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L. Rasche et al.
upregulation of CD38, such as all-trans retinoic acid, his- tone deacetylase inhibitors or ruxolitinib.2-4
B-cell maturation antigen (BCMA)
BCMA is preferentially expressed on mature B cells including plasma cells. It is important for B-cell develop- ment and critical for proliferation and survival. BCMA is a cell surface receptor of the tumor necrosis factor recep- tor superfamily and binds to B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). BCMA expression can vary due to cleavage by γ-secretase leading to shedding from the cell surface.
Transmembrane activator, calcium modulator, and cyclophilin ligand (TACI)
TACI is another member of the tumor necrosis factor receptor superfamily expressed on B-cell subsets and plas- ma cells.
Cluster of differentiation 19 (CD19)
CD19 is widely expressed on B cells but considerably less on plasma cells. It has been postulated that it may be expressed on “myeloma stem cells”. Recent analysis by super-resolution microscopy revealed a broader low-level expression on a fraction of myeloma cells (10-80%).5
G protein-coupled receptor class C group 5 member D (GPRC5D)
GPRC5D is an orphan receptor ubiquitously expressed on healthy and malignant plasma cells but not on normal tissues except the immune-privileged tissue of hair folli- cles. High GPRC5D expression on MM cells was associ- ated with adverse prognosis in the CoMMpass dataset.6
Fc receptor-homolog 5 (FcRH5)
FcRH5, also known as FcRL5, IRTA2, and CD307, is a 120 kDa protein with sequence homology to classical Fc receptors. The type 1 transmembrane FcRL family pro- teins contain from three to nine immunoglobulin-like domains. They are differentially expressed within the B- cell lineage and can either promote or inhibit B-cell prolif- eration and activation. FcRH5 is expressed on MM cells and plasma cells and, to a lesser extent, on normal B cells.7
Antibody-drug conjugates
ADC are monoclonal antibodies conjugated via a linker to a cytotoxic moiety.8 After binding to the respective tar- get protein on the myeloma cell, the ADC is internalized and the cytotoxic drug released intracellularly; they can be thought of as targeted chemotherapeutic agents. ADC differ with respect to the target protein, the linker or the cytotoxic payload.8 In the following section, some key ADC, the study results and our perspectives are high- lighted. This selection is far from exhaustive and the interested reader is referred to more detailed reviews regarding this topic.8,9
Belantamab mafodotin
By far the most clinically advanced ADC is belantamab mafodotin, a humanized IgG1 anti-BCMA monoclonal antibody that is conjugated, via a non-cleavable linker, to the microtubule inhibitor, monomethyl auristatin F (MMAF). MMAF blocks the myeloma cell cycle at the
G2/M phase leading to apoptosis. Afucosylation of the ADC Fc portion enhances the affinity to Fc receptors of innate immune cells, which increases immune-mediated recognition and elimination. Therefore, belantamab mafodotin can also be considered as immunotherapy.10 (Figure 1)
Two dose levels (2.5 mg/kg or 3.4 mg/kg, intravenously every 3 weeks) of belantamab mafodotin were tested in the pivotal randomized phase II DREAMM-2 study in heavily pretreated (6-7 prior lines of therapy) patients with relapsed and/or refractory MM (RRMM): The efficacy of the ADC was comparable at the two dose levels, with the overall response rate (ORR) being 31% versus 35% and the progression-free survival (PFS) being 2.8 months versus 3.9 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respec- tively. Duration of response was 11.0 and 6.2 months, while the overall survival was 14.9 and 14.0 months, respectively (Table 1).11
The MMAF component of belantamab mafodotin is responsible for clinically significant ocular toxicity: micro- cyst-like epithelial changes of the cornea.12 Clinically, patients experience blurred vision, decreased visual acuity and dry eyes. In DREAMM-2, keratopathy was noted in 70-75% of patients and was grade ≥3 in 27% (with the 2.5 mg/kg dose) and 21% (with the 3.4 mg/kg dose) of the patients. Keratopathy was the most common adverse event leading to dose reductions and delays as well as to permanent treatment discontinuation. It is therefore mandatory to schedule regular ophthalmological examina- tions when treating MM patients with this novel ADC.
In summary, the DREAMM-2 study demonstrated that belantamab mafodotin has clinically significant efficacy as a single agent and it was approved (at a dose of 2.5 mg/kg every 3 weeks) in both the USA and in Europe in 2020 for the treatment of RRMM patients after four lines of therapy (including a proteasome inhibitor, immunomodulatory drug and an anti-CD38 monoclonal antibody).
Based on the DREAMM-2 study results, belantamab mafodotin is currently being assessed in trials at earlier lines of treatment and with different combination part- ners:9 immuno-oncological antibodies (DREAMM-4,13 DREAMM-5) or established MM therapeutics lenalido- mide + dexamethasone (DREAMM-6),14 pomalidomide + dexamethasone,15 bortezomib + dexamethasone (DREAMM-6,14 DREAMM-7) and bortezomib + lenalido- mide + dexamethasone (DREAMM-9).
Table 1 summarizes key studies of this program for which efficacy and toxicity data are already available. Further details and summaries of all ongoing studies with belantamab mafodotin are provided in comprehensive recent reviews.8,9,16
MEDI2228
MEDI2228 is another ADC targeting BCMA. The cyto- toxic moiety is tesirine, a DNA crosslinking pyrroloben- zodiazepine dimer attached to the antibody via a pro- tease-cleavable linker. This toxin induces DNA crosslink- ing and the DNA damage response.17 The ADC was designed to specifically target the membrane-bound BCMA protein, so that its activity is not affected by the levels of soluble BCMA.
The results of the phase I, first-in-human, dose escala- tion and expansion study (NCT03489525) involving 82 heavily pretreated RRMM patients were presented at the 2020 ASH annual meeting.18 The maximum tolerated
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haematologica | 2021; 106(10)