**2. mAbs targeting CD38**

CD38 is a multifunctional 45 kDa type II transmembrane glycoprotein, lacking an internal signaling domain, that is expressed at high levels on both malignant and normal plasma cells and has attracted much interest as a target for drug development in MM [6]. It also is found normally, but at lower levels, on the surfaces of T and B lymphocytes, natural killer (NK) cells, and monocytes. Among its several roles, CD38 acts as a receptor for CD31 (platelet endothelial cell adhesion molecule; PECAM-1) [7] and as a cyclic ADP ribose hydrolase, an ectoenzyme whose reaction products play an essential role in regulation of intracellular calcium levels [8].

Antibodies directed against CD38 kill myeloma cells by a number of possible mechanisms, chief among them being antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complementdependent cytotoxicity (CDC). Intracellular signal cascade disruption, the result of crosslinks formed between myeloma cell CD38 and Fcγ receptors on effector cells, may also play an important role in initiating apoptotic events in myeloma cells [9]. In addition, anti-CD38 antibodies have been shown to exhibit immunomodulatory effects that cause blockage of regulatory T- and B-cells and myeloid-derived suppressor cells [10].

Daratumumab (Darzalex®), a fully human IgG1κ mAb targeting CD38, initially was approved for the management of MM in patients who had relapsed following at least three prior therapies including an immunomodulator and a proteasome inhibitor [11]. Approval was supported by the results of two phase III trials - POLLUX (NCT02076009) and CASTOR (NCT02136134) - in which daratumumab/dexamethasone was combined respectively with either lenalidomide [12] or bortezomib [13]. Further encouraging data from phase III trials, demonstrating deeper and more sustained responses combined with good tolerability, soon enabled daratumumab/corticosteroid combinations with immunomodulators or proteasome inhibitors to assume an important role in even earlier courses of treatment [14, 15], as well as in newly diagnosed patients, whether ASCT-eligible [16] or -ineligible [17, 18]. Several network meta-analytic studies of random controlled trials covering a number of different settings, including in patients with newly diagnosed disease, have demonstrated the benefits of daratumumabcontaining regimens in MM therapy with respect to efficacy and safety [19]. Furthermore, several reports have indicated the efficacy of daratumumab monotherapy in patients who have failed earlier lines of anti-myeloma therapy [20], as well as in patients with smoldering MM [21]. Also, the FDA recently has approved a subcutaneous formulation of daratumumab plus hyaluronidase, which enables shorter infusion times without compromising safety or efficacy [22].

**141**

*Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma*

Isatuximab (Sarclisa®, SAR650984) is a chimeric mouse-human IgG1κ CD38 targeting mAb that was approved by the FDA in March 2020 for the treatment of relapsing and/or refractory MM (RRMM) in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor [23]. Approval was predicated primarily on the results of the phase III ICARIA-MM trial (NCT02990338) in which addition of isatuximab to a pomalidomide/dexamethasone regimen resulted in a five month increase in median progression free survival (PFS), from 6.5 to 11.5 months [24]. Upper respiratory infections and diarrhea were the most frequently encountered adverse events noted in both groups. Although infusion reactions (mostly, grades 1 and 2) were reported in 38% of patients in the isatuximab cohort, this reaction was not noted in any patients in the pomalidomide/dexamethasone group. An additional five phase III trials that include isatuximab/dexamethasone currently are in progress for: newly diagnosed MM (NDMM) (NCT03617731 and NCT03319667 IMROZ - lenalidomide/bortezomib; NCT04483739 - lenalidomide/carfilzomib); RRMM (NCT03275285 IKEMA - carfilzomib); and high-risk smoldering MM

The mechanism of action of isatuximab exhibits some significant differences from that of daratumumab. For example, the former appears to work principally through ADCC with only minor contributions from CDC [25]. Also, unlike daratumumab, crosslinking induced by isatuximab is not a prerequisite for initiation of target cell apoptosis [26]. Moreover, isatuximab is a much more potent inhibitor of

MOR202 (MOR03087, TJ202) is a fully humanized IgG1λ mAb that exhibited an objective response rate (ORR) of 29% in a phase II trial with dexamethasone in patients who had previously received four lines of therapy [28]. In addition, this drug has shown some promising efficacy when combined with immunomodulators [29, 30]. MOR202 also appears to offer the advantage of requiring reduced infusion times and is associated with reduced infusion-related reactions compared to daratumumab or isatuximab, possibly due to its lack of dependency on CDC as a function of its activity. However, the drug's sponsor, MorphoSys AG, recently decided to discontinue further development of MOR202 for MM. Two additional anti-CD38 mAbs from Takeda Oncology currently are in the early stages of clinical development for RRMM: TAK-573, an IgG4 antibody conjugated to an attenuated form of interferon α [31], and TAK-079, a fully humanized IgG1λ mAb [32].

A group of surface proteins belonging to the signaling lymphocytic activation molecule family (SLAMF) has elicited considerable interest in recent years due to the high expression of four family members (SLAMF2, 3, 6, and 7) on both normal plasma cells and those from MM patients at all stages of disease. No trials of SLAMF2 targeting mAbs have been initiated and clinical studies of the SLAMF3 and SLAMF6 mAbs SGN-CD48A and azintuxizumab vedotin (ABBV-838), respectively, both were halted early in phase I trials. On the other hand, SLAMF7 (CS1 or CD319) has emerged as the principal focus for new anti-myeloma mAb development in this group of targets with the introduction of elotuzumab (Empliciti®), a humanized IgG1κ mAb [33]. Preclinical studies revealed that the anti-myeloma activity of elotuzumab is the result of ADCC involving direct activation and engagement of NK cells [34]. FDA approval in 2015 of elotuzumab, which lacks activity as a single agent, was the result of the ELOQUENT-2 trial (NCT01239797) involving 646 randomly assigned RRMM patients who received the mAb plus dexamethasone

ectoenzyme activity although the significance of this is unknown [27].

*DOI: http://dx.doi.org/10.5772/intechopen.94196*

(NCT04270409 - lenalidomide).

**3. mAbs targeting SLAMF7**

#### *Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma DOI: http://dx.doi.org/10.5772/intechopen.94196*

*Monoclonal Antibodies*

**2. mAbs targeting CD38**

suppressor cells [10].

and pomalidomide), which were added to the long-established treatments based on alkylating agents (melphalan and cyclophosphamide) and corticosteroids (dexamethasone). These measures, together with autologous stem cell transplantation (ASCT), first introduced for MM in the 1990's, have increased the five-year survival rate for the disease from 24% in the mid-1970s to 55% in the 2010–2016 period [5]. Furthermore, the relatively recent arrival on the scene of monoclonal antibodies (mAbs), beginning with the U.S. Food and Drug Administration (FDA) approval of daratumumab in 2015, has greatly expanded the therapeutic options available to treat MM. However, in spite of these advances, MM remains incurable as patient relapse and refractoriness to treatment continue as major issues. This review focuses on the contributions made by those mAbs currently approved for MM, as well as on

CD38 is a multifunctional 45 kDa type II transmembrane glycoprotein, lacking an internal signaling domain, that is expressed at high levels on both malignant and normal plasma cells and has attracted much interest as a target for drug development in MM [6]. It also is found normally, but at lower levels, on the surfaces of T and B lymphocytes, natural killer (NK) cells, and monocytes. Among its several roles, CD38 acts as a receptor for CD31 (platelet endothelial cell adhesion molecule; PECAM-1) [7] and as a cyclic ADP ribose hydrolase, an ectoenzyme whose reaction products play an essential role in regulation of intracellular calcium levels [8]. Antibodies directed against CD38 kill myeloma cells by a number of possible mechanisms, chief among them being antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complementdependent cytotoxicity (CDC). Intracellular signal cascade disruption, the result of crosslinks formed between myeloma cell CD38 and Fcγ receptors on effector cells, may also play an important role in initiating apoptotic events in myeloma cells [9]. In addition, anti-CD38 antibodies have been shown to exhibit immunomodulatory effects that cause blockage of regulatory T- and B-cells and myeloid-derived

Daratumumab (Darzalex®), a fully human IgG1κ mAb targeting CD38, initially was approved for the management of MM in patients who had relapsed following at least three prior therapies including an immunomodulator and a proteasome inhibitor [11]. Approval was supported by the results of two phase III trials - POLLUX (NCT02076009) and CASTOR (NCT02136134) - in which daratumumab/dexamethasone was combined respectively with either lenalidomide [12] or bortezomib [13]. Further encouraging data from phase III trials, demonstrating deeper and more sustained responses combined with good tolerability, soon enabled daratumumab/corticosteroid combinations with immunomodulators or proteasome inhibitors to assume an important role in even earlier courses of treatment [14, 15], as well as in newly diagnosed patients, whether ASCT-eligible [16] or -ineligible [17, 18]. Several network meta-analytic studies of random controlled trials covering a number of different settings, including in patients with newly diagnosed disease, have demonstrated the benefits of daratumumabcontaining regimens in MM therapy with respect to efficacy and safety [19]. Furthermore, several reports have indicated the efficacy of daratumumab monotherapy in patients who have failed earlier lines of anti-myeloma therapy [20], as well as in patients with smoldering MM [21]. Also, the FDA recently has approved a subcutaneous formulation of daratumumab plus hyaluronidase, which enables

shorter infusion times without compromising safety or efficacy [22].

those under investigation as potential future therapies for this disease.

**140**

Isatuximab (Sarclisa®, SAR650984) is a chimeric mouse-human IgG1κ CD38 targeting mAb that was approved by the FDA in March 2020 for the treatment of relapsing and/or refractory MM (RRMM) in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor [23]. Approval was predicated primarily on the results of the phase III ICARIA-MM trial (NCT02990338) in which addition of isatuximab to a pomalidomide/dexamethasone regimen resulted in a five month increase in median progression free survival (PFS), from 6.5 to 11.5 months [24]. Upper respiratory infections and diarrhea were the most frequently encountered adverse events noted in both groups. Although infusion reactions (mostly, grades 1 and 2) were reported in 38% of patients in the isatuximab cohort, this reaction was not noted in any patients in the pomalidomide/dexamethasone group. An additional five phase III trials that include isatuximab/dexamethasone currently are in progress for: newly diagnosed MM (NDMM) (NCT03617731 and NCT03319667 IMROZ - lenalidomide/bortezomib; NCT04483739 - lenalidomide/carfilzomib); RRMM (NCT03275285 IKEMA - carfilzomib); and high-risk smoldering MM (NCT04270409 - lenalidomide).

The mechanism of action of isatuximab exhibits some significant differences from that of daratumumab. For example, the former appears to work principally through ADCC with only minor contributions from CDC [25]. Also, unlike daratumumab, crosslinking induced by isatuximab is not a prerequisite for initiation of target cell apoptosis [26]. Moreover, isatuximab is a much more potent inhibitor of ectoenzyme activity although the significance of this is unknown [27].

MOR202 (MOR03087, TJ202) is a fully humanized IgG1λ mAb that exhibited an objective response rate (ORR) of 29% in a phase II trial with dexamethasone in patients who had previously received four lines of therapy [28]. In addition, this drug has shown some promising efficacy when combined with immunomodulators [29, 30]. MOR202 also appears to offer the advantage of requiring reduced infusion times and is associated with reduced infusion-related reactions compared to daratumumab or isatuximab, possibly due to its lack of dependency on CDC as a function of its activity. However, the drug's sponsor, MorphoSys AG, recently decided to discontinue further development of MOR202 for MM. Two additional anti-CD38 mAbs from Takeda Oncology currently are in the early stages of clinical development for RRMM: TAK-573, an IgG4 antibody conjugated to an attenuated form of interferon α [31], and TAK-079, a fully humanized IgG1λ mAb [32].
