Combination of Adoptive Cellular Immunotherapy and Bortezomib-Based Regimens Increase the Progression Free Survival of the Patients with Multiple Myeloma

Objective: In our previous studies show that bortezomib can enhance the sensitivity of multiple myeloma (MM) cells to the cytotoxity of γδT, nature killer (NK) cells and cytokine-induced killer (CIK) cells, and there is synergistic effect among these three types of cells as well. Therefore, the efficacy and safety of combination of adoptive cellular immunotherapy (ACI) with NK, γδT and CIK cells and bortezomib-based chemotherapy was investigated in this study.

Method: 27 patients were recruited in this study with newly-diagnosed MM and received Bortezomib-based therapy during September 2008 and September 2013 in the First Hospital of Jilin University. The patients were divided into study group (ACI plus bortezomib-based therapy) and control group (bortezomib-based therapy alone). There are 14 patients in study group with median age of 60.5 (54-73) years old, while 13 patients in control group with median age of 56 (41-80) years old. In the study group, autologous peripheral blood mononuclear cells (PBMCs) were collected from the peripheral blood by apheresis at the first day, and were induced into NK, γδT and CIK cells, then the expanded immunocytes were infused back to the patients after 14 days culture ex vivo. The number of cells for each transfusion ranged from 1.2×10⁹- 2.0×10⁹ cells. Progression-free survival (PFS) and adverse effects were investigated. One course of ACI would be done within 3 weeks and contain six times of infusion in total. This study was approved by the Ethical Committee of the First Hospital of Jilin University. Written informed consent was obtained from all patients before their enrollment into the study.

Result:In this study, the percentage of CIK (CD56+CD3+), NK (CD56+CD3-) and γδT (Vγ9+) before and after induction were 4.39% (1.5%-8%) vs 46.32% (27%-50%), 10.35% (5.1%-12.6%) vs 95.28% (70.1%-99.6%), 4.72% (2.61%-11.2%) vs 90.64% (60.5%-97.9%), respectively. The median follow-up time was 18 months. The characteristics including age, gender, stage, chemotherapy regimen etc. had no significant difference between the two groups. The median PFS in study group was 24.5m (12-48), and the median PFS was 12m (5-32) in control group (P=0.018). For subgroup analysis, the median PFS in the study group receiving >3 courses and ≦3 courses group were 36m (24-48) and 20m (12-36), respectively (P=0.141). Among the patients receiving ACI, one patient felt mild fatigue after infusion. One patient had transient fever after one infusion (38 °C) and recovered 1 h later. No other significant side effects were observed.

Conclusion: Combination of NK, γδT and CIK cells based ACI and bortezomib-based chemotherapy is well tolerated and shows a great potential to improve the PFS of the patients with MM. This study provided a novel strategy for the treatment of MM, and it is worthwhile to study this combination strategy in multi-center randomized clinical trials.