Correlative Analyses of Cereblon (CRBN), cMYC, IRF4, BLIMP1, and XBP1 with Clinical Outcomes in Stratus (MM-010), a Phase 3b Study of Pomalidomide (POM) + Low-Dose Dexamethasone (LoDEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

BACKGROUND

CRBN, the molecular target for thalidomide (THAL), lenalidomide (LEN), and POM, mediates both the tumoricidal and immunomodulatory activities of these agents. The potential utility of CRBN as a predictive biomarker of response and/or resistance to these agents was investigated in several small retrospective studies, with conflicting results. Downregulation of CRBN was linked to POM and LEN resistance (Zhu, 2011), and high expression of CRBN was associated with improved clinical response to LEN (Heintel, 2013) and to THAL maintenance therapy (Broyl, 2013). In a POM + LoDEX study (N = 53; Schuster, 2014), longer progression-free survival (PFS) and overall survival (OS) were observed for the highest vs lowest quartile of CRBN expressers. In contrast, CRBN protein levels did not correlate with intrinsic sensitivity or resistance to LEN in a diverse panel of MM cell lines (Gandhi, 2014) or with clinical response to POM + LoDEX treatment in pts with RRMM (Sehgal, 2015). These studies used a variety of methods to detect CRBN mRNA or protein in MM cell lines and pt samples.

The current study evaluated gene expression levels of 5 biomarkers in purified CD138⁺ tumor cell samples from 224 pts from STRATUS to investigate their potential as predictive biomarkers of POM response or resistance. STRATUS, a multicenter, single-arm, open-label, European, phase 3b trial (CC-4047-MM-010; ClinicalTrials.gov: NCT01712789; EudraCT 2012-001888-78), demonstrated the safety and efficacy of POM + LoDEX in pts with RRMM (Dimopoulos, 2016).

METHODS

Gene expression level of 5 biomarkers (CRBN, cMYC, IRF4, BLIMP1, and XBP1) was determined by a validated RT-qPCR assay in CD138⁺ tumor cells isolated from bone marrow aspirates. The biomarker-evaluable population consisted of 224 pts from STRATUS who consented to biomarker research. The baseline-normalized expression level of each target gene was defined by its ΔCt value (difference in cycle time of target gene vs normalizing genes). Correlative analyses were performed between baseline normalized ΔCt values of the biomarkers and the clinical outcomes (best overall response, PFS, and OS). Clinical outcomes were analyzed in subgroups of biomarker-evaluable populations defined by < or ≥ median baseline normalized ΔCt values (ie, higher or lower expressers of the gene, respectively) for each biomarker.

RESULTS

Pts in the biomarker-evaluable subgroups had comparable demographic and disease characteristics, similar to those of the 682 pts in the intent-to-treat (ITT) population.

Clinically relevant ORRs (29%-42%) were observed in subgroups of pts with either higher or lower gene expression of each of the 5 tested biomarkers. There was no correlation between the gene expression levels of IRF4, BLIMP1, or XBP1 in CD138⁺ plasma cells and any of the clinical outcomes in the biomarker-evaluable population.

A trend for ORR in favor of pts with higher vs lower expression of the cMYC gene was observed (42.0% vs 28.6%; P= .050). There was a trend for PFS in favor of pts with higher vs lower expression of the CRBN gene (median, 29.3 vs 17.7 wks; P= .038) and a potential trend in OS in favor of pts with higher vs lower expression of the CRBN gene (median, 71.6 vs 52.3 wks; P= .059). No other notable differences in PFS or OS were observed with high vs low gene expression for any other biomarker (including cMYC).

Of note, clinical outcomes (ORR, 30%; median PFS, 17.7 wks; median OS, 52.3 wks) in the low CRBN gene expression subgroup were comparable to those in the POM + LoDEX group in pivotal study CC-4047-MM-003 (ORR, 31%; median PFS, 17.4 wks; median OS, 55.2 wks) and in the STRATUS ITT population (ORR, 33%; median PFS, 20.0 wks; median OS, 51.7 wks).

CONCLUSIONS

The current study is the most robust analysis of putative biomarkers of response or resistance to POM + LoDEX to date. The study found no correlation between the gene expression levels of IRF4, BLIMP1, and XBP1 in CD138⁺ plasma cells and any of the clinical outcomes in the biomarker-evaluable population of 224 pts in STRATUS. A trend in PFS, and potentially a trend in OS, in favor of higher expressers of CRBN was observed; however, this was not associated with a notable difference in ORR. Efficacy outcomes in lower CRBN expressers were comparable to those in the MM-003 trial. A trend in ORR in favor of higher expressers of cMYC was also observed, with no notable difference in either PFS or OS.

Acknowledgment: PM and AT are co-primary investigators.