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. Author manuscript; available in PMC: 2014 Jan 29.
Published in final edited form as: Leuk Res. 2013 Sep 5;38(1):23–28. doi: 10.1016/j.leukres.2013.08.015

The clinical significance of cereblon expression in multiple myeloma

Steven R Schuster a,*, K Martin Kortuem b, Yuan Xiao Zhu b, Esteban Braggio b, Chang-Xin Shi b, Laura A Bruins b, Jessica E Schmidt b, Greg Ahmann b, Shaji Kumar c, S Vincent Rajkumar c, Joseph Mikhael b, Betsy LaPlant e, Mia D Champion b, Kristina Laumann e, Bart Barlogie d, Rafael Fonseca b, P Leif Bergsagel b, Martha Lacy c, A Keith Stewart b
PMCID: PMC3905958  NIHMSID: NIHMS546405  PMID: 24129344

Abstract

Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). We demonstrate here that no patient with very low CRBN expression responded to IMiD plus dexamethasone therapy. In 53 refractory MM patients treated with pomalidomide and dexamethasone, CRBN levels predict for decreased response rates and significant differences in PFS (3.0 vs. 8.9 months, p < 0.001) and OS (9.1 vs. 27.2 months, p = 0.01) (lowest quartile vs. highest three quartiles). While higher CRBN levels can serve as a surrogate for low risk disease, our study demonstrates that low CRBN expression can predict resistance to IMiD monotherapy and is a predictive biomarker for survival outcomes.

Keywords: Multiple myeloma, Cereblon, Gene expression profiling, Immunomodulatory drugs, Biological markers

1. Introduction

Immunomodulatory drugs (IMiDs) are key components of treatment for multiple hematologic malignancies [1]. The first drug in this class, thalidomide, was originally used as a sedative in pregnant women and became infamous for its teratogenic effects. Early studies implicated thalidomide-induced oxidative stress and anti-angiogenesis as possible mechanisms of these malformations [2, 3]. Recently, Ito et al. revealed in a landmark paper that cereblon (CRBN) is the primary target of thalidomide teratogenicity [4]. Thalidomide binds CRBN to inhibit the function of the E3 ubiquitin ligase complex (composed of CRBN, DDB1, and Cul4). This complex regulates DNA repair, replication and transcription, and its inhibition by thalidomide causes teratogenic effects by preventing degradation of proteins that play a crucial role in embryonic limb development (e.g. down regulation of fibroblast growth factor 8) [4]. Drug-induced downstream effects of CRBN inhibition include cell cycle arrest with up regulation of the cyclin-dependent kinase inhibitor p21WAF-1 [5] and down regulation of interferon regulatory factor 4 (IRF4), a MM cell survival factor that targets critical genes like MYC, CDK6 and CASP3 [6–8].

We recently demonstrated that CRBN is also required for the anti-MM action of the thalidomide derivatives lenalidomide and pomalidomide, thus more accurately referred to collectively as “cereblon inhibitors” [9]. Furthermore, we observed that CRBN expression decreases in MM patients that developed resistance to lenalidomide therapy [9, 10]. Conversely, loss of CRBN expression did not affect response to other agents, such as bortezomib, dexamethasone, and melphalan [4]. Recent studies have observed a positive association between CRBN and response with thalidomide maintenance and upfront lenalidomide and dexamethasone therapy [11, 12]. Furthermore, we and others have observed CRBN mutations in relapsed and refractory patients, supporting the key role of CRBN in the response to IMiDs [13]. However, many patients with low CRBN levels have no mutation evident, thus transcriptional or post-transcriptional factors (e.g. regulation by microRNA) may influence CRBN gene expression and responsiveness to IMiD therapy [14].

Since IMiDs are also effective in myelodysplasia, chronic lymphocytic leukemia and some non-Hodgkin lymphomas, we assume that CRBN inhibition is the inherent mechanism of action in all of these malignancies [15–17]. This inhibition is also possibly implicated in the increased incidence of secondary malignancies when IMiDs are used for extended periods of time with, or following, alkylating agent therapy.

In the current study, we analyze CRBN gene expression levels in a cohort of homogeneously treated MM patients in order to examine the relationship of CRBN expression level with clinical outcomes following IMiD therapy.

2. Methods

2.1. Patient population

We screened the University of Arkansas Medical School (UAMS) gene expression profiling (GEP) database of MM patients treated on the Total therapy 2 (TT2) and Total therapy 3 (TT3) combination therapy regimens. This included 176 patients that received TT2 without thalidomide (TT2−), 175 patients that received TT2 with thalidomide (TT2+), and 441 MM patients treated with TT3. TT3 involves the following combination therapy: induction with bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE) followed by tandem autologous stem cell transplantation with melphalan conditioning, followed by 3 years of maintenance that includes bortezomib, thalidomide, and dexamethasone. Thalidomide was substituted by lenalidomide in many TT3 patients.

We further screened GEP levels from 148 MM patients from Mayo Clinic treated with IMiDs with or without steroids, 77 of them had only an IMiD plus dexamethasone treatment, of which 53 were homogeneously treated in two prospective clinical trials with pomalidomide and dexamethasone [18, 19]. The first trial included 35 relapsed or refractory patients that received pomalidomide 2 mg daily, continuously on a 28 day cycle, and dexamethasone 40 mg weekly. The second trial included 35 relapsed or refractory patients that received pomalidomide 4 mg daily, continuously on a 28 day cycle, as well as dexamethasone 40 mg weekly. 53 of the 70 patients on these two trials were successfully analyzed for CRBN expression prior to therapy initiation.

2.2. Gene expression profiling (GEP)

RNA was isolated from marrow CD138 positive plasma cells using RNeasy Plus Mini Kit (Qiagen). GEP was performed from total RNA using the Affymetrix U133Plus2.0 array. All technical steps were performed by the MicroArray facility at the Mayo Clinic Gene Expression Core following the manufacturer's protocol. Microarrays were scanned with an Affymetrix Scanner 3000 and data normalization was performed using Expression Console (Affymetrix) and the Robust Multi-array Average (RMA). Additional databases were used for comparative expression studies, including datasets from different stages of plasma cell neoplasm (GSE6477 and GSE5900), pre-treatment MM (GSE2658 and http://www.broadinstitute.oig/mmgp/home), relapse MM (http://www.bioadinstitute.org/mmgp/home), and other B cell lymphomas (Marginal Zone (GSE35348), Follicular and Diffuse Large Cell Lymphomas(GSE12195)and multiple cell lines established from hematological malignancies and solid tumors (source: Broad-Novartis Cancer Cell Line Encyclopedia, http://www.broadinstitute.org/ccle/home).

Intensity values were median normalized across the entire cohort for subsequent analyses. A median normalized CRBN expression <0.8 was defined `a priori' as `very low CRBN expression' to be used for determining the response rate of the cohort.

In order evaluate progression free survival and overall survival, we also determined the quartile cut-off points for CRBN median normalized expression (for all MM patients) to be 0.889, 1.027 and 1.211, respectively, with a goal of comparing the lowest quartile and the higher three quartiles of CRBN expression.

2.3. Response criteria

Response was assessed according to the International Myeloma Working Group criteria [20]. A positive response to therapy in this study required a partial response or better.

2.4. Statistical analysis

For the comparison of gene expression levels between groups, we used Fisher two-tailed test (comparison between 2 groups) and Kruskal–Wallis test (3 or more groups). Differences in overall survival (time from registration to death) and progression free survival (time from registration to the earlier of disease progression or death) were estimated using Kaplan Meier methods and log-rank statistics. Optimal cutoff points for survival analyses were determined using the Contal and O'Quigley method.

3. Results

3.1. Cereblon gene expression

We compared CRBN expression levels across different human tissues and malignancies. Overall, CRBN expression tended to be higher in cell lines originated from hematologic malignancies, including MM, compared to solid tumors (Fig. 1).

Fig. 1.

Fig. 1

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Cereblon expression across tumor ceil lines. Higher expression of CRBN is observed in hematologic malignancies compared to solid tumors. (Source: Broad-Novartis Cancer Cell Line Encyclopedia). These data suggest that leukemias and neuroblastoma will be relatively sensitive to IMiDs while solid tumors will be relatively resistant.

Furthermore, we found that normal B cells and low grade B-lymphoid cell tumors (marginal zone lymphoma, lymphoplasmacytic lymphoma and follicular lymphoma) share similar CRBN levels with MM. Interestingly, levels in diffuse large cell B-cell lymphoma (DLBCL) were significantly lower (p < 0.0001, Kruskal–Wallis test), but without any significant differences between the activated B-cell (ABC) and the germinal center B-cell (GCB) types (data not shown).

We did not find differences in CRBN expression levels between normal plasma cells, MGUS, smoldering and symptomatic MM (Fig. 2A). But when we compared the CRBN expression level across genetic MM subclasses, the TC (translocation/cyclin D) groups “D1” and “None” showed higher expression levels (p < 0.0001) compared to the remaining groups (Fig. 2B) [21]. Conversely, the TC group 4p16 (t(4; 14) was associated with lower CRBN expression (p = 0.03).

Fig. 2.

Fig. 2

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(a)–(d) CRBN expression in MM and its precursors. (A) CRBN median normalized expression is similar in (MM) and its precursors; (NPC, normal plasma cells; MGUS, monoclonal gammopathy of undetermined significance; and SMM, smoldering myeloma). (B) CRBN expression in MM TC genetic subtypes reveals lower expression in t(4; 14) patients. (C) CRBN expression analysis revealed higher expression in hyperdiploid MM (p < 0.001). This increase is not only explained by copy number dependency of CRBN expression (shown in D).

When we looked at differences in CRBN expression based on the ploidy status, the hyperdiploid MM group showed higher expression than the non-hyperdiploid group (Fig. 2C, p < 0.001). This suggests that a component of higher CRBN expression is copy-number dependent, as CRBN is located on chromosome 3 and trisomy 3 is commonly, but not universally, found in hyperdiploid MM [22].

3.2. No IMiD response in patients with very low Cereblon levels

One hundred and forty-eight patients with MM at Mayo Clinic were identified as having had CRBN expression measured by GEP prior to initiation of chemotherapy. Seventy-one patients were excluded from further analysis because IMiD therapy was combined with bortezomib or an alkylating agent, or because there was insufficient follow up data. As a result, 77 patients who received single agent IMiD therapy alone in combination with dexamethasone were available for analysis. Of these 77 patients, 53 patients received pomalidomide 2 mg or 4 mg daily combined with low dose dexamethasone 40 mg weekly as part of two clinical trials performed at Mayo Clinic [23]. Of the remaining 24 patients, 19 received lenalidomide with or without dexamethasone, while 5 patients received thalidomide with or without dexamethasone.

We were struck by the lack of clinical response in patients at the lower range of CRBN expression. When looking at all 77 patients with single agent IMiD therapy, 14 patients had CRBN median normalized expression <0.8, and none of these patients responded to treatment. Response rates were 40% for CRBN expression of 0.8–0.9, and 49% for CRBN expression >0.9.

3.3. Cereblon expression levels predict response and survival outcomes in pomalidomide clinical trials

In order to further study the correlation between CRBN expression level and clinical survival outcomes, we next analyzed only the homogeneously treated subgroup of 53 MM patients, refractory to both lenalidomide and bortezomib, that received pomalidomide (CC4047) and dexamethasone on two phase II clinical trials at Mayo Clinic [18,19]. Overall response rates for all patients on this study were 49% in the Pomalidomide 2 mg cohort and 43% in the pomalidomide 4 mg cohort with no statistically significant differences in overall survival at 6 months between the trials (78% vs. 67%, respectively) [23].

In the two trials, 53 of the 70 patients had CRBN expression levels determined prior to initiation of therapy and were used for our final analysis. We utilized the quartile cut-off points for CRBN median normalized expression (0.889, 1.027 and 1.211 for all MM patients) with a goal of determining differences between progression free survival and overall survival between the lowest quartile and the higher three quartiles of CRBN expression. Here we saw a clear trend of improved response rates in patients having higher CRBN expression levels by quartile; however this trend was not statistically significant p = 0.0857 (Fig. 3). The differences in progression free survival (PFS) (3.0 months vs. 8.9 months, p = 0.0006, Fig. 4A) and overall survival (OS) (9.1 months vs. 27.2 months, p = 0.01, Fig. 4B) were highly significant in patients with CRBN expression in the lowest quartile (median normalized CRBN expression <0.889) compared to patients with CRBN expression in the highest three quartiles (median normalized CRBN expression ≥0.889). PFS and OS differed even more profoundly when the lowest quartile was compared to the highest quartile (PFS: 3.0 months vs. 16.8 months, p = 0.0001, OS: 9.1 months vs. not reached, Fig. 4C+D).

Fig. 3.

Fig. 3

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Association between CRBN expression and response in 53 pomalidomide treated patients. We see a strong trend with a p value of 0.0857 (Fisher's exact (2-tailed) analysis) between the first vs. the third and fourth quartile and a high R2 in the exponential trendline analysis.

Fig. 4.

Fig. 4

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CRBN expression correlates with PFS (A+C) and OS (B+D). (A+B) the lowest quartile of CRBN expression vs. the higher 3 quartiles (median PFS 3.0 vs 8.9 months, p = 0.0006; median OS 9.1 vs 27.2 months, p = 0.01).(C+D) the lowest quartile vs. the highest quartile (median PFS 3.0 vs 16.8 months, p = 0.0001; median OS 9.1 vs NR months, p = 0.005).

3.4. CRBN expression and survival in multi-agent combination therapies

In order to investigate any association between CRBN expression and survival in patients treated with IMiD containing multi agent combination chemotherapies, we screened the University of Arkansas Medical School (UAMS) gene expression (GEP) database of MM patients treated on the Total therapy 2 (TT2) and Total therapy 3 (TT3) regimens.

As a continuous variable, CRBN expression did not correlate with survival in any of the protocols. Even with identifying the optimal cutoffs based on all TT2 (not shown) and TT3 data, the results showed no significant differences (Fig. 5).

Fig. 5.

Fig. 5

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Influence of CRBN expression on survival data in multidrug treatment (TT 3, University of Arkansas). There are no statistically significant associations, but a trend for shorter survival in the lowest quartile of CRBN expression. No association was seen in TT 2 (data not shown).

4. Discussion

Our group recently demonstrated CRBN expression to be an indispensible requirement for the activity of immunomodulatory drugs (IMiDs), more accurately referred to as “cereblon inhibitors” [9]. Additionally, we confirmed lower CRBN expression levels in patients that had acquired resistance during IMiD therapy and in lenalidomide resistant MM cell lines [9]. Here we describe differences in CRBN expression levels between solid tumor and hematologic malignancy with generally higher levels in hematologic malignancies. MM patients showed relatively high CRBN levels, but no differences were seen within different stages of the disease progression from normal B cells to active MM. However, statistically significant differences could be demonstrated within genetic subtypes, in particular lower levels in high risk t(4;14) and higher levels in hyperdiploid compared to non-hyperdiploid patients (Fig. 2B). This observation needs to be considered in respect to our PFS and OS data, since CRBN expression is copy-number dependent. Thus, high CRBN expression levels might be an surrogate for low risk disease, as trisomy 3 (CRBN is located on chromosome 3p) is commonly found in hyperdiploid MM, a lower risk subgroup [22]. Nevertheless, there are differences between hyperdiploid and non-hyperdiploid MM that go beyond the trisomy 3 status. When we compared hyperdiploid and non-hyperdiploid patients that do not bear trisomy 3, we still found a small but significant difference in CRBN expression levels (Fig. 2D), suggesting that trisomy 3 is a major but not the only factor contributing to higher CRBN levels in hyperdiploid MM.

We also demonstrated that CRBN expression levels were similar across normal B-cells and different B-cell malignancies, except in diffuse large B cell lymphoma (DLBCL) where CRBN expression was found to be significantly lower [9], As the ABC and GCB subtypes of DLBCL differ significantly in response to IMiD therapy, we expected to find lower CRBN expression levels in the less responsive GCB subtype however, we did not find significant differences based on analysis of published datasets [24].

As CRBN expression is required for IMiD action, we hypothesized a correlation between CRBN expression levels and survival. Indeed, when we focused on a homogenously treated cohort of 53 MM patients from Mayo Clinic treated with single agent pomalidomide and dexamethasone, we could clearly demonstrate a significant correlation between low CRBN expression and decreased survival outcomes. We further determined a clear trend of decreased response at lower CRBN expression levels. Indeed when we looked at MM patients treated with any single agent IMiD and dexamethasone, no patient with median normalized CRBN expression less than 0.8 responded to therapy. Our findings are supported by recent studies that show low CRBN to be associated with decreased response to thalidomide maintenance or upfront therapy with lenalidomide [11,12].

These findings suggest that CRBN expression serves as a predictive biomarker for resistance to IMiD therapy when determined prior to therapy. According to our analysis from the UAMS GEP database, the negative impact on OS and PFS due to low CRBN levels might be overcome by use of combination therapies. Consequently, consideration of combination or alternative therapies absent an IMiD may be warranted in MM patients presenting with low CRBN expression levels. Further studies are necessary to determine the optimal treatment strategy for these patients with low CRBN expression.

In summary, this study demonstrates a clinical correlation between CRBN expression level, response to IMiDs and survival. Low CRBN expression showed statistically and clinically significant decreases in PFS and OS, and no patient with median normalized CRBN expression less than 0.8 responded to IMiD therapy. CRBN expression is therefore a potential predictive biomarker for response and survival in MM when quantified prior to therapy with single agent IMiD and dexamethasone.

Acknowledgements

This manuscript has been funded by MMRF.

Conflict of interest SRS, KMK, YXZ, EB, CXS, LAB, JES, GA, VR, BLB, MDC, KL have no conflict of interest, but KMK is supported by a research grant (Ko 4604/1–1) from the Deutsche Forschungsgemeinschaft (Germany); SK and ML received clinical trial support from Celgene, Millennium, Cephalon, Novartis, Genzyme and consultant with Celgene, Abbott, Millennium, Onyx; JM received research funding from Celgene, Onyx; BB received research funding from Celgene, Millennium and is consultant to Celgene and Millennium; RF is consulting with Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Oynx, Binding Site, Millenium and Amgen; PLB is a consultant with Onyx; AKS received honoraria and research funding with Millennium and honoraria from Celgene and research funding from Onyx.

Footnotes

Authors' contributions SRS and KMK contributed equally. All authors made significant contributions to the work.

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