Low Expression of Nuclear Glucocorticoid Receptor Gene NR3C1 in Newly Diagnosed Myeloma Correlates with Inferior Prognosis and Is Rescued by Thalidomide

Dexamethasone remains a key component of myeloma therapy. We previously showed that expression levels of the nuclear glucocorticoid receptor NR3C1 were associated with OS and PFS in patients treated on Total Therapy 3 (TT3). Post relapse survival (PRS) is an important component of OS following initial PFS. In this study we investigate the effect of NR3C1 expression levels at baseline (BL) and at relapse (RL) on OS, PFS and PRS for patients treated on Total Therapy 2 (TT2).

TT2 was a randomized phase-III trial evaluating the impact of the up-front addition of thalidomide (T) to a multi-agent chemotherapy and high-dose melphalan program supported by tandem autotransplants. Between October 1998 and February 2004, 668 patients with newly diagnosed progressive or symptomatic multiple myeloma up to age 75 were enrolled. 351 patients had gene expression profiling (GEP) obtained at BL and 121 had GEP data obtained at RL. There was no significant difference in OS, PFS or PRS between patients with or without GEP data at BL or at RL. This analysis is based on the cohort of patients with GEP data with a cut-off date of April 22, 2011. OS and PFS were measured from the time of initiation of protocol-based therapy while PRS was measured from the initiation of salvage therapy.

Among patients randomized to the control arm (-T), OS improved progressively with the transition from lower to middle to upper NR3C1 tertiles. No such difference was noted in the experimental group with T (+T). Examining treatment arms within NR3C1 expression tertiles showed significant benefit from T in both OS and PFS among patients presenting with lower tertile expression; in the mid tertile, this effect was limited to PFS while such benefit was absent in the top-tertile subgroup. Multivariate analysis accounting for the interaction between NR3C1 expression and T showed that randomization to T and lower tertile NR3C1 expression reduced the hazard of death, while high risk designation by GEP, elevated B2M, elevated LDH, cytogenetic abnormalities and MS subgroup designation all conveyed a higher HR for death. With an overall median PRS of 3.0 years, there was no difference related to the initial treatment randomization or between baseline NR3C1 expression levels. In the context of treatment arms in patients randomized to -T, high- and mid-tertile NR3C1 levels at baseline dramatically improved PRS; such an effect was not observed in +T. We next investigated the implications of NR3C1 levels at relapse on PRS, revealing a significant shortening of PRS with transition from top- to mid- to low-tertile expression. Patients maintaining low NR3C1 levels also at relapse had the shortest PRS, followed by those who lost mid to high expression levels of NR3C1 at relapse, while those with higher than low-tertile levels at relapse enjoyed the longest PRS regardless of NR3C1 expression levels at baseline. Multivariate analysis including data from baseline and relapse as well as accounting for interaction between NR3C1 and T identified GEP high risk status at relapse as the only feature linked to inferior PRS whereas upper tertile expression of NR3C1 conveyed improved PRS.

Low expression of NR3C1 at baseline is associated with poor PFS and OS in patients treated on the control arm of TT2. This confirms our previously reported findings in TT3. Addition of T overcomes the poor OS in patients with low NR3C1 expression. Low expression of NR3C1 at relapse correlated with poor PRS. This study indicates that patients with low NR3C1 expression levels at baseline benefit from the addition of T and offers a scientific rationale for NR3C1 gene expression level testing. Future trials, that include thalidomide or lenalidomide in their treatment regimen, will have to take NR3C1 expression levels into account.

Shaughnessy:Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.