*2.3.2 Elotuzumab clinical trials*

The large phase III ELOQUENT 2 trial (NCT01239797) evaluated the addition of Elotuzumab at the dose of 10 mg/kg to Lenalidomide and dexamethasone (Rd) in 646 patients with RRMM (94% lenalidomide naïve patients) who had received 1–3 prior lines of treatment. Patients received Lenalidomide 25 mg for days 1–21 and dexamethasone 40 mg on a weekly basis on 28-day cycles. Elotuzumab administration was 10 mg/kg weekly for the first two cycles, and 20 mg/kg on a monthly basis thereafter. Primary endpoints included PFS and ORR. OS was one of the key secondary endpoints. After an initial follow-up of 24.5 months, the rates of median PFS and ORR were 19.4 versus 14.9 months (HR for progression or death 0.70; 95% CI 0.57 to 0.85; P < 0.001) and 79%, versus 66% in the ELO Rd. and Rd. groups respectively. 26035255. PFS rates demonstrate sustained improvement after two (52%) and three (44%) years of follow-up (relative risk of disease progression or death by 30% and 27% respectively) 30204239. More recent data, after a 4-year follow-up, demonstrate sustained OS benefit (50 months for ELO Rd. versus 43 months for Rd. HR: 0.78; 95%CI: 0.63–0.96). 30719202 Administration of Elotuzumab was relatively safe. Most common grade 3 or 4 AEs in both arms included lymphopenia, neutropenia, pneumonia, and fatigue. Based on this trial Elotuzumab was granted approval by the FDA in December 2015 and EMA in 2016, in combination with Rd., for patients with RRMM, who had received at least one prior line of treatment [51].

Elotuzumab has also been evaluated in combination with Pomalidomide and dexamethasone (Pd). Eloquent 3 (NCT02654132) is a randomized phase II trial, comparing the combination of ELO Pd versus Pd in 117 patients who were refractory or relapsed and refractory to Lenalidomide and a proteasome inhibitor. Patients received Pomalidomide 4 mg for day 1–21 and dexamethasone 40 mg on a weekly basis on 28-day cycles. Elotuzumab administration was 10 mg/kg weekly for the first two cycles and 20 mg/kg on a monthly basis thereafter. Sixty patients were assigned to the ELO Pd group and 57 patients to the Pd group. After a follow up of 9.1 months, patients in the ELO Pd group had significantly increased PFS (10.3 vs. 4.7 months HR 0.54 CI0.34 to 0.86; P = 0.008) and ORR (53% vs. 26% odds ratio, 3.25; 95% CI, 1.49 to 7.11) in comparison with the Pd group. No significant differences were reported in the safety profiles of the two arms. Based on the results of the ELOQUENT III trial, Elotuzumab granted approval by the FDA in 2018

**53**

*Antibody Therapies for Multiple Myeloma DOI: http://dx.doi.org/10.5772/intechopen.98656*

**2.4 Antibody drug conjugates (ADCs)**

Lenalidomide and a PI [52].

for RR patients who had received at least two prior lines of treatment, including

BCMA, is a and member of the tumor necrosis factor receptors (TNFR) superfamily [53, 54]. BCMA is primarily expressed in late-stage B-lineage cells, normal and malignant plasma cells, and B-lymphocytes, with very low expression on nonhematologic cells [55]. BCMA has two main ligands: a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) [56–58]. Following binding of APRIL and BAFF, BCMA expression is selectively upregulated during malignant transformation of plasma cells, playing a critical role in survival, drug resistance, and tumor cell growth through activation of intracellular signal transduction pathways such as STAT3, phosphoinositide 3-kinase (PI3K), AKT, NFB and MAPK [59–63]. As demonstrated in BCMA knock-down mouse models, BCMA is not required for normal B-cell differentiation and homeostasis [64]. The shedding of BCMA from the cell surface is mediated by γ-secretase and results in a soluble form (soluble BCMA, sBCMA). Higher sBCMA levels have been associated with inferior clinical outcomes. In preclinical models, inhibition of BCMA, with specific antibodies, showed significant anti-myeloma activity. The aforementioned facts make BCMA an ideal therapeutic target for the treatment of Multiple Myeloma and provide the

rationale for the development of anti-BCMA monoclonal antibodies.

included in the eligibility criteria of study [66].

Updated results of this study, after an extended median follow-up of 12.5 months, demonstrate that was effective in this heavily pretreated group of patients [67]. Achievement of response occurred early during the study after the first or second infusion. Interestingly, dose reduction did not affect the depth and duration of response. 21/65 patients in the dose-expansion part achieve partial or better response, including 2PRs, 14VGPRs, 3CRs, and two sCRs. 18/32 (56.3%)

GSK2857916 (Belantamab Mafodotin) is the first anti-BCMA ADC that has been investigated in clinical trials. This afucosylated, humanized, IgG1 monoclonal antibody is conjugated to monomethyl auristatin F (MMAF), an inhibitor of tubulin polymerization, through a protease-resistant maleimidocaproyl linker. Following binding to the plasma cell surface, GSK2857916 is internalized and the active cytotoxic drug (cys-mcMMAF) is released following enzymatic cleavage leading to cell death. Mechanisms of action include NK-cell mediated ADCC and ADCP [65]. DREAMM 1 (NCT02064387) is a first in human phase I, open-label study, which evaluated the administration of GSK2857916 in patients with RRMM and other hematologic malignancies expressing BCMA in terms of efficacy and safety. Dose escalation cohort (part I) included solely patients with MM who have failed previous treatment regimens, including stem cell transplant (if eligible) IMiDs, PIs, and alkylators, while the dose-expansion cohort (part2) included both patients with MM and relapsed follicular lymphoma or diffuse large B-cell lymphoma. Regarding MM patients in the expansion cohort, 57% had five or more prior lines of therapy; 89% were double (PI and IMiD) and 34% triple (PI, IMiD, and daratumumab) refractory. GSK2857916 was administered intravenously every three weeks as a 1 hr. infusion in 38 patients at different dose levels (0.03–4.6 mg/kg). Primary endpoints were safety, determination of maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary objectives were the determination of pharmacodynamics and pharmacokinetics parameters, anti-drug antibodies, and clinical activity. In dose-expansion, patients received the selected recommended phase 2 dose of 3.4 mg/kg. Overall, 73 patients were recruited, thirty-eight in dose escalation and thirty-five in the dose-expansion cohort. Notably, BCMA expression was not

for RR patients who had received at least two prior lines of treatment, including Lenalidomide and a PI [52].
