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Association between c-MYC expression and progression free survival in multiple myeloma patients treated with ixazomib-lenalidomide-dexamethasone

Results of an exploratory biomarker analysis of the TOURMALINE-MM1 study showed that the benefit of ixazomib-lenalidomide-dexamethasone (IRd) on progression-free survival (PFS) was more pronounced in patients with a higher c-MYC expression. This analysis also revealed that tumors from patients relapsing after one prior therapy without a stem cell transplantation (SCT) and patients who previously received 2 or 3 therapies had high levels of c-MYC expression, while tumors from patients relapsing directly after a SCT tended to have a lower c-MYC expression. This could in part provide a potential explanation for the enhanced PFS benefit seen with IRd as compared to placebo-Rd in patients with 2-3 prior therapies.

In the double-blind, placebo-controlled phase 3 TOURMALINE-MM1 study, including 722 patients with relapsed/refractory multiple myeloma (RRMM), IRd was shown to be associated with a superior PFS as compared to placebo-Rd (HR 0.74). A pre-specified subgroup analysis of this study showed a consistent PFS benefit with IRd, but with a differential treatment effect according to prior therapy exposure. The objective of this exploratory analysis was to evaluate the potential relationship between treatment outcomes and tumor gene expression patterns. C-MYC is a proto-oncogene that encodes a transcription factor regulating cell proliferation, growth, protein translation, metabolism, and apoptosis, and increased c-MYC expression is involved in MM pathogenesis/progression. In this analysis, the impact of c-MYC expression on PFS was assessed in RRMM patients treated with IRd or placebo-Rd.

In TOURMALINE-MM1, RRMM patients after 1–3 prior lines of therapy were randomized 1:1 to receive oral IRd, or placebo-Rd until disease progression or unacceptable toxicity. Bone marrow aspirate samples were collected at screening for tumor gene expression analysis. The c-MYC expression was evaluated by treatment arm and according to the number of prior therapies (1 versus. 2-3).

RNAseq data were available for 58% (419/722) of enrolled patients. Of them 210 (50%) had high and 209 (50%) had low c-MYC expression (dichotomized according to the median). The impact of c-MYC expression (high versus low) on PFS, irrespective of treatment arm, was not significant (p=0.77). However, a significant treatment effect of IRd versus. placebo-Rd was seen in patients with high c-MYC expression. In these patients (IRd: N=107; placebo-Rd: N=102) a significant PFS benefit was seen with IRd (median PFS 21.4 versus 11.1 months; HR[95%CI]: 0.41[0.27–0.66], p< 0.001). In the patients with low c-MYC expression (IRd: N=93; placebo-Rd: N=117), the difference in PFS with IRd and placebo-Rd was not statistically different (median PFS 20.6 versus 17.5 months; HR[95%CI]: 0.81[0.52–1.3], p= 0.338).

The impact of c-MYC expression was then analyzed by number of prior therapies. After a median follow-up of ~15 months, the median PFS in patients with 1 prior therapy was 20.6 versus 16.6 months with IRd versus placebo-Rd (HR[95%CI]: 0.88[0.65–1.20]). In patients with 2-3 prior therapies, the median PFS was not reached with IRd and was 12.9 months with placebo-Rd (HR[95%CI]: 0.58[0.40–0.84], p=0.0033). The level of c-MYC expression was shown to be significantly higher in patients with 2-3 prior therapies as compared to 1 prior therapy, with a median expression of 6.94 as compared to 6.52 (p= 0.0153). In patients with 1 prior therapy, without SCT, no differences in PFS were observed between patients with low c-MYC expression (HR[95%CI]: 0.7[0.29-1.7]; p=0.439), while a prolonged PFS benefit was observed in patients with a high c-MYC expression (HR[95%CI]: 0.41[0.19-0.86]; p=0.0146). In patients with 2-3 prior therapies, both the c-MYC-high and c-MYC-low patients showed improved PFS with IRd over placebo-Rd. However, the difference in PFS was only statistically significant in c-MYC-high patients (HR[95%CI]: 0.26[0.12-0.6]; p< 0.01). For patients with a low c-MYC expression, the HR was 0.64 (95%CI: 0.31-1.3).

The researchers concluded with the hypothesis that immunomodulatory drugs and proteasome inhibitors appear to target different clones, with Rd preferentially targeting low c-MYC expressing and less differentiated cells and proteasome inhibitors targeting high c-MYC expressing and more differentiated cells. This might in part explain their synergistic action and the increased benefit observed with IRd. As such, these data are hypothesis-generating and further validation in prospective studies is warranted.


Di Bacco A, Bahlis N, Munshi N, et al. Higher c-MYC Expression Is Associated with Ixazomib-Lenalidomide-Dexamethasone (IRd) Progression-Free Survival (PFS) Benefit Versus Placebo-Rd: Biomarker Analysis of the Phase 3 Tourmaline-MM1 Study in Relapsed/Refractory Multiple Myeloma (RRMM). Presented at ASH 2016; Abstract 243.

Speaker Alessandra Di Bacco

Di Bacco

Alessandra Di Bacco, PhD,
Millennium Pharmaceuticals Inc.


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