Effect of Immunomodulatory Drugs (IMiDs) on Immune Effectors after Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma

INTRODUCTION: Patients with multiple myeloma have several phenotypic and functional immune aberrations that suppress host anti-myeloma immune responses. The degree and type of immune dysfunction can be targeted and reversed in many patients with active treatment. Therapies that result in deep and sustained remissions play a part in immunological control of disease in long-term responders. IMiD-mediated immunomodulatory effects conferring immune system reactivation have been reported in MM in the maintenance setting. We hypothesized that the circulating effector immune cell profile post-ASCT will be impacted by depth of response and IMiD based maintenance therapy.

METHODS: Thirty multiple myeloma patients who underwent ASCT and IMiD based maintenance and consented for specimen collection protocol were included in this study. Blood and bone marrow samples were collected before starting IMiD based maintenance therapy on Day 60+ post ASCT (time point defined as baseline). Blood samples were then serially collected after 1 month (n=24), 3 months (n=26) and 6 months (n=19) of maintenance treatment. Multicolor flow cytometry was used for NK, NK-T and T cell distribution/activation immunotyping, and for measurement of bone marrow minimal residual disease (MRD) status. Threshold for MRD positivity was established as 1.5x10^-5 abnormal/clonal plasma cells. Clinical response assessment was performed post-ASCT at baseline per IMWG guidelines. Welch's t-test was used to compare each immune variable between MRDpos and MRDneg groups and one-way ANOVA was used to analyze changes of each immune variable over time. The association of individual immune variable with progression free survival (PFS) was assessed by Cox regression analysis.

RESULTS: In total, 16 patients achieved CR/sCR, 13 VGPR and 1 PR. MRD status was determined for 20 of 30 patients, 5 were MRDneg and 15 MRDpos. MRDpos patients had an immunotype characterized by higher expression of KIR2DS4 on NK (p=0.002) and NK-T cells (p=0.048) at baseline, compared with MRDneg patients. Twenty-six patients received single agent IMiD maintenance, 4 received IMiD/proteasome inhibitor combination. During IMiD maintenance therapy, NK and NK-T cell acquired phenotypes associated with greater effector functions as shown by increase in NK NKG2D+ (p=0.04), NK Tim3+ (p=0.049) and NK-T Tim3+ (p=0.01). T cells were marked by a NKG2D loss (p<0.001) and Tim3 gain (p<0.001) of expression. The median follow-up of the cohort was 19.3 months (IQR 14.8-21.3). Seven patients (5 MRDpos, 2 MRD status unknown) relapsed within 12 to 24 months post-ASCT. High KIR2DS4 (HR=1.072, 95% CI: 1.019-1.128; p=0.008), NKp46 (HR=1.05, 95% CI: 1.004-1.098; p=0.031) and NKG2A (HR=1.222, 95% CI: 1.018-1.466; p=0.032) expression by NK-T cells at baseline were associated with shorter PFS. NK and NK-T cells retained higher KIR2DS4 expression after 1, 3 and 6 months of IMiD maintenance therapy in relapsing patients compared with those in remission (Figure1).

CONCLUSIONS: Our results demonstrate that KIR2DS4 expression by NK and NK-T cells is associated with MRD status post-transplant, as well as PFS in multiple myeloma patients treated with IMiD maintenance therapy. This simple blood-based immunotype, if validated in larger studies, could be used for longitudinal assessment to predict early on after starting IMiD maintenance treatment whether to continue this treatment or change to different treatment. Patients predicted to derive less clinical benefit from IMiDs could be offered alternative treatment regimens such as monoclonal antibodies, other immunotherapies or epigenetic therapy.

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