Impact of Lenalidomide Plus Low-Dose Dexamethasone Treatment on Immune Cell Populations of the Patients with Refractory/Relapsed Multiple Myeloma

Background: Lenalidomide combined with low-dose dexamethasone (Len-dex) is an effective treatment for the patients with refractory/relapsed multiple myeloma (RRMM). The anti-myeloma effect of lenalidomide is associated with activation of the immune system, but the exact immunomodulatory mechanisms in vivo and clinical impact of Len/dex in RRMM patients remains unclear. In this study, we analyzed immune cell populations in patients receiving Len-dex for the treatment of RRMM.

Methods: Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len/dex therapy. CD3⁺, CD4⁺, CD8⁺, CD161⁺ T cells, natural killer (NK) cell (CD16⁺/CD56⁺), NKT-like cell (CD3⁺/CD56⁺) and myeloid-derived suppressor cell (MDSC) including granulocytic (G-MDSC) and monocytic (M-MDSC) were analyzed by flow cytometry. In addition, response was assessed in 81 patients receiving more than 4 cycles of Len-dex and the comparison of cell populations according to an achievement of ≥very good partial response (VGPR) was performed.

Results: Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). At baseline, peripheral blood CD3⁺ cell frequency was 51.65 ± 1.79% which was significantly decreased to 41.67 ± 2.44% (P=0.001) and 39.72 ± 2.90% (P< 0.001) after 2 and 3 cycles of therapy, respectively. Frequency of both CD4⁺ cell and CD8⁺ cells was also significantly decreased by 3 cycles of therapy, while NK cell frequency was significantly increased after Len-dex treatment (P<0.05). For the T-cell subset, the frequency of CD8⁺CD161^high cells was significantly decreased (1.13 ± 0.16% at baseline to 0.65 ± 0.13% at post-3 cycles, P< 0.05), while no trend was observed in CD4⁺CD161⁺ cell frequency. No significant change was observed in frequency of G-MDSC and M-MDSC after Len-dex. Among 81 evaluable patients, 36 patients obtained ≥VGPR and 45 ≤ partial response. After adjusting for factors affecting failure of achieving a response of ≥VGPR on univariate analyses, multivariate analyses showed that decrease in CD8⁺ cell frequency (P=0.043) and increase in M-MDSC frequency (P=0.033) by post-3 cycles of Len-dex treatment were predictors for failure of achieving ≥VGPR. High frequency of NKT-like cell prior to Len-dex treatment could predict a longer time to progression (RR of 0.40, P=0.011). In addition, patients with less decrease in frequency of both CD3⁺ cell and CD8⁺ cells by post-3 cycles had a longer time to next treatment (RR of 0.24, P=0.024 and RR of 0.33, P=0.044, respectively).

Conclusion: Our data demonstrate that Len-dex therapy in patients with RRMM is associated with decreased frequency of T cells with a trend of increased NK cell frequency. Change in CD8⁺ cell and M-MDSC frequency can correlate with the quality of response to Len-dex. Baseline NKT-like cell frequency and change in CD3⁺ and CD8⁺ cells early after treatment may predict continuation of anti-myeloma effect of Len-dex therapy.