Novel immunotherapeutic strategies for multiple myeloma

Abstract

Outline and aim of this thesis In this thesis, we investigated the determinants of response and resistance to currently used immunotherapy-based regimens in multiple myeloma. We also evaluated novel immunotherapies, including T-cell redirecting therapies and cereblon E3 ligase modulators, in both preclinical and clinical studies. These studies aim to advance therapeutic strategies and improve survival in patients with multiple myeloma. First, we provide an overview of the efficacy and safety of CD38-targeting antibody based regimens as first-line treatment for patients with newly diagnosed MM, both transplant-eligible and transplant-ineligible (chapter 2). We then focused on understanding the factors influencing response and resistance to daratumumab based quadruplet regimens, concentrating on the role of NK cells in newly diagnosed patients. Understanding these mechanisms may help to refine therapeutic strategies and optimize the use of available therapies. In chapter 3, we investigated the effects of daratumumab-based treatment on immune cells in the bone marrow and peripheral blood in NDMM patients. NK cell fitness was associated with enhanced functional activity, including degranulation and cytokine secretion in response to daratumumab and with an increased probability of achieving measurable (or minimal) residual disease (MRD) negativity. Considering that relapse occurs in most patients and new treatment options are still needed, we explored novel agents in preclinical and clinical studies. In chapter 4, we assessed the preclinical activity of allogeneic SLAMF7-specific CAR T-cells in patients with newly diagnosed and relapsed/refractory MM, and observed comparable efficacy across all patient groups. As new therapies become available in the clinic, we aimed to optimize their use by minimizing treatment-related side effects and assessing the feasibility of outpatient dosing instead of hospitalization. In chapter 5, we evaluated the prophylactic use of tocilizumab to mitigate cytokine release syndrome (CRS) in patients treated with the BCMA-targeting bispecific antibody teclistamab. Finally, we evaluated a novel agent, iberdomide, as part of a triplet combination in the clinical setting. In chapter 6, we present the results of the ICON study, a multicenter, single-arm, phase 2 trial evaluating the safety and activity of iberdomide combined with low-dose cyclophosphamide and dexamethasone in patients with relapsed/refractory MM. Chapter 7 summarized the main findings of this thesis and discusses the implications for patient care and future research.