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].