MCT1 is a predictive marker for lenalidomide maintenance therapy in multiple myeloma

Abstract

Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples of 654 patients with MM who received lenalidomide (n = 455), thalidomide (n = 98), or bortezomib (n = 101) maintenance were assessed by gene expression profiling and RNA sequencing, followed by correlation of MCT1 and CD147 expression with data for progression-free survival (PFS) and overall survival (OS). Patients with high expression levels of MCT1 showed significantly reduced PFS (31.9 months vs 48.2 months in MCT1high vs MCT1low; P = .03) and OS (75.9 months vs not reached [NR] in MCT1high vs MCT1low; P = .001) in cases with lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in cases with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients who received thalidomide (OS, 83.6 months vs NR in MCT1high vs MCT1low; P = .03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced the efficacy of lenalidomide, whereas no change was observed with bortezomib treatment, either in vitro or in a MM xenograft model. Our findings have established MCT1 expression as a predictive marker for response to lenalidomide-based maintenance in patients with MM.

Figure 1.

Expression of MCT1 determines PFS and OS in patients receiving IMiD-based maintenance therapy. (A) MCT1 gene expression in plasma cell disorders (n = 1486) and normal bone marrow plasma cells (BMPC, n = 19). MGUS, monoclonal gammopathy of unknown significance; AMM, asymptomatic MM; MM, previously untreated, therapy-requiring MM; MMR, relapsed/refractory MM; and HMCL, human myeloma cell line. Numbers in blue (red) indicate the number of patients expressing (not expressing) MCT1. (B-E) Landmark analysis of patients with MM who underwent maintenance treatment after autologous stem cell transplantation. Expression of MCT1 was assessed by gene expression profiling in CD138-purified myeloma cell samples and correlated with PFS and OS data. P-values are log-rank. (B) PFS of 455 patients who underwent lenalidomide maintenance therapy in the GMMG-MM5-trial (31.9 months vs 48.2 months; MCT1^high vs MCT1^low). (C) OS of 455 patients who underwent lenalidomide maintenance therapy in the GMMG-MM5-trial (75.9 months vs not reached months; MCT1^high vs MCT1^low). (D) PFS of 62 patients who underwent bortezomib maintenance therapy in the GMMG-MM4-trial (39.8 months vs 32.6 months; MCT1^high vs MCT1^low). (E) OS of 101 patients who underwent bortezomib maintenance therapy in the GMMG-MM4-trial, 125.8 months vs 129.8 months; MCT1^high vs MCT1^low).

Figure 2.

Overexpression of MCT1 attenuates lenalidomide cytotoxicity in vitro and in vivo. (A-B) Cell proliferation analysis of MM1S (A) and U266 (B) cells, which were infected with lentivirus via control constructs (empty vector [EV]) or constructs to induce MCT1 or CD147 expression, treated with dimethyl sulfoxide (DMSO) or 10 µM lenalidomide for 72 h. (C) Quantification of tumor growth during lenalidomide or vehicle control treatment using caliper measurements (Ctrl, Len: n = 4 tumors). Xenograft tumors from U266 cells expressing MCT1 or the EV control. (D) Positron emission tomography (PET) images, using ¹⁸F-fluorodeoxyglucose, of representative immunocompromised NOD-SCID mice bearing xenograft tumors expressing MCT1 or the EV control. Images were taken after 7 days of respective treatment. Arrows indicate tumors. The color scale indicates the percentage of injected dose per gram (% ID/g). Bars represent 10 mm. (E) Total lesion glycolysis of tumors determined by PET-MRI on day 7 after respective treatments. (F) Representative immunohistochemical analysis of tumors derived from the mice shown in panel D, with histomorphology visualized with hematoxylin-eosin staining and expression of cleaved caspase 3 (CC-3), MCT1, and CD79a. Analysis was performed on 10 high-power fields for each stain. Bars represent 100 µm. (G) Quantification of CC-3 staining shown in panel F. Data are expressed as means ± standard deviation. n.s., not significant; *P < .05, **P < .01, by 1-sample t test or Student t test.