Resistance to daratumumab in patients with multiple myeloma

Katrine Fladeland Iversen1
1 Institute of Regional Health Science, University of Southern Denmark, and Department of Internal Medicine, Section of Hematology, Lillebaelt Hospital, University Hospital of Southern Denmark, Beriderbakken 4, 7100 Vejle, Denmark; katrine.fladeland.iversen@rsyd.dk
Abstract: 80 words
Body: 3304 words
References: 50

Abstract / Plain English summary

MM is an incurable cancer in the bone marrow. The treatment of MM has developed significantly during the last 20 years, which has resulted in increased survival. Daratumumab is the first CD38 antibody approved for treatment of MM. It has improved the treatment of MM even further. This is an evaluation of the modes of action of daratumumab and a description of the development of resistance with focus on inhibitory checkpoint receptors on CD8+ T-cells, complement activation and extracellular vesicles.

Multiple myeloma

Multiple myeloma (MM) is an incurable malignancy of the B-cell lineage, characterized by neoplastic, monoclonal expansion of plasma cells in the bone marrow (BM), which may cause anaemia, osteolytic lesions of the bones, hypercalcemia and renal failure also known as CRAB criteria [1]. MM accounts for 10% of all hematologic cancers, which makes it the second most prevalent hematologic malignant disorder after non-Hodgkin’s lymphomas. The mean age at diagnosis is 70 years, and five year overall survival is around 50%.

Treatment of multiple myeloma

Since MM is an incurable disease, the main purpose of treatment is to give the patients deep and durable responses with as few side effects as possible. The typical disease course consists of remissions and relapses. Generally, with increasing lines of therapy, the more superficial is the response, and the shorter is the duration of the remission [2, 3]. The following types of drugs constitute the backbone of MM therapy: immunomodulatory drugs (IMIDs): thalidomide, lenalidomide and pomalidomide; proteasome inhibitors (PIs): bortezomib, carfilzomib, and ixazomib; alkylating drugs: melphalan and cyclophosphamide; corticosteroids: dexamethasone and prednisone; and the newcomer monoclonal antibodies targeting CD38: daratumumab (DARA) and isatuximab or SLAM-F7: elotuzumab. Very recently, approved therapies encompass B-cell maturation antigen (BCMA)-targeting approaches such as Belantamab Mafodotin, bispecific antibodies, chimeric antigen receptor (CAR) T-cells, and a whole new range of active therapies are in the pipeline.
The initial treatment is dependent on the age and co-morbidities of the patient. For young (≤ 70 years) patients without severe co-morbidities, an induction regimen followed by high dose treatment (HDT) and autologous stem cell treatment (ASCT) is standard first line. A typical induction regimen consists of four cycles of lenalidomide, bortezomib and dexamethasone [4]. For older (> 70 years) patients the initial treatment usually also consists of lenalidomide, bortezomib and dexamethasone until a proper disease control has been obtained or side effects to bortezomib emerge [5]. Most patients with MM will eventually relapse and be in need for a second line of therapy [3]. Treatment for relapse is less standardized and more tailored to the individual patient taking into account the former treatment, response to treatment, duration of response and co-morbidities. In Denmark, most patients are treated with DARA in combination with dexamethasone and lenalidomide or bortezomib in their second line of treatment [6].

Daratumumab

Modes of action

Daratumumab (DARA) is a human immunoglobulin G1 (IgG1) kappa monoclonal antibody (mAb) that targets CD38. CD38 is a 45-kDa type II transmembrane glycoprotein acting as both a receptor and an ectoenzyme. It is highly expressed on plasma cells (PCs) – and especially on malignant PCs (MM cells), and to a lesser extent on red blood cells, platelets, natural killer (NK) cells, a subset of B and T cells, and numerous non-haematological tissues such as airway epithelium, smooth muscle cells, striated-muscle cells including heart tissue, central and peripheral nerve tissue, glial cells, osteoclasts and endocrine cells of the pancreas [7].
Three different effector mechanisms seem to be essential for the direct killing of malignant PCs by DARA: antibody-dependent cellular phagocytosis (ADCP), where the Fc region of DARA bound to CD38 (the “tumour antigen”) on MM cells, reacts with the Fc receptor on effector cells, e.g. macrophages (Figure 1 ). This induces phagocytosis of the MM cell. If the antigen-bound DARA reacts with the Fc receptor on a NK-cell or T-/NK-cell, they will release perforin and GrB, which will result in cytolysis of the MM cell termed antibody-dependent cellular cytotoxicity (ADCC). In the preclinical studies, it seems that especially complement dependent cytotoxicity (CDC) is important for MM cell lysis [8]. During complement activation, the complement protein C1q binds to the Fc region of DARA attached to CD38. Each Fc region has a single binding site for C1q, and each C1q molecule must bind to at least two DARA Fc regions to become activated. Since each DARA molecule has only one Fc region, multiple DARA molecules must be brought together to initiate the process of complement activation [8, 9]. An in vitro comparison of DARA and three other CD38 mAbs indicates that DARA is the most efficient activator of CDC [10].
Beside these abilities to directly kill tumour cells, DARA affects the immune system through several different modes of action. Studies of patient material collected during clinical trials where DARA was given as monotherapy showed that DARA may eliminate CD38+populations of regulatory T-cells, B-cells and monocytes/macrophages that impose a break on the cytotoxic T-cells [11]. Consequently, cytotoxic T-cells proliferate and become activated following treatment with DARA. This immune response correlates with the clinical response to the treatment. Furthermore, DARA inhibits MM cell adhesion to the bone marrow stromal cells (BMSCs) via CD38 internalization through the endocytic machinery rendering the myeloma cells more sensitive to concomitant therapy [12]. Recently, another function of CD38 was identified. Marlein et al. showed that CD38-dependent tumour-derived tunnelling nanotubes (TNT) could be established between BMSCs and MM cells. Mitochondrial transfer via these TNT is a method for the MM cell to provide energy for further tumour growth. This transfer was dependent on CD38 and was significantly decreased when using a CD38 blocking antibody or “knock down” of CD38 in vitro [13].