The cytotoxic moiety is tesirine, a DNA crosslinking pyrrolobenzodiazepine dimer attached to the antibody via a protease- cleavable linker. published in peer-reviewed journals or been presented at international conferences, including the 2020 American Society of Clinical Oncology, European Hematology Association, and American Society of Hematology (ASH) meetings. In the second part, we discuss these new reports in the context of current treatment paradigms in MM. Given the plethora of immunological approaches in MM, we focus here on the three most advanced classes of novel immunotherapies, antibody- drug conjugates (ADC), bispecific antibodies or T-cell-engaging antibodies (TCE), and chimeric antigen receptor (CAR) T cells, targeting the antigens described below. Antigens Signaling lymphocytic activation molecule family member 7 (SLAMF7) SLAMF7 (or CS1) is expressed SGI 1027 on a variety of lymphocytes, including subsets of B and T cells, natural killer cells and plasma cells. SLAMF7 is the target of the mono clonal antibody elotuzumab. The development of CAR T cells directed against SLAMF7 may be more challenging because of this antigens expression on T-cell subsets which may lead to fratricide.1 Cluster of differentiation 38 (CD38) CD38 is expressed on plasma cells and is the target of monoclonal antibodies such as daratumumab and isatuximab. It is also expressed on several other lymphoid and myeloid cells, including hematopoietic precursors, raising concerns about on-target, off-tumor toxicity. The levels of expression of CD38 may also decline during the course of the disease or under the selective pressure of SGI 1027 CD38- targeted treatment. This problem may be overcome by agents inducing SGI 1027 selective upregulation of CD38, such as all-retinoic acid, histone 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 development and critical for proliferation and survival. BCMA is a cell surface receptor of the tumor necrosis factor receptor superfamily and binds to B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). BCMA expression can vary due to cleavage by -secretase SGI 1027 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 plasma 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 CD264 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 follicles. High GPRC5D expression on MM cells was associated 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 proteins contain from three to nine immunoglobulin-like domains. They are differentially expressed within the Bcell lineage and can either promote or inhibit B-cell proliferation 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 target 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 highlighted. 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 SGI 1027 every 3 weeks) of belantamab mafodotin were tested in the pivotal randomized phase II DREAMM-2 study in heavily pretreated (6-7.
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