myeloma (MM) was associated poor prognosis. Their analysis included patients on varying treatment regimens over a number of years and, therefore, they were unable to determine if proteasome inhibitors (PIs), immunomodulatory drugs (IMIDs), or high-dose chemotherapy and transplantation (HDCT) can overcome the negative effect of EZH2 overexpression, as they have been shown to do for some other high-risk genetic profiles.

Objectives: To independently confirm EZH2 overexpression is associated with poor outcomes and determine if PI, IMIDs, or HDCT can overcome this poor risk.

Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis 10 from the CoMMpass study. The CoMMpass study enrolled 1000 newly diagnosed MM patients who are being tracked longitudinally for 5 years. CoMMpass collects sequential tissue samples as well as relevant clinical data. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving a PI and/or and IMID for initial MM treatment; and no prior malignancies in the past 5 years. RNA sequencing was performed on CD138-enriched bone marrow cells at MM diagnosis. EZH2 overexpression was defined as > 1 SD above mean expression. High-risk cytogenetics, defined as amp1q, del17p, t(4;14), t(14;16), t(14;20), were identified using custom SeqFISH software on long-insert whole genome sequencing data. All sequencing was performed by the Translational Genomics Research Institute (TGEN).

Results: 646 patients in the dataset had EZH2 expression data and were included in the analysis. The median age was 63 at MM diagnosis, 58% were male and 76% were white. 33% were ISS stage I, 37% ISS stage II, and 30% ISS stage III. Cytogenetics was not available for 17% of cases. Of those with cytogenetics available, 53% had high-risk disease; 38% amp1q, 12% del17p, 12% t(4;14), 4% t(14;16), and 1% (14;20).

15% of patients (n = 97) were classified as EZH2 overexpressors. Patients with ISS stage III disease were more likely to have EZH2 overexpression (26%) than stage II (13%) and stage I (9%) (p < 0.0001). EZH2 overexpression was also more common among patients with high-risk cytogenetics than those without (19% compared to 9%, p = 0.0022). Of patients with high-risk cytogenetics available, overexpression was most common among patients with del17p (24%) and least common among patients with t(4;14) (11%). EZH2 expression was not associated with age, race, or gender.

629 patients had first-line treatment data available, of which 93% received a PI, 72% an IMID, 70% both. 45% of patients underwent HDCT during first-line treatment. In the multivariate analysis, EZH2 expression was consistently associated with poor prognosis regardless of regimen, with an increase in hazard ratio for progression or mortality ranging from 106%-173%. The results of the multivariate analysis are summarized in Table 1.

Conclusions: We found that EZH2 expression was consistently associated with poor prognosis across all treatment regimens. It is important to note that we were unable to control for HRD by cytogenetics due to the high rate of missing data. EZH2 expression has previously been shown to predict response independent of HRD and, therefore, its omission should not alter the findings. Patients with myeloma overexpressing EZH2 are at increased risk of progression and death regardless of therapeutic regimen. Early-stage clinical trials of EZH2 inhibitors are currently ongoing in solid tumors and lymphomas and their testing should be expanded to MM.

View largeDownload slide

View largeDownload slide

Close modal