**2. Monoclonal antibodies**

## **2.1 Daratumumab**

## *2.1.1 Daratumumab mechanism of action*

Daratumumab (Dara) is the first in class humanized IgG1-κ monoclonal antibody targeting CD38 through binding to a unique epitope which includes amino acids 233–246 and 267–280 [6]. Following binding to CD38, Dara exerts its action through canonical (classical) and noncanonical mechanisms [7]. Canonical mechanisms are immune-mediated, dependent on Dara binding to CD38 on the tumor cell, and include complement-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), direct cytotoxicity upon secondary cross-linking, and inhibition of CD38 enzymatic activity. Canonical mechanisms could be either Fcgamma receptor (FcgR) dependent or independent [6, 8, 9]. Whilst the canonical mechanisms explain the activity of Dara against CD38+ cells, noncanonical mechanisms are independent of Dara binding to CD38 and based on modulation of immune cells [10]. Dara targets three main categories of immunosuppressor cells that express CD38. These categories are Regulatory B cells (Bregs), which promote tumor growth and immune escape, a subset of regulatory T cells (Tregs), and Myeloidderived suppressor cells (MDSC). After Dara binding to the CD38 in the surface of the above-mentioned cells causes depletion of their population [11]. Following the depletion of regulatory cells, there is a significant increase in the populations of CD4+ and CD8+ effector T-cells [12–15]. Effector T-cells have increased levels of granzyme-B, which results in enhanced killing capacity [12, 16].

#### *2.1.2 Daratumumab combinations in the newly diagnosed setting*

### *2.1.2.1 Transplant-ineligible patients*

The combination of bortezomib melphalan and prednisone (VMP) is considered a standard of care regimen for patients who are not candidates for transplant. ALCYONE (NCT02195479) is a phase 3 trial in which patients with NDMM were randomized to receive bortezomib melphalan and prednisone either alone or in combination with Dara. The primary endpoint was PFS. The comparison of PFS rates at 16.5 and 40.08 months showed a sustained superiority of Dara-VMP versus VMP groups. At 16.5 and 40.08 months, PFS rates for Dara VMP and VMP groups were 71.6% (95% [CI], 65.5 to 76.8) vs. 50.2% (95% CI, 43.2 to 56.7) and 36.4 vs. 19.3 months respectively [17, 18]. At the time point of 40.08 months, the median PFS2 was not reached versus 42.3 months for the Dara-VMP and the VMP arm, respectively 32376237. The combination of Dara-VMP also demonstrated a significant reduction in the risk of death by 40% in comparison with VMP (HR 0.60 95% CI 0.46–0.80; p = 0·0003) [19]. At the time point of 42 months, the estimated overall survival rate in Dara-VMP and VMP groups was 75% vs. 62% (median not reached in either group HR: 0.60; 95% CI: 0.46 to 0.80; P = 0.0003) respectively [17, 18, 20]. The proportion of patients achieving MRD negativity was better in the Dara-VMP group (28% versus 7%) 32376237 After a median follow-up of 40.1 months, Dara-VMP increased the ORR (90.9% vs. 73.9%) and the rates of ≥VGPR (73% vs. 50%), ≥CR (46% vs. 25%), MRD-negativity (28% vs. 7%; all P < 0.0001), and ≥ CR with MRD-negativity (27% vs. 7%) vs. VMP. Time to subsequent therapy, OS, and PFS was prolonged for patients with deeper responses in both groups Alcyone 2020.

**47**

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

*2.1.2.2 Transplant-eligible patients*

both PFS and OS [24].

MAIA trial **(**NCT02252172) is a phase 3 trial in which the addition of Dara to Rd. was compared to Rd. alone. Seven hundred thirty-seven patients who were ineligible for transplant were recruited. Patients were randomly assigned to receive Rd. with or without Dara in 28-day cycles until disease progression or unacceptable toxicity. The primary end-point was progression-free survival [21]. Results from the primary analysis (median follow-up 28 months) showed that the addition of Dara to Rd. improved PFS and MRD-negativity rates. After a longer follow up period (36.4 months), patients in the DRd arm maintained deeper and durable response along with PFS benefit [22]. After a median follow-up of 47.9 months, patients in the DRd arm had better PFS in comparison with the control group (median, not reached [NR] vs. 34 mo; HR, 0.54; 95% CI, 0.43–0.67; P < 0.0001). Median PFS2 was not reached for DRd vs. 51 months in the Rd. arm. (HR, 0.65; 95% CI, 0.52– 0.83; P = 0.0005). The addition of Dara to Rd. resulted in deeper responses with higher rates of CR or better and VGPR or better. The median duration of response was not reached for responders in the DRd arm vs. 44 months in the Rd. arm [23].

The combination of Dara Bortezomib, cyclophosphamide, and dexamethasone (Dara-VCD) resulted in ORR and VGPR or better rates of 81% and 56%, respectively, in NDMM patients enrolled in the LYRA (NCT02951819) study 30828799. After 6–8 cycles of Dara-VCD induction, eligible patients underwent ASCT. All patients received Dara maintenance. The administration of Dara as maintenance therapy improved the depth of response and was associated with prolongation of

GRIFFIN (NCT02874742) is a phase 2 trial evaluating the addition of Dara to the induction regimen Bortezomib Lenalidomide and Dexamethasone (VRD) in NDMM transplant eligible patients. Patients were randomized to receive Dara-VRD or VRD as induction regimen, ASCT, two cycles of Dara-VRD or VRD consolidation, and Revlimid alone or in combination with Dara as maintenance for 24 cycles. The primary endpoint was the rate of s CR post-consolidation. Regarding the randomized phase of the trial, results indicated that the combination of Dara-VRD was safe and potent. Regarding the primary endpoint results favored the quadruplet regimen (D-VRD)) 42 patients (42.4%) in the D-VRD and 31 patients (32.0%) in the VRD group achieved sCR by the end of consolidation (odds ratio, 1.57; 95% [CI], 0.87–2.82 1-sided P = .068) Response improved over time. After a median follow up of 22.1 months, the sCR (62.6% vs. 45.4%; P = .0177) and MRD negativity (51.0% vs. 20.4%; P < .0001, threshold 10−5) improved in the D-VRD arm in the intent to treat population [25]. In the final analysis of the safety run-in cohort, at the end of consolidation, 9 (56.3%) patients achieved sCR, and 8 (50.0%) were MRD negative (10–5 threshold). After maintenance, 15 (93.8%) patients achieved sCR, and 13 (81.3%) were MRD (10−5) negative. Estimated 36-month overall and progression-free survival rates were 93.8% and 78.1%, respectively. Results showed that the addition of Dara to R AND VRD resulted in durable responses and sustained MRD negativity. The depth of response improved over time [26].

CASSIOPEIA (NCT02541383) is an ongoing phase III clinical trial in newly diagnosed transplant eligible MM patients divided into two parts. Patients were randomized to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd with (VTd group) or without daratumumab (D-VTd group). The primary endpoint of part 1 was the Scr rate assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. After completion of induction and consolidation, the sCR rate in the D-VTd group was 28.9% vs. 20.3% in the VTd group (odds ratio 1.60, 95%CI 1.21–2.12, p = 0.0010). Additionally, the D-VTd

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

MAIA trial **(**NCT02252172) is a phase 3 trial in which the addition of Dara to Rd. was compared to Rd. alone. Seven hundred thirty-seven patients who were ineligible for transplant were recruited. Patients were randomly assigned to receive Rd. with or without Dara in 28-day cycles until disease progression or unacceptable toxicity. The primary end-point was progression-free survival [21]. Results from the primary analysis (median follow-up 28 months) showed that the addition of Dara to Rd. improved PFS and MRD-negativity rates. After a longer follow up period (36.4 months), patients in the DRd arm maintained deeper and durable response along with PFS benefit [22]. After a median follow-up of 47.9 months, patients in the DRd arm had better PFS in comparison with the control group (median, not reached [NR] vs. 34 mo; HR, 0.54; 95% CI, 0.43–0.67; P < 0.0001). Median PFS2 was not reached for DRd vs. 51 months in the Rd. arm. (HR, 0.65; 95% CI, 0.52– 0.83; P = 0.0005). The addition of Dara to Rd. resulted in deeper responses with higher rates of CR or better and VGPR or better. The median duration of response was not reached for responders in the DRd arm vs. 44 months in the Rd. arm [23].

### *2.1.2.2 Transplant-eligible patients*

The combination of Dara Bortezomib, cyclophosphamide, and dexamethasone (Dara-VCD) resulted in ORR and VGPR or better rates of 81% and 56%, respectively, in NDMM patients enrolled in the LYRA (NCT02951819) study 30828799. After 6–8 cycles of Dara-VCD induction, eligible patients underwent ASCT. All patients received Dara maintenance. The administration of Dara as maintenance therapy improved the depth of response and was associated with prolongation of both PFS and OS [24].

GRIFFIN (NCT02874742) is a phase 2 trial evaluating the addition of Dara to the induction regimen Bortezomib Lenalidomide and Dexamethasone (VRD) in NDMM transplant eligible patients. Patients were randomized to receive Dara-VRD or VRD as induction regimen, ASCT, two cycles of Dara-VRD or VRD consolidation, and Revlimid alone or in combination with Dara as maintenance for 24 cycles. The primary endpoint was the rate of s CR post-consolidation. Regarding the randomized phase of the trial, results indicated that the combination of Dara-VRD was safe and potent. Regarding the primary endpoint results favored the quadruplet regimen (D-VRD)) 42 patients (42.4%) in the D-VRD and 31 patients (32.0%) in the VRD group achieved sCR by the end of consolidation (odds ratio, 1.57; 95% [CI], 0.87–2.82 1-sided P = .068) Response improved over time. After a median follow up of 22.1 months, the sCR (62.6% vs. 45.4%; P = .0177) and MRD negativity (51.0% vs. 20.4%; P < .0001, threshold 10−5) improved in the D-VRD arm in the intent to treat population [25]. In the final analysis of the safety run-in cohort, at the end of consolidation, 9 (56.3%) patients achieved sCR, and 8 (50.0%) were MRD negative (10–5 threshold). After maintenance, 15 (93.8%) patients achieved sCR, and 13 (81.3%) were MRD (10−5) negative. Estimated 36-month overall and progression-free survival rates were 93.8% and 78.1%, respectively. Results showed that the addition of Dara to R AND VRD resulted in durable responses and sustained MRD negativity. The depth of response improved over time [26].

CASSIOPEIA (NCT02541383) is an ongoing phase III clinical trial in newly diagnosed transplant eligible MM patients divided into two parts. Patients were randomized to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd with (VTd group) or without daratumumab (D-VTd group). The primary endpoint of part 1 was the Scr rate assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. After completion of induction and consolidation, the sCR rate in the D-VTd group was 28.9% vs. 20.3% in the VTd group (odds ratio 1.60, 95%CI 1.21–2.12, p = 0.0010). Additionally, the D-VTd group had significantly prolonged PFS in comparison with VTd (HR: 0.47; 95%CI: 0.33–0.67, p < 0.0001) [27].

MASTER (NCT03224507) is an ongoing phase II clinical trial. Newly diagnosed transplant eligible MM patients received four cycles of Dara-Carfilzomib Dexamethasone (Dara-KRD) induction, followed by autologous stem cell transplantation (ASCT) and consolidation with Dara-KRD based on the MRD status. The MRD assessment method was next-generation sequencing (NGS), and the threshold was 10−5. Evaluation of MRD status was performed at specific time points. At the end of the induction, post ASCT and post cycles 4 and 8 of consolidation. Patients with two consecutive negative MRD results stopped treatment. Patients who concluded treatment underwent imaging. The administration of Dara-KRD resulted in rapid and durable responses. More than 90% of patients achieved VGPR or better response by the end of induction. The MRD negative rates at the end of induction at ASCT and at best response were 34%, 70%, and 80% (threshold 10−5) and 28%, 45%, and 65% (threshold 10−6), respectively. Until today 11 patients have concluded treatment after achieving MRD negativity without evidence of relapse. The trial is ongoing, and long term follow up results are awaited [28].

PERSEUS (NCT03710603) is a randomized, phase 3 study comparing DARA-VRd vs. VRd in transplant eligible NDMM patients, which has recently concluded its enrollment of patients. PFS is the primary endpoint, while key secondary endpoints include, ORR, MRD-negative rate and OS.

#### *2.1.3 Daratumumab combinations in the R/R setting*

POLLUX (NCT02076009) is a phase III clinical trial that compared the combination of Lenalidomide Dexamethasone with or without daratumumab in MM patients who had received at least one prior line of treatment and were not refractory to Lenalidomide [15]. The addition of Dara significantly improved PFS at 12 (83.2%, 95% CI, 78.3 to 87.2 vs. 60.1%, 95% CI, 54.0 to 65.7), 25,4 (median not reached vs. 17.5 months; HR 0.41; 95% CI,0.31–0.53; P < 0.0001) and 44,3 (median 44.5 vs. 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) months follow up in comparison with the control group [15, 29, 30]. The overall response rate was significantly better in the DRd group (92.9% vs. 76.4%, P < 0.001) 30237262. Post hoc analyses revealed that Dara improved PFS independently of the prior lines of treatment and high-risk cytogenetics [29]. At 25.4 months, the assessment of MRD status (threshold 10−5) revealed deeper responses in the DRd arm (26.2% vs. 6.4% P < 0.0001) [29].

CASTOR study (NCT02136134) compared the combination of Dara Vd (Dvd) versus Vd in 498 patients who had received at least one prior line of therapy (median of 2, range, 1–10; 10% three or more) and were not Bortezomib refractory. The study met its primary endpoint with a significant prolongation of PFS in the Dvd group after 7.4 months follow up (not reached in the Dvd versus 7.2 months in the Vd group), along with a significant reduction (61%) regarding the risk of disease progression or death (HR: 0.39; 95% CI, 0.28–0.53; p < 0.001). ORR was 82.9% in the Dvd vs. 63.2% in the Vd group, P < 0.001 [31]. Updated results of this trial after 40 months, reinforce the tolerability and effectiveness of Dvd. PFS was improved in all subgroups (16.7 vs. 7.1 months, [HR], 0.31; 95% [CI], 0.25–0.40; P < .0001). 32482541. The addition of Dara to Vd manage to overcome the impact of high-risk cytogenetic abnormalities (12.6 vs. 6.2 months; HR, 0.41; 95% CI, 0.21–0.83; P = 0.0106) 32819447 Patients in the Dvd group had 2.5 fold higher MRD negativity rate (10–5 threshold) [31]. Based on the results of CASTOR trial FDA and EMA approved in 2016 Dvd for RRMM patients who had received at least one prior line of treatment.

**49**

**2.2 Isatuximab**

*2.2.1 Mechanism of action*

activity in a dose-dependent manner [40].

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

In a phase 1b study (MMY1001), the addition of Dara to Pomalidomide and Dexamethasone was tested. The study included 103 patients with a median age of 64 years and a median of four prior lines of therapy. Notably, 89% were refractory to Lenalidomide, 71% to Bortezomib, and 30% to Carfilzomib. The median OS and PFS were 17,5 and 8,8 months, respectively. The ORR was 60%. The combination of Dara Pom Dex was clearly safe and effective in this group of heavily pretreated patients [32]. Based on these results, FDA approved this triple combination for patients who had received at least two prior lines, including both a PI and Lenalidomide [32]. APOLLO trial (NCT03180736) explored the addition of Dara to Pomalidomide

and dexamethasone (Pd) in 304 patients with RRMM who had received ≥one prior line of therapy, including a PI and Lenalidomide. PFS was the primary endpoint. Patients received Pomalidomide 4 mg d1–21, dexamethasone 40 mg (20 mg for patients ≥75 years of age) on 28 days cycles. Patients initially received Daratumumab iv 16 mg/kg. After protocol amendment, patients continued with Dara sc 1800 mg. Administration of Dara every week for cycles one and two, every two weeks for cycles 3–6, and every month thereafter. Prior Pomalidomide or anti-CD-38 administration was not permitted. The patient's median age was 67 (35–90) years, 35% had high-risk cytogenetics, and 63% were refractory to both Len and PI. The study met its primary endpoint. The addition of Dara to Pd led to a significant prolongation of PFS (12.4 months) versus 6.9 months in the Pd arm (HR 0.63 (95% CI, 0.47–0.85; P = 0.0018), which represents a 37% reduction in the risk of death or progression. Data regarding OS are immature, and longer follow-up is warranted. No new safety signals have emerged. Additionally, the sc formulation of Dara shortens the duration of administration. These data suggest that the D-Pd combination is

CANDOR (NCT03158688) is another phase 3 trial exploring the addition of Dara to Carfilzomib and dexamethasone (Kd). Four hundred sixty-six patients were randomized to receive Dara Carfilzomib dexamethasone (DKd) vs. Kd. All patients received iv Dara at 16 mg/kg, every week for the first two cycles (the first dose was administered on days 1 and 2 of the first cycle), every two weeks for cycles

week (20 mg for patients 75 years or older). After an initial follow up of 17 months, median PFS was not reached in the DKd group versus 15.8 months in the Kd group (HR 0.63; 95% CI 0.46–0.85; two-sided p = 0.0027) [34]. Data presented in the last ASH meeting showed further improvement in PFS for patients in the KRd arm. After 28 months of follow-up, the median PFS for KRd and Kd group were 28.6 and 15.2 months, respectively (HR, 0.59, 95% CI, 0.45–0.78]. PFS benefit was consistent among subgroups, especially in Lenalidomide refractory patients. Additionally, the MRD negativity rate at 12 months was significantly better in the DKd arm at 12.5%

Isatuximab (SAR650984) is another chimeric IgG1κ monoclonal antibody, which binds on human CD38 by targeting a different epitope in comparison with Daratumumab [36]. Isatuximab and Daratumumab have several differences regarding the mechanism of action. 1/Isatuximab anti-tumor activity is mainly dependent on ADCC [37, 38] 2/Isatuximab induces direct apoptosis of CD-38 even in the absence of cross-linking agents [39] 3/Isatuximab inhibits CD-38 enzymatic

thereafter and dexamethasone 40 mg every

on days

3–6, and every month thereafter, Carfilzomib, twice per week at 20 mg/m2

vs. 1.3% P < 0.0001. No new safety alerts have emerged [35].

safe, effective, and convenient in the RR setting [33].

1 and 2 of cycle 1 and at 56 mg/m2

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

In a phase 1b study (MMY1001), the addition of Dara to Pomalidomide and Dexamethasone was tested. The study included 103 patients with a median age of 64 years and a median of four prior lines of therapy. Notably, 89% were refractory to Lenalidomide, 71% to Bortezomib, and 30% to Carfilzomib. The median OS and PFS were 17,5 and 8,8 months, respectively. The ORR was 60%. The combination of Dara Pom Dex was clearly safe and effective in this group of heavily pretreated patients [32]. Based on these results, FDA approved this triple combination for patients who had received at least two prior lines, including both a PI and Lenalidomide [32].

APOLLO trial (NCT03180736) explored the addition of Dara to Pomalidomide and dexamethasone (Pd) in 304 patients with RRMM who had received ≥one prior line of therapy, including a PI and Lenalidomide. PFS was the primary endpoint. Patients received Pomalidomide 4 mg d1–21, dexamethasone 40 mg (20 mg for patients ≥75 years of age) on 28 days cycles. Patients initially received Daratumumab iv 16 mg/kg. After protocol amendment, patients continued with Dara sc 1800 mg. Administration of Dara every week for cycles one and two, every two weeks for cycles 3–6, and every month thereafter. Prior Pomalidomide or anti-CD-38 administration was not permitted. The patient's median age was 67 (35–90) years, 35% had high-risk cytogenetics, and 63% were refractory to both Len and PI. The study met its primary endpoint. The addition of Dara to Pd led to a significant prolongation of PFS (12.4 months) versus 6.9 months in the Pd arm (HR 0.63 (95% CI, 0.47–0.85; P = 0.0018), which represents a 37% reduction in the risk of death or progression. Data regarding OS are immature, and longer follow-up is warranted. No new safety signals have emerged. Additionally, the sc formulation of Dara shortens the duration of administration. These data suggest that the D-Pd combination is safe, effective, and convenient in the RR setting [33].

CANDOR (NCT03158688) is another phase 3 trial exploring the addition of Dara to Carfilzomib and dexamethasone (Kd). Four hundred sixty-six patients were randomized to receive Dara Carfilzomib dexamethasone (DKd) vs. Kd. All patients received iv Dara at 16 mg/kg, every week for the first two cycles (the first dose was administered on days 1 and 2 of the first cycle), every two weeks for cycles 3–6, and every month thereafter, Carfilzomib, twice per week at 20 mg/m2 on days 1 and 2 of cycle 1 and at 56 mg/m2 thereafter and dexamethasone 40 mg every week (20 mg for patients 75 years or older). After an initial follow up of 17 months, median PFS was not reached in the DKd group versus 15.8 months in the Kd group (HR 0.63; 95% CI 0.46–0.85; two-sided p = 0.0027) [34]. Data presented in the last ASH meeting showed further improvement in PFS for patients in the KRd arm. After 28 months of follow-up, the median PFS for KRd and Kd group were 28.6 and 15.2 months, respectively (HR, 0.59, 95% CI, 0.45–0.78]. PFS benefit was consistent among subgroups, especially in Lenalidomide refractory patients. Additionally, the MRD negativity rate at 12 months was significantly better in the DKd arm at 12.5% vs. 1.3% P < 0.0001. No new safety alerts have emerged [35].

#### **2.2 Isatuximab**

#### *2.2.1 Mechanism of action*

Isatuximab (SAR650984) is another chimeric IgG1κ monoclonal antibody, which binds on human CD38 by targeting a different epitope in comparison with Daratumumab [36]. Isatuximab and Daratumumab have several differences regarding the mechanism of action. 1/Isatuximab anti-tumor activity is mainly dependent on ADCC [37, 38] 2/Isatuximab induces direct apoptosis of CD-38 even in the absence of cross-linking agents [39] 3/Isatuximab inhibits CD-38 enzymatic activity in a dose-dependent manner [40].

#### *2.2.2 Isatuximab clinical trials*

In a phase I dose-escalation study, 84 patients with RRMM (median 5, range 1–13 prior lines of therapy) received Isatuximab monotherapy. Isatuximab administration showed clinical activity and a manageable safety profile. ORR was 24%, median PFS was 3.7 months. IRRs were mainly grade 1 or 2 that occurred during the first cycle [40]. These results were confirmed in a dosefinding phase II trial. Patients with RRMM who had received three or more prior lines of therapy were allocated to four different dosing schedules of isatuximab monotherapy: 3 mg/kg or 10 mg/kg every two weeks, 10 mg/kg every two weeks for one month and every month thereafter, and 20 mg/kg every week for one month and every two weeks thereafter. At doses ≥10 mg/kg 10 mg/kg OS and PFS were 18.7 and 4.6 months respectively, whereas ORR was 24.3% [41]. During the second part of the same study, patients with RRMM (median 4, range 2–10 prior lines of therapy) were randomized to receive isatuximab 20 mg/kg every week for one month, followed by 20 mg/kg every two weeks, with (n = 109) or without (n = 55) dexamethasone. Median PFS and OS were 4.9 and 18.9 and 10.2 for Isatuximab monotherapy and 10.2 and 17.3 for Isatuximab DEX group, respectively [42].

Isatuximab has also shown a synergistic effect when combined with Lenalidomide and dexamethasone. Fifty-seven patients with RRMM (median 5, range 1–12 prior lines of therapy) with 83% refractory to Lenalidomide received Isatuximab in combination with Lenalidomide and dexamethasone in this phase Ib dose-escalation study. The primary objective of the study was the determination of maximum tolerated dose (MTD) of Isatuximabwithin the combination with Lenalidomide and dexamethasone. The ORR was similar in both cohorts, 56%. Only one dose-limiting toxicity was reported (pneumonia grade II at 20 mg/ kg/QW/Q2W), which resolved after discontinuation of treatment. The MTD was not reached. IRRs occurred mostly during the first infusion and were mild (grade I or II) regarding severity. These results demonstrate that the combination of Isatuximab with standard doses of Lenalidomide and Dexamethasone was active and well-tolerated in patients with RRMM [43].

Another phase Ib trial (NCT02283775) evaluated the tolerability and safety of Isatuximab in combination with Pomalidomide and low-dose dexamethasone in patients with RRMM, who had received prior treatment with a PI and Lenalidomide. Forty-five patients with a median of three (range 1–10) prior lines of therapy were recruited. 91% of patients were refractory to their last line of therapy, 84% were PI refractory, and 82% Lenalidomide refractory. Patients received Isatuximab at 5, 10, or 20 mg/kg (every week for four weeks and every two weeks thereafter), Pomalidomide 4 mg (days 1–21), and dexamethasone 40 mg weekly, in 28-days cycles until progressive disease or unacceptable toxicity. The primary objective was the determination of the recommended dose of Isatuximab within this combination, along with safety. Secondary objectives included evaluation of efficacy, pharmacokinetics, and immunogenicity. Among 45 enrolled patients, 8 received Isatuximab at 5 mg/kg, 31 at 10 mg/kg and 6 at 20 mg/kg for median duration of 9.6 months. The most common adverse events included fatigue (62%), infusion reactions (42%), and upper respiratory tract infections. Infusion-related reactions, which were mainly grade I or II, occurred mostly during the first administration of the drug and were manageable with corticosteroids and antihistamines. Median PFS and median duration of response were 17.6 and 18.7 months, respectively. ORR was 62%. These results demonstrated that the combination of Isatuximab with Pomalidomide and dexamethasone was safe and effective in heavily pretreated patients with MM [44].

**51**

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

nation of IPd, in patients with RRMM.

thereafter, in combination with K at dose 27 mg/m 2

Based on these encouraging results, the phase III ICARIA trial (NCT02990338) compared the combination Of Isatuximab Pom Dex (IPd) versus Pom dex (Pd) in 307 patients with RRMM who had received at least two prior lines of treatment, including Lenalidomide and a proteasome inhibitor (median three range 2–4). Patients received Isatuximab 10 mg/kg every week for the first cycle and on days 1 and 15 in the subsequent cycles, plus pomalidomide 4 mg/day (day 1–21) and dexamethasone 40 mg (or 20 mg for patients >75 years) weekly on 28 days cycles. Progression-free survival was the primary endpoint. After a median follow-up of 11.6 months, median progression-free survival was 11.5 months (95% CI 8.9–13.9) in the IPd group versus 6.5 months (4.5–8.3) in the Pd group;(HR 0.596, 95% CI 0.44–0.81; p = 0·001). Responses in the IPd arm occurred faster with a significantly longer duration in comparison with the IPd arm. Additionally, patients in the IPd arm achieved a higher percentage of MRD negativity. The addition of Isatuximab to Pom dex, resulted in significant improvement of PFS [45]. The consistency of the results from the primary analysis was evaluated in patients with soft tissue plasmacytomas. Data presented at the last ASH meeting showed that PFS and ORR were improved from the addition of Isatuximab to Pd in the subgroup of patients with extramedullary disease. Median PFS was 4.57 (95% CI: 2.40, not calculable) vs. 1.56 (95% CI: 0.95, 4.47) months in the IPd and Pd arm, respectively, whereas ORR was 50% (7/14 responders) and 10% (1/10 responders) in the IPd and Pd group. ASH 2289 Based on the results of the ICARIA trial, FDA and EMA approved the combi-

The combination of Isatuximab with Carfilzomib has been evaluated in a phase

. Fifteen patients received

Ib clinical trial (NCT02332850) [46]. In the dose-escalation part of the study, patients with RRMM who had received at least two prior (median three range 2–8) lines of treatment were randomized to receive Isatuximab in 3 different dose levels (DL) 10/kg every two weeks, 10 mg/kg every week for a month and every two weeks thereafter and 20 mg/kg every week for a month and every two weeks

treatment in the dose-escalation and 18 in the dose-expansion cohort at DL2. The primary objective was the determination of the maximum tolerated dose (MTD). Secondary objectives included the assessment of efficacy and safety. Preliminary results showed a 66% ORR in all dose levels. Median PFS was not reached. Based on these results, the phase III IKEMA study (NCT03275285) compared the combination of IKd vs. Kd in the RR setting. Three hundred two patients with RRMM were randomized to receive IKd (n = 179) or Kd (n = 123). The administration of Isatuximab was 10 mg/kg iv weekly during the first month and every two weeks thereafter, whereas administration of Carfilzomib was 20 mg/m2 and 56 mg/m2 thereafter. The primary endpoint was PFS, and the secondary endpoints were OS and ORR [47]. Preliminary data were presented in the last ASH meeting. After a median follow-up of 20.7 months there was a statistically significant improvement of PFS in the IKd group (median PFS was not reached for IKd vs. 19.15 months for Kd; HR 0.531 (99% CI 0.318–0.889), one-sided p = 0.0007, with consistency among subgroups. ORR was 86.6% IKd vs. 82.9% for Kd, one-sided p = 0.1930. MRD negativity (10–5) in the intent to treat population (ITT) was 29.6% (53/179) vs. 13.0% (16/123) in the IKd and Kd groups, respectively descriptive p = 0.0004. Data regarding OS were immature at the time of primary analysis. The percentages of AES and SAEs were similar between the two groups. To conclude, the addition of Isatuximab to Kd lead to a significant improvement in PFS and depth of response. IKD may represent a new standard of care regimen for patients with RRMM [48]. Isatuximab is currently under investigation in the upfront setting. In transplant-

ineligible patients, IMROZ trial (NCT03319667) is comparing the quadruplet combination Isatuximab-VRd with VRD, while another ongoing trial is comparing

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

Based on these encouraging results, the phase III ICARIA trial (NCT02990338) compared the combination Of Isatuximab Pom Dex (IPd) versus Pom dex (Pd) in 307 patients with RRMM who had received at least two prior lines of treatment, including Lenalidomide and a proteasome inhibitor (median three range 2–4). Patients received Isatuximab 10 mg/kg every week for the first cycle and on days 1 and 15 in the subsequent cycles, plus pomalidomide 4 mg/day (day 1–21) and dexamethasone 40 mg (or 20 mg for patients >75 years) weekly on 28 days cycles. Progression-free survival was the primary endpoint. After a median follow-up of 11.6 months, median progression-free survival was 11.5 months (95% CI 8.9–13.9) in the IPd group versus 6.5 months (4.5–8.3) in the Pd group;(HR 0.596, 95% CI 0.44–0.81; p = 0·001). Responses in the IPd arm occurred faster with a significantly longer duration in comparison with the IPd arm. Additionally, patients in the IPd arm achieved a higher percentage of MRD negativity. The addition of Isatuximab to Pom dex, resulted in significant improvement of PFS [45]. The consistency of the results from the primary analysis was evaluated in patients with soft tissue plasmacytomas. Data presented at the last ASH meeting showed that PFS and ORR were improved from the addition of Isatuximab to Pd in the subgroup of patients with extramedullary disease. Median PFS was 4.57 (95% CI: 2.40, not calculable) vs. 1.56 (95% CI: 0.95, 4.47) months in the IPd and Pd arm, respectively, whereas ORR was 50% (7/14 responders) and 10% (1/10 responders) in the IPd and Pd group. ASH 2289 Based on the results of the ICARIA trial, FDA and EMA approved the combination of IPd, in patients with RRMM.

The combination of Isatuximab with Carfilzomib has been evaluated in a phase Ib clinical trial (NCT02332850) [46]. In the dose-escalation part of the study, patients with RRMM who had received at least two prior (median three range 2–8) lines of treatment were randomized to receive Isatuximab in 3 different dose levels (DL) 10/kg every two weeks, 10 mg/kg every week for a month and every two weeks thereafter and 20 mg/kg every week for a month and every two weeks thereafter, in combination with K at dose 27 mg/m 2 . Fifteen patients received treatment in the dose-escalation and 18 in the dose-expansion cohort at DL2. The primary objective was the determination of the maximum tolerated dose (MTD). Secondary objectives included the assessment of efficacy and safety. Preliminary results showed a 66% ORR in all dose levels. Median PFS was not reached. Based on these results, the phase III IKEMA study (NCT03275285) compared the combination of IKd vs. Kd in the RR setting. Three hundred two patients with RRMM were randomized to receive IKd (n = 179) or Kd (n = 123). The administration of Isatuximab was 10 mg/kg iv weekly during the first month and every two weeks thereafter, whereas administration of Carfilzomib was 20 mg/m2 and 56 mg/m2 thereafter. The primary endpoint was PFS, and the secondary endpoints were OS and ORR [47]. Preliminary data were presented in the last ASH meeting. After a median follow-up of 20.7 months there was a statistically significant improvement of PFS in the IKd group (median PFS was not reached for IKd vs. 19.15 months for Kd; HR 0.531 (99% CI 0.318–0.889), one-sided p = 0.0007, with consistency among subgroups. ORR was 86.6% IKd vs. 82.9% for Kd, one-sided p = 0.1930. MRD negativity (10–5) in the intent to treat population (ITT) was 29.6% (53/179) vs. 13.0% (16/123) in the IKd and Kd groups, respectively descriptive p = 0.0004. Data regarding OS were immature at the time of primary analysis. The percentages of AES and SAEs were similar between the two groups. To conclude, the addition of Isatuximab to Kd lead to a significant improvement in PFS and depth of response. IKD may represent a new standard of care regimen for patients with RRMM [48].

Isatuximab is currently under investigation in the upfront setting. In transplantineligible patients, IMROZ trial (NCT03319667) is comparing the quadruplet combination Isatuximab-VRd with VRD, while another ongoing trial is comparing

Isatuximab-VRd to Isatuximab VCD(NCT02513186). In transplant-eligible patients, ISKIA trial is currently investigating the combination of Isatuximab-KRd vs. KRd as part of induction and consolidation regimen (NCT04483739).
