Improving immunotherapeutic treatment strategies for relapsed/refractory multiple myeloma patients

Multiple myeloma (MM) is a malignant disease characterized by the clonal proliferation of malignant plasma cells in the bone marrow, or in extramedullary sites. It accounts for 1.1% of all diagnosed malignancies worldwide, and represents the second most prevalent hematological malignancy. In the Netherlands, approximately 1300 patients are diagnosed with MM each year. The clinical characteristics of MM are a result of multi-organ dysfunction secondary to the proliferation of monoclonal plasma cells in the BM, and/or high concentrations of the monoclonal protein (M-protein) or light chains, produced by these monoclonal plasma cells, in the peripheral blood. Signs and symptoms include hypercalcemia, renal failure, anemia and other cytopenias, and osteolytic bone lesions or fractures. In addition, patients are more susceptible to infections. Since the introduction of the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide, as well as the proteasome inhibitors (PIs) bortezomib, carfilzomib and ixazomib, the prognosis and survival of MM patients has significantly improved. More recently, the development of the monoclonal antibody daratumumab, targeting CD38, which is expressed on malignant plasma cells, has been proven effective and safe both as a single agent in relapsed/refractory MM (RRMM) patients, as well as in combination with IMiDs and/or PIs in both relapsed as well as newly diagnosed MM (NDMM) patients. However, MM remains an incurable disease to date, and the prognosis for patients who have become refractory to IMiDs, PIs and CD38-targeting antibodies, is poor. The research described in this thesis has aimed to further elucidate mechanisms of response and resistance to daratumumab, in order to improve its efficacy. In addition, since trials have shown that daratumumab adds to the susceptibility of MM patients to infections, we aimed to improve the supportive care for these daratumumab-treated patients. Finally, we investigated a novel immunotherapeutic treatment option for MM patients, the BCMA-targeting bispecific antibody. In this thesis, we have shown that improved understanding of the mechanisms of action, as well as mechanisms of resistance to daratumumab treatment, result in improved treatment options for multiple myeloma patients. Our two clinical studies demonstrate that targeting only one of the factors, in this thesis CD38 and PD-L1, is not enough to overcome resistance to daratumumab. Future research should aim to combine therapeutic options targeting different factors contributing to daratumumab-refractoriness. Next, the understanding of mechanisms of action of daratumumab can attribute to understanding adverse events. In this thesis, we showed that daratumumab also targets normal plasma cells, thereby increasing the risk of infections. However, not all healthy plasma cells are affected, and a majority of patients is able to produce protective antibody titers following vaccination, indicating that routine vaccination as recommended by international guidelines, is also applicable in patients treated with daratumumab. Finally, novel immunotherapeutic agents targeting BCMA have shown to be effective in extensively pretreated MM patients. Bispecific antibodies are promising combination partners with other immune stimulating drugs, and the combination with daratumumab has been shown to be effective in vitro. Clinical trials evaluating these combinations are ongoing.