Low-Dose Dexamethasone Does Not Abrogate the Immunomodulatory Effects of Lenalidomide and Both Reactivate the Impaired Immune System of High-Risk Smoldering Multiple Myeloma Patients
Authors: Paiva Bruno , Mateos Maria-Victoria , Sánchez-Abarca Luis Ignacio , Vidriales Maria Belen , Lopez-Corral Lucia , Corchete Luis A , Hernandez Miguel T , Bargay Joan , De Arriba Felipe , De La Rubia Javier , Teruel Ana Isabel , Giraldo Pilar , Rosiñol Laura , Prosper Felipe , Oriol Albert , Hernandez Jose Mariano , Esteves Graça , Leal da Costa Fernando , Lahuerta Juan Jose , Blade Joan , Perez-Simon Jose A. , San Miguel Jesus 
Published: October 2019

Abstract
Introduction: While dexamethasone (Dex) has been commonly used in the treatment of multiple myeloma (MM), its immunosuppressive effect is becoming a matter of concern with the advent of immune-based therapies. One example is the combination of lenalidomide and Dex (LenDex) because it has been reported that Dex abrogates the immunomodulatory effects of Len; however, most of the studies have been performed in vitro, using high-doses of Dex, and in small series of relapsed patients previously exposed to other drugs.
Methods: Because the potentially antagonist effect of Dex may represent a dilemma in the design of clinical trials, here we aim to shed light into the question about whether or not low-dose Dex abrogates the immunomodulatory effect of Len by studying the phenotypic profile of T-lymphocytes, NK-cells and dendritic cells (DCs) of 31 previously untreated high-risk smoldering MM (SMM) patients enrolled in the Quiredex trial at baseline, after 3 and 9 cycles of LenDex, and during maintenance with Len as single-agent.
Results: Patients with high-risk SMM showed at baseline normal numbers of CD4 and CD8 T-lymphocytes as well as CD56dim and CD56bright NK-cells compared to age-matched healthy individuals. By contrast, they displayed an increment of TCRγδ positive T-lymphocytes (P=.02) and Tregs (P=.04), as well as an altered distribution of BDCA-1 positive myeloid DCs (P=.02) and tissue macrophages (P=.06). Moreover, the expression levels of activation markers (CD25, CD28 and CD54) as well as Th1-related markers (CD195, IFN-γ, TNF-α, or IL-2) were significantly inferior in T-lymphocytes from high-risk SMM patients. A significantdown-regulation of proliferation-related markers (CD119 and CD120b) was also noted. To assess the combined effect of LenDex in T-lymphocytes and NK-cells, we compared the immune status of the 31 high-risk SMM patients at baseline vs. after 3 and 9 cycles of LenDex. Interestingly, TCRγδ positive T-lymphocytes as well as Tregs were further increased with LenDex; conversely, CD4 T-lymphocytes were significantly decreased at the end of induction. There was a marked shift on the distribution of antigen-related maturation subsets induced by LenDex, and reflected by a significant increase of central memory CD4 (P<.001) and effector memory CD8 (P<.001) T-lymphocytes. Accordingly, CD4 and/or CD8 T-lymphocytes showed an increased expression of activation markers (CD69, CD25, CD28, and CD54), together with an up-regulation of the Th1 related chemokine CCR5 (CD195) and increased cytokine production of IFNγ, TNFα, and IL-2. NK-cells showed an up-regulation of the activation marker HLA-DR (P<.001), the ADCC associated receptor CD16 (P≤0.005), and the adhesion molecules CD11a (P≤0.001) and CD11b (P≤0.005) after 3 and 9 courses of LenDex. The percentage of cells in S-phase progressively increased from baseline vs. 3 and 9 cycles of LenDex for CD4 (P<0.001) and CD8 (P<0.001) T-lymphocytes as well as NK-cells (P<0.001). Most interestingly, high-risk SMM patients treated with LenDex and without disease progression showed higher numbers of functionally active T-lymphocytes as compared to those progressing to MM. To address the question whether Dex antagonizes Len, we compared the immune profile of 13 patients with PB samples collected at cycle 9 of induction vs. during maintenance (single-agent Len at least 3 months after Dex discontinuation). No significant differences were observed for the absolute numbers of all cell populations analyzed. From the total 63 phenotypic parameters analyzed, only 7 were found to be differently expressed. Namely, the expression of CD94, CD154 and CD212 positive T-lymphocytes as well as CD11a in T-lymphocytes and NK-cells were down-regulated during maintenance.
Conclusions: Our results, obtained from a carefully selected population of patients without previous exposure to anti-MM therapy and with available longitudinal samples after consecutive cycles of LenDex, shed new light on the synergy between lenalidomide and dexamethasone which, at low doses, does not abrogate the immune modulatory effects of lenalidomide here analyzed. Accordingly, high-risk SMM patients have an impaired immune system that could be re-activated with LenDex, and support the value of therapeutic immunomodulation to delay the progression to MM.

Disclosures
Paiva: Millenium: Consultancy; BD Bioscience: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Sanofi: Consultancy; EngMab AG: Research Funding; Binding Site: Consultancy. Mateos:Takeda: Consultancy; Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria. San Miguel:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen-Cilag: Honoraria; Sanofi-Aventis: Honoraria; Millennium: Honoraria; Novartis: Honoraria; Onyx: Honoraria.