Approaches to potentiate immunotherapy in multiple myeloma

Abstract

The prognosis of multiple myeloma (MM) patients has significantly improved over the last decades. However, the disease is still incurable, and eventually all patients will relapse. Therefore, there is a continuing need for improvement of existing therapies and development of new, more effective treatments. In this thesis, we investigated two immunotherapeutic modalities used in MM: allogeneic stem cell transplantation (allo-SCT) and immunomodulatory agents (IMiDs). In chapter 2 we outlined our single-center experience with allo-SCT in 147 patients with MM. We show that although we obtained beneficial results with allo-SCT as part of first line treatment, allo-SCT should not be considered an option for first line treatment due to the high treatment-related mortality (TRM) and superior alternatives with novel agent-based therapy, regardless of cytogenetic risk. For the relapsed/refractory setting the data are less clear. If applied at all, strategies to lower non-relapse mortality and graft-versus-host disease incidence should be actively explored. In chapter 3 we demonstrated the feasibility, safety and efficacy of minor histocompatibility antigen (mHag)-peptide-loaded donor dendritic cell (DC) vaccination combined with donor lymphocyte infusions (DLI) in patients with persistent or relapsed disease after allo-SCT and previous DLI. The use of this vaccination was shown to be feasible and safe. However, immune-responses were variable and clinical responses were lacking. The mechanisms behind this lack of clinical response should be evaluated in future studies, but as has been described in chapter 4, it seems highly plausible that the expansion or even the cytotoxic function of tumor-specific CTLs can be actively suppressed by tumor (microenvironment)-related factors. In chapter 5 we investigated in a phase 1/2 trial, the maximum tolerated dose as well as the safety and efficacy of the combination of lenalidomide, cyclophosphamide and prednisone (REP) in heavily pretreated, lenalidomide-refractory MM patients. The REP regimen was well tolerated and highly active with an overall response rate (≥ partial response of 67% and a clinical benefit rate (≥ minimal response) of 82%. The median PFS was 12.1 months, and the median OS was 29.0 months. In chapter 6, to gain insight into the expression levels of lenalidomide targets in lenalidomide-refractory patients, we analyzed the protein expression of Cereblon, Ikaros, Aiolos, IRF4 and c-Myc in BM-localized plasma cells. We show that Cereblon downregulation and c-Myc upregulation in MM cells are two of the characteristics of lenalidomide refractory disease. In chapter 7 we further investigated the hypothesis that despite the presence of lenalidomide resistance in the MM cells, the immune system might still be susceptible to lenalidomide-induced activation. Our results indicate that the Cereblon-mediated immunomodulatory properties of lenalidomide are maintained in lenalidomide-refractory myeloma patients and contribute to immune-mediated killing of MM cells. Therefore, combining lenalidomide with other drugs can still have potent effects, even in patients considered to be lenalidomide-refractory.