Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis
Paiva B, Mateos MV, Sanchez-Abarca L, et al. Blood. 2016;127(9):1151-1162.
Article summary written by Patrick Brooks, PharmD, Medical Director, Oncology
The randomized, open-label, multicenter, phase 3 QUIREDEX trial (Figure 1) investigated the efficacy of lenalidomide and dexamethasone (Rd) induction therapy and lenalidomide maintenance therapy versus observation for patients with high-risk smoldering multiple myeloma (HRSMM); the primary endpoint was time to progression (TTP) to symptomatic disease. HRSMM was defined as having ≥2 of the following criteria: bone marrow plasma cell ≥10%, high M-component (IgG ≥30 g/L or IgA ≥20 g/L or Bence-Jones protein >1 g/24 hours), or ≥95% clonal plasma cells from total bone marrow plasma cells plus immunoparesis.1
Figure 1. QUIREDEX Trial Design1
Unfortunately, there are no data available regarding the immune status of patients with smoldering multiple myeloma (SMM), which would be useful to better understand the interplay between immunosurveillance and transformation to active multiple myeloma (MM), in addition to defining whether patients with SMM may benefit from immunomodulation. This preplanned exploratory analysis2 of 31 of the 57 HRSMM patients enrolled in the treatment arm of the QUIREDEX study, consisted of three major components:
1. Evaluating the immunophenotypic profiles of T lymphocytes, natural killer (NK) cells, and dendritic cells (DCs) from 119 peripheral blood (PB) samples from the 31 patients, compared to samples from healthy, age-matched individuals
2. Evaluating the role of T cell and NK cell-functionality in delaying disease progression to symptomatic MM in the 31 patients after three and nine cycles of Rd
3. Comparing the immune profiles of T cells and NK cells during lenalidomide maintenance therapy to measure the potential antagonistic, immunosuppressive effect of dexamethasone
Patients with HRSMM had normal absolute levels of CD4 T cells, CD8 T cells, CD56dim NK cells, and CD56bright NK cells, compared to healthy individuals. However, the immunophenotypic protein expression profiles (iPEPs) of the CD4 and CD8 T cells from SMM patients demonstrated downregulation of activation markers (eg, CD25, CD28, CD54), type 1 T helper (Th1)-related markers (eg, CD195), and proliferation markers (eg, IFN-γ, TNF-α, IL-2). In the PB of HRSMM patients versus healthy individuals, there were higher concentrations of T-cell receptor (TCR)γδ-positive T cells and regulatory T cells (Tregs). In contrast, there were no differences in the iPEPs of NK cells from HRSMM patients compared to healthy individuals. Regarding DCs, patients with HRSMM had lower counts than healthy individuals.
Patients with HRSMM who were treated with Rd demonstrated a distribution of T cell antigen-related maturation subsets after three and nine cycles, in which CD4 and CD8 T cells became enriched in central and effector memory cells (Figure 2). This suggests that these cells are not terminally differentiated and may be candidates for antitumor response. In addition, treatment with Rd restored expression of the downregulated activation-, Th1-, and proliferation-related markers in CD4 and CD8 T cells. Regarding NK cells, both CD56dim cytotoxic and CD56bright immune regulatory NK cells were significantly activated after Rd therapy.
Figure 2. Distribution of Antigen-Maturation Subsets within Total CD4 and CD8 T Cells
It was determined that lenalidomide was able to effectively modulate the iPEP of T cells and NK cells in the presence of dexamethasone, as evidenced by the lack of difference between PB samples from patients treated with lenalidomide maintenance versus Rd induction, with regards to the absolute numbers of T cells and NK cells, the relative distribution of CD4/CD8 T cells and CD56dim/CD56bright NK cells, and the antigen-related maturation subset distribution of CD4 and CD8 T cells. It is important to note that even though immune profiling was performed at least three months after discontinuation of dexamethasone, the long-lasting effects of the nine cycles of Rd are not known at this time.
The authors conclude that the characterization of immune effector cell profiles in HRSMM, and the potential readiness for antitumor response post-immunomodulation, provides an immunologic rationale for the treatment of HRSMM patients with Rd. In addition, these results demonstrate that therapeutic doses of dexamethasone do not abrogate the immunomodulatory effects of lenalidomide, supporting the synergy of lenalidomide and dexamethasone for patients with high-risk smoldering multiple myeloma.
1. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447.
2. Paiva B, Mateos MV, Sanchez-Abarca L, et al. Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis. Blood. 2016;127(9):1151-1162.