Isatuximab for the treatment of relapsed/refractory multiple myeloma

ABSTRACT

Introduction

Although new drug classes have significantly extended survival of patients with multiple myeloma, they continue to experience multiple relapses and/or become refractory to treatment. Therefore, novel therapies and treatment combinations with different mechanisms of action are needed to improve the outcomes of patients with relapsed/refractory multiple myeloma.

Areas covered

Here, the authors review the published data regarding the development and clinical investigation of isatuximab, a CD38 monoclonal antibody, for treatment of patients with relapsed/refractory multiple myeloma. The mechanisms of action, clinical efficacy, and safety of isatuximab treatment are summarized.

Expert opinion

Isatuximab is approved in combination with pomalidomide/dexamethasone for the treatment of adults with relapsed/refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Isatuximab displays a manageable safety profile, with infusion reactions being the most common adverse events. Isatuximab is currently being further evaluated in combination with other backbone regimens in relapsed/refractory and newly diagnosed multiple myeloma.

KEYWORDS:

• CD38
• isatuximab
• monoclonal antibody
• relapsed/refractory
• multiple myeloma

1. Introduction

Multiple myeloma (MM) is a clonal plasma cell neoplasm that accounts for 1% of all cancers and approximately 10% of all hematologic malignancies worldwide [1,2]. Each year, there are over 138,500 incident cases of MM reported globally [3].

MM is still largely incurable, as the majority of patients relapse or become refractory to treatment [4]. Relapsed MM is regarded as a recurrence of the disease after prior response to treatment; relapsed and refractory MM is a disease that stops responding or becomes progressive in patients receiving therapy, or within 60 days of stopping a prior treatment regimen in patients who had a response on prior therapy [5]. The management of patients with relapsed/refractory multiple myeloma (RRMM) requires a meticulous clinical appraisal of previous therapy, management of toxicities associated with current treatment, and an evaluation of the prognosis of the individual patient [5]. The introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs) combined with standard chemotherapy has significantly extended survival of MM patients [6–8]. Even so, the urgent need for new therapies continues to grow as patients live longer but continue to relapse and become resistant to prior therapies [9].

Global guidelines include the International Myeloma Working Group, the National Comprehensive Cancer Network, the European Society for Medical Oncology, the European Myeloma Network, and the American Society of Clinical Oncology and Cancer Care Ontario joint guidelines [10–13]. These guidelines recommend combination therapy for the treatment of RRMM, which should be individualized based on patients’ characteristics and treatment availability and accessibility in different countries.

2. Overview of multiple myeloma therapies

With the introduction of novel therapies during the past decade, patient outcomes have improved extensively. However, MM still remains incurable, with residual malignant cells post-treatment confounding curative treatment. As MM patients relapse, they can become increasingly refractory and resistant to existing therapies. There is thus an ongoing need for new agents with different mechanisms of action, so patients can be both treated in the long term and their outcomes further improved.

Currently, four drug classes combined with conventional therapy are most commonly used for the treatment of MM, PIs (bortezomib, carfilzomib, and ixazomib), IMiDs (thalidomide, lenalidomide, and pomalidomide), mAbs (daratumumab, elotuzumab, and isatuximab), and the selective inhibitor of nuclear export, selinexor.

Daratumumab is a human mAb targeting CD38, and has been approved as monotherapy and in combination with (i) lenalidomide/dexamethasone (Rd); (ii) bortezomib/melphalan/prednisone; (iii) bortezomib/thalidomide/dexamethasone; (iv) bortezomib/dexamethasone; and (v) pomalidomide/dexamethasone (Pd) to treat both RRMM and newly diagnosed MM (NDMM) [14]. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recently approved a new subcutaneous formulation of daratumumab that is co-formulated with hyaluronidase-fihj [15,16].

Elotuzumab is a mAb designed to target signaling lymphocytic activation molecule family member 7 (SLAMF7). It has been approved in combination with Rd and Pd for the treatment of RRMM [17].

This review will focus on the mechanisms of action, clinical efficacy, and safety profile of the CD38 mAb isatuximab in RRMM patients (Box 1). Isatuximab has been recently approved in combination with Pd for the treatment of adults with RRMM [18,19].

3. Introduction to isatuximab

Isatuximab (SAR650984) is a mAb targeting a specific epitope on CD38, a transmembrane glycoprotein that acts as a receptor and regulates migration and receptor-mediated adhesion by interaction with CD31 or hyaluronic acid [20–22]. Additionally, CD38 acts as an ectoenzyme with adenosine diphosphate ribose cycling and hydrolase activity, catalyzing the metabolism of calcium messengers and activating several signaling pathways [23–25]. CD38 is an attractive target for therapeutic antibodies to treat MM because it is expressed at relatively low levels on myeloid and lymphoid cells and in some non-hematopoietic tissues, and at high levels in normal and MM plasma cells [20].

Isatuximab binds to a specific discontinuous epitope on CD38, triggering several mechanisms of action, summarized in Figure 1. Some of these mechanisms are mediated by the fragment crystallizable (Fc) portions of the antibodies that bind to the FcγRs expressed on effector natural killer (NK) cells and macrophages to trigger antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) or that allow the fixation of the human complement to trigger complement-dependent cytotoxicity [26–29]. Moreover, the binding of isatuximab directly triggers MM cell death in the absence of cross-linking agents and independent of effector cells, both via the caspase-dependent apoptotic pathway and the lysosome-mediated cell death pathway [26,30]. Isatuximab is the only anti-CD38 mAb that induces direct apoptosis in MM cells, even in cells harboring p53 mutations; other anti-CD38 mAbs (daratumumab, MOR202, and TAK-079) may induce apoptosis but only in the presence of cross-linking agents [30,31]. Additionally, isatuximab was shown to inhibit CD38 enzymatic activity more effectively than daratumumab, while TAK-079 and MOR202 had a modest effect on CD38 enzyme activity [28,31]. Inhibition of CD38 ectoenzymatic activity and consequent decrease in the production of immunosuppressive adenosine likely alleviate the immunosuppressive microenvironment of the bone marrow niche in MM patients [28,32]. Finally, isatuximab also induces indirect antitumor activity through (i) the elimination of CD38⁺ immunosuppressive regulatory T cells, thus restoring immune effector functions against MM [33] and (ii) an ‘in vivo vaccination’ effect where patients treated with isatuximab develop a T-cell adaptive immune response against CD38 as well as other MM-associated antigens (New York esophageal squamous cell carcinoma 1 [NY-ESO-1], melanoma-associated antigen [MAGE] C1, and MAGE-C2) [34].

Figure 1. Mechanisms of action of isatuximab. The CD38 antibody isatuximab was shown to kill multiple myeloma (MM) cells by antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptosis. Isatuximab induces indirect antitumor activity through the elimination of CD38⁺ immunosuppressive regulatory T cells, and thus restoring immune effector functions against MM, and through the induction of autologous T-cell responses against CD38 and other MM-associated antigens (‘in vivo vaccination’ effect). Isatuximab also inhibits CD38 ectoenzyme activity and the production of immunosuppressive adenosine, which likely alleviate immunosuppressive microenvironment in bone marrow niche of MM patients

Isatuximab and daratumumab have several mechanistic differences: (i) isatuximab and pomalidomide demonstrate synergistic ADCC induction both in vitro and in vivo [30], whereas daratumumab-induced ADCC can be augmented by lenalidomide and bortezomib [35,36]; (ii) isatuximab induces direct apoptosis of CD38-expressing cancer cells [30], whereas daratumumab induces apoptosis only in the presence of cross-linking agents [37]; and (iii) isatuximab led to a dose-dependent inhibition of CD38 enzymatic activity, whereas daratumumab, under the same experimental conditions, produced a more limited inhibition without obvious dose response [28].

Interestingly, preclinical data demonstrated that pomalidomide and isatuximab act synergistically to induce MM cell death [28,30]. In in vitro experiments, pretreatment of peripheral blood mononuclear cells with 2 µM pomalidomide increased isatuximab-induced ADCC of CD38-positive MM cells from below 40% to above 80%. Also, isatuximab-induced cytotoxicity was significantly increased in the presence of pomalidomide (p < 0.001) in six patient-derived MM cell lines [30]. In in vivo experiments using an MOLP-8 MM mouse xenograft model, the combination of isatuximab and pomalidomide resulted in enhanced antitumor activity with a treated-to-control ([T/C] value of 22%) compared with the activity of isatuximab (T/C value of 56%) and pomalidomide alone (T/C value of 46%), without affecting body weight [28].

3.1. Pharmacodynamics, pharmacokinetics, and metabolism of isatuximab

During the first-in-human, dose-escalation Phase I/II study (ClinicalTrials.gov identifier: NCT01084252), the concentrations of isatuximab were below the lower limit of quantification for most time points at 0.0001 to 0.03 mg/kg doses. Following the first administration at doses from 1 to 20 mg/kg every other week (Q2W), isatuximab area under the curve up to the last measurable concentration (AUC_last) increased more than proportionally by 163-fold over the 20-fold increase in dose, suggesting the presence of target-mediated drug disposition. Between the two highest doses of 10 and 20 mg/kg, there was a 3.2-fold increase. Following 10 to 20 mg/kg weekly (QW) doses, there was a 1.9-fold (C_max) to 2.3-fold (C_trough) accumulation at Cycle 3. Accumulation was of the same magnitude based on the area under the curve over a 1-week dosing interval (AUC_1week), with 1.7- to 2.6-fold accumulation [38,39].

The isatuximab recommended dose and schedule is four QW doses for the first cycle, followed by Q2W doses for subsequent cycles to overcome target elimination and reach the optimal target saturation [40]. Isatuximab achieves a high level of CD38 receptor occupancy on plasma cells, reaching a plateau of 80% with isatuximab 20 mg/kg (highest dose tested) [38].

Isatuximab does not affect the pharmacokinetics or activity of co-administered anti-myeloma agents, including dexamethasone, pomalidomide, lenalidomide, and cyclophosphamide [38,41]. Pharmacokinetic and pharmacodynamic analyses determined that 20 mg/kg QW/Q2W isatuximab was optimal for monotherapy and 10 mg/kg QW/Q2W isatuximab was appropriate for combination therapy [38].

Because isatuximab is a mAb, its metabolism is expected to be limited to proteolytic catabolism of small peptides and individual amino acids; hence, no metabolism or excretion studies have been conducted.

3.2. Clinical efficacy of isatuximab

Isatuximab was assessed as monotherapy and in combination with Pd in RRMM (Table 1 and Table 2). Outcomes of the isatuximab Phase I–III clinical trials have been described in detail elsewhere [28].

Table 1. Selected published clinical trials assessing isatuximab for the treatment of relapsed/refractory multiple myeloma

Clinical trial	Phase	Design	Population	Key messages	Reference
NCT02283775	Ib	Isatuximab + Pd administered from a fixed infusion volume	RRMM patients who had received ≥2 prior lines of therapy, including R and a PI, and demonstrated PD	ORR = 53% IR = 40%	[46]
NCT01749969	Ib	Isatuximab + Rd	RRMM patients who had received ≥2 prior lines of therapy, and demonstrated PD	ORR = 56% IR = 56%	[56]
NCT01084252	I/II	Assess DLT and ORR of isatuximab monotherapy	RRMM patients who had PD on therapy including an IMiD and a PI	ORR^a = 24% IR^a = 47%	[38]
NCT02990338(ICARIA)	III	Isatuximab + Pd vs Pd	RRMM patients who had received ≥2 prior lines of therapy, including R and a PI, and demonstrated PD	Isa-Pd vs Pd PFS = 11.5 mo vs 6.5 mo ORR = 60.4 vs 35.2% IR = 38% vs 0%	[47]
NCT03275285(IKEMA)	III	Isatuximab + Kd vs Kd	RRMM patients who had received 1–3 prior lines of therapy	Isa-Kd vs Kd PFS = NR vs 19.2 mo ORR = 86.6% vs 82.9% IR = 45.8% vs 3.3%	[55]

^aIn patients receiving isatuximab ≥ 10 mg/kg dose.

d – low-dose dexamethasone; DLT – dose-limiting toxicity; IMiD – immunomodulatory drug, IR – infusion reaction; K – carfilzomib; mo – months; NR – not reached; ORR – overall response rate; P – pomalidomide; PD – progressive disease; PFS – progression-free survival; PI – proteasome inhibitor; R – lenalidomide; RRMM – relapsed/refractory multiple myeloma.

Table 2. Clinical trials assessing isatuximab in patients with relapsed/refractory multiple myeloma

Clinical trial	Phase	Treatment	Objectives	Status
NCT03733717	I	Isatuximab monotherapy	Assess safety, tolerability and PK of isatuximab in Chinese patients	Active, not recruiting
NCT02514668	I	Isatuximab monotherapy	Assess ORR, tolerability and safety of isatuximab in patients who had previously received daratumumab	Active, not recruiting
NCT04045795	Ib	Isatuximab IV + Pd; Isatuximab SC + Pd	To assess the tolerability and safety of isatuximab SC vs IV. To evaluate the PK of isatuximab SC and IV	Recruiting
NCT02812706	I/II	Isatuximab monotherapy	Assess DLT and ORR of isatuximab monotherapy in Japanese patients	Active, not recruiting
NCT03194867	I/II	Isatuximab + cemiplimab (anti-PD-1)	To evaluate safety and tolerability of isatuximab and cemiplimab. To compare ORR based on IMWG criteria	Active, not recruiting
NCT04083898^a	I/II	Isatuximab + BPr	MTD of isatuximab (Phase I) or recommended Phase II dose and ORR	Not yet recruiting

^aSponsored by Sanofi in collaboration with Washington University School of Medicine.

B – bendamustine; d – low-dose dexamethasone; DLT – dose-limiting toxicity; IMWG – International Myeloma Working Group; IV–intravenous; MTD – maximum tolerated dose; ORR – overall response rate; P – pomalidomide; PD-1 – programmed cell death-1; PK – pharmacokinetics; Pr – prednisone; SC – subcutaneous.

In the first-in-human Phase I/II study (ClinicalTrials.gov identifier: NCT01084252), isatuximab was evaluated as a single agent for the treatment of RRMM [38,42,43]. Briefly, a dose-escalation investigation assessed the maximum tolerated dose of isatuximab monotherapy in 84 patients with RRMM who were experiencing advancement of their disease during or post-current therapy. The isatuximab dosage ranged from 0.0001 to 20 mg/kg QW or Q2W [44]. The maximum tolerated dose of isatuximab was not attained, as no cumulative adverse events (AEs) were detected. After the dose-escalation phase, two groups of patients were further evaluated for their response to therapy, with standard- and high-risk patients in expansion group 1 and high-risk patients in expansion group 2. In this study, high-risk patients were defined as those who had del(17p), gain(1q), t(4;14), t(14;16), or a relapse of the disease within 6 months of autologous stem cell transplant. Patients in both expansion groups received isatuximab at 10 mg/kg Q2W. In patients given ≥10 mg/kg, the overall response rate (ORR) was 23.8% and in high-risk patients, the ORR was 16.7% (Table 1) [38].

An open‐label, single‐arm, multicenter Phase I/II trial (ClinicalTrials.gov identifier: NCT02812706) investigated the safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated RRMM (3 or more prior lines), and who were refractory to an IMiD and a PI [45]. In Phase I, patients were sequentially assigned to receive two doses of isatuximab: 10 mg/kg QW/Q2W (n = 3) or 20 mg/kg QW/Q2W (n = 5). No dose‐limiting toxicities occurred during Phase I, and the recommended dose for the single‐arm Phase II was 20 mg/kg QW/Q2W. The ORR was 36.4% and the median progression-free survival (PFS) was 4.7 (95% CI 3.75−not reached) months. Median overall survival (OS) was not reached (Table 1)[45].

The open-label, multicenter, two-part, Phase Ib study (NCT02283775) showed positive results with the administration of 10 mg/kg of isatuximab as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd. Median durations of the first, second, and ≥3 infusions of isatuximab were 3.7, 1.8, and 1.2 hours, respectively. The ORR was 53.2% in all patients; median PFS and OS were not reached. The one-year probability of PFS was 56% (95% CI: 40–69%), and of OS was 71% (95% CI: 54–82%), respectively (Table 1) [46].

The pivotal Phase III ICARIA-MM study (ClinicalTrials.gov identifier: NCT02990338) was a prospective, multicenter, randomized, open-label, trial evaluating the efficacy of isatuximab combined with Pd (Isa-Pd) compared with Pd for the treatment of patients with RRMM who had received at least two prior lines of therapy, including lenalidomide and a PI alone or in combination, and have demonstrated disease progression on or within 60 days of completion of the last therapy. A total of 307 patients were randomly assigned in a 1:1 ratio to receive Isa-Pd (n = 154) or Pd (n = 153). Isatuximab was administered at 10 mg/kg QW/Q2W intravenously (IV). Pomalidomide was administered at 4 mg per day for 21 days of each 28-day cycle, and dexamethasone at 40 mg QW (or 20 mg QW in patients ≥75 years) via oral or IV on Day 1, 8, 15, and 22 in each cycle. Median PFS was 11.5 months (95% confidence interval [CI]: 8.9–13.9) with Isa-Pd vs 6.5 months (95% CI: 4.5–8.3) with Pd; hazard ratio (HR) 0.60 (95% CI: 0.44–0.81); p = 0.001. ORR was 60.4% with Isa-Pd vs 35.3% with Pd (p < 0.0001) (Table 1) [47].

Overall, the ICARIA-MM study population was representative of the global population with RRMM, including important subgroups of patients with poor prognostic characteristics. Subgroup analyses of ICARIA-MM showed that the PFS benefit with Isa-Pd was maintained in patients: (i) ≥75 years of age (4.5 to 11.4 months; HR 0.48; 95% CI: 0.24–0.95) [48]; (ii) with renal impairment (3.7 to 9.5 months; HR 0.50; 95% CI: 0.30–0.85) [49]; (iii) with high-risk cytogenetic abnormalities (3.8 to 7.5 months; HR 0.66; 95% CI: 0.33–1.28) [50]; (iv) with ≥3 prior lines of treatment (5.9 to 11.4 months; HR 0.62; 95% CI: 0.44–0.89) [51]; and (v) with soft-tissue plasmacytomas (1.6 to 4.6; HR 0.22; 95% CI: 0.07–0.69) [52].

A subgroup analysis of the ICARIA-MM study analyzed data from 36 East Asian patients (21 Isa-Pd vs 15 Pd) whose characteristics were comparable with the whole ICARIA-MM cohort [53]. After a median follow-up of 11.6 months, ORR was 71.4% in the Isa-Pd arm and 60% in the Pd arm. The very good partial response or better rate was 61.9% vs 13.3% in the Isa-Pd arm vs Pd arm, respectively. The efficacy and tolerability of Isa-Pd were comparable with the whole ICARIA-MM cohort.

The Phase III IKEMA study (ClinicalTrials.gov identifier: NCT03275285) is a prospective, randomized, open-label trial that was designed to examine isatuximab in combination with carfilzomib/dexamethasone (Isa-Kd) vs carfilzomib/dexamethasone (Kd) alone in patients with relapsed MM who have been previously treated with 1–3 lines of therapy (Table 1) [54]. A pre-specified interim analysis was recently reported [55]. A total of 302 patients were randomized 3:2 to receive Isa-Kd (n = 179) or Kd (n = 123). The Isa-Kd arm received 10 mg/kg QW/Q2W of isatuximab IV and both arms received carfilzomib IV (20 mg/m² on Days 1–2, 56 mg/m² thereafter) twice-weekly for 3 of 4 weeks, and dexamethasone (20 mg) twice-weekly. Median PFS was not reached for Isa-Kd vs 19.2 months with Kd (HR 0.53; 99% CI: 0.32–0.89); one-sided p = 0.0007, crossing the pre-specified efficacy boundary (p = 0.005). Although the ORR was similar in both arms (86.6% with Isa-Kd vs 82.9% with Kd; one-sided p = 0.1930), deeper responses were seen with Isa-Kd. Numerically more patients in the Isa-Kd arm achieved a complete response or better rate (39.7% Isa-Kd vs 27.6% Kd) and very good partial response or better rate (72.6% Isa-Kd vs 56.1% Kd; descriptive p = 0.0011). Minimal residual disease negativity rate in the intent-to-treat population, at sensitivity level 10⁻⁵, was observed in 53 (29.6%) patients in the Isa-Kd arm vs 16 (13.0%) in the Kd arm; descriptive p = 0.0004 (Table 1) [55].

3.3. Safety and tolerability of isatuximab

Early-phase isatuximab monotherapy trials demonstrated a clinically favorable safety profile in patients with MM. The overall safety profile of isatuximab is consistent with its biological class, route of administration, and mode of action [38,42,43]. The most common non-hematologic AEs with isatuximab monotherapy were infusion reactions ([IRs] 51%), fatigue (37%), nausea (32%), upper respiratory tract infections (24%), and cough (23%) [38]. The most common Grade 3–4 hematologic laboratory abnormalities with isatuximab monotherapy were lymphopenia (34%), anemia (20%), thrombocytopenia (17%), and neutropenia (12%) [38]. Discontinuation of treatment due to AEs was reported in 4–16% of patients in clinical studies of isatuximab, with IRs being responsible for <10% of treatment discontinuations [38,42,43]. The AEs associated with isatuximab in combination with standard-of-care therapies demonstrate minimal incremental toxicity to the known safety profile of the individual agents. In a Phase Ib study (ClinicalTrials.gov identifier: NCT01749969), the combination of isatuximab with Rd (Isa-Rd) showed the following most common non-hematologic AEs: IRs (56%), diarrhea (53%), fatigue (49%), upper respiratory tract infection (40%), and nausea (35%) (Table 1) [56].

In a Phase Ib study (ClinicalTrials.gov identifier: NCT02283775), the use of Isa-Pd resulted in the following most common non-hematologic AEs with Isa-Pd: fatigue (64%), IRs (40%), upper respiratory tract infection (40%), and cough (40%) (Table 1) [46].

In the Phase III ICARIA-MM study, Isa-Pd demonstrated a manageable safety profile in patients with RRMM (Table 1) [47]. AEs of any grade occurred in 99.3% of patients in the Isa-Pd arm vs 98.0% in the Pd arm. Grade ≥3 AEs were observed in 86.8% patients (Isa-Pd) vs 70.5% (Pd); 7.2% (Isa-Pd) and 12.8% (Pd) of patients discontinued due to AEs. The most frequent AEs (any grade) were IRs (38% Isa-Pd vs 0% Pd), upper respiratory tract infections (28% Isa-Pd vs 17% Pd), diarrhea (26% Isa-Pd vs 20% Pd), bronchitis (24% Isa-Pd vs 9% Pd), and pneumonia (20% Isa-Pd vs 17% Pd). Grade ≥3 IRs were reported in 2.6% of patients in the Isa-Pd arm and no delayed IRs were reported. The most common hematologic laboratory abnormalities (any grade) were neutropenia (96% Isa-Pd vs 93% Pd), thrombocytopenia (84% Isa-Pd vs 80% Pd), and anemia (99% Isa-Pd vs 99% Pd). Neutropenia and infections were reversible and manageable with granulocyte colony-stimulating factors and antibiotics [47]. The clinically relevant leukopenia observed with Isa-Pd requires monitoring and intervention.

In the Phase III IKEMA study, Grade ≥3 AEs were observed in 76.8% of patients in Isa-Kd vs 67.2% in Kd. Serious AEs and fatal AEs were comparable in Isa-Kd and Kd: 59.3% vs 57.4% and 3.4% vs 3.3%, respectively. IRs were reported in 45.8% (Grade 3–4, 0.6%) patients in Isa-Kd and 3.3% (Grade 3–4, 0%) patients in Kd. Grade ≥3 respiratory infections and cardiac failure were observed in 32.2% Isa-Kd vs 23.8% Kd and 4.0% Isa-Kd vs 4.1% Kd, respectively. As per laboratory results, Grade 3–4 thrombocytopenia and neutropenia were reported in 29.9% Isa-Kd vs 23.8% Kd and 19.2% Isa-Kd vs 7.4% Kd, respectively (Table 1) [55].

In the ICARIA-MM and IKEMA Phase III trials, the majority of IRs occurred at first infusion and were reversible [47,55]. Standard prophylaxis for isatuximab IRs consisted of acetaminophen (650–1000 mg oral), ranitidine (50 mg IV or equivalent), and diphenhydramine (25–50 mg IV or equivalent). However, on 1 April 2020, the FDA requested the removal of all ranitidine products from the market and is no longer available [57]. As so, ranitidine is no longer recommended and has been removed from the investigator brochure. Dexamethasone 40 mg QW (or 20 mg QW in patients ≥75 years) via oral or IV was administered as part of premedication and study treatment. Patients who did not experience an IR upon their first four isatuximab administrations had their need for subsequent premedications reconsidered as per investigator judgment. No post-infusion corticosteroid or bronchodilator prophylaxis was mandated during isatuximab clinical studies [38,42,43,47,55,58].

3.4. Regulatory affairs

Based on the pivotal Phase III ICARIA-MM study, Sarclisa® (isatuximab-irfc) was first approved in the U.S. on 2 March 2020 in combination with Pd for the treatment of adults with RRMM who have received at least two prior therapies, including lenalidomide and a PI. To date, Isa-Pd has also been approved in Europe, Switzerland, Canada, Australia, Japan, and Russia for the treatment of adults with RRMM [19,59,60].

4. Conclusion

Isa-Pd provides clinical benefit in patients with RRMM, as demonstrated by significant increases in PFS and ORR, and a decrease in the risk of disease progression or death. Furthermore, Isa-Kd resulted in a superior, statistically significant improvement in PFS with clinically meaningful improvement in depth of response in patients with relapsed MM. Importantly, isatuximab is well tolerated with IR being the most common AE. However, the majority of IRs are Grade 1 or 2, occur during the first infusion, and can be managed with premedication. Finally, isatuximab administration can be progressively increased to deliver infusions after the third infusion in 1.2 hours (75 minutes). Studies of isatuximab in combination with other agents to treat RRMM are currently underway.

5. Expert opinion

Isa-Pd was recently approved for the treatment of RRMM. This is an important addition to the treatment options for patients with RRMM and it is likely to have an impact, particularly as triplet therapy in PI- and lenalidomide-refractory patients, a population reflecting clinical practice. Subgroup analyses of ICARIA-MM support the use of this regimen in patients with poor prognostic factors, such as age ≥75 years, renal impairment, high-risk cytogenetic abnormalities, ≥3 prior lines of treatment, and soft-tissue plasmacytomas. Furthermore, isatuximab has a manageable safety profile as demonstrated by low discontinuation rates. A subcutaneous formulation of isatuximab is being developed and tested in combination with Pd in a Phase Ib study (ClinicalTrials.gov identifier: NCT04045795, Table 2).

Isatuximab can be differentiated from daratumumab in several aspects. First, these mAbs bind to distinct epitopes of human CD38 [28]. There are several mechanistic differences between isatuximab and daratumumab described above in the introduction to isatuximab. Isatuximab does not require post-infusion corticosteroid or bronchodilator prophylaxis, but daratumumab does. The approved isatuximab infusion rate starting at the third and following infusions is 1.2 hours [46], vs the approved daratumumab infusion rate starting at the third infusion being about 3 hours, with a recently published accelerated infusion rate of 1.5 hours [61]. Both mAbs bind to CD38 on red blood cells and may result in a false-positive indirect antiglobulin test ([IAT], indirect Coombs test). Although routine blood screening during GEN501 and SIRIUS studies revealed that all patients receiving daratumumab showed false-positive IAT results [62,63], in ICARIA-MM, the IATs were positive during isatuximab treatment in 67.7% of the 99 tested patients [47].

It remains to be established if isatuximab will be effective in patients who become refractory to daratumumab and vice versa. Data are forthcoming regarding isatuximab monotherapy in very heavily pretreated RRMM patients refractory to daratumumab (ClinicalTrials.gov identifier: NCT02514668, Table 2). The Phase Ib, part B study (ClinicalTrials.gov identifier: NCT02283775, Table 1) of Isa-Pd administered by a fixed-volume infusion method in RRMM enrolled 7 (out of 47) patients with prior daratumumab exposure. All seven patients were refractory to daratumumab and none of the patients received daratumumab as the last regimen. Of those, six patients were evaluable for response at interim data analysis: one had partial response, two had minimal response, and three had stable disease [46].

Another ongoing study (ClinicalTrials.gov identifier: NCT04045795, Table 2) of the approved Isa-Pd combination therapy allowed the enrollment of patients previously exposed to daratumumab, and its results will be informative. Likewise, 6 of 60 (10%) patients with subsequent therapy in the ICARIA-MM Isa-Pd arm and 10 of 47 (21.3%) patients with subsequent therapy in the IKEMA Isa-Kd arm had started subsequent daratumumab at the time of their respective analyses [47,55], and their outcomes will be available at updated analyses of these Phase III trials.

Further long-term efficacy and safety data are required for Isa-Pd for the treatment of adult patients with RRMM who have received at least two prior therapies, including lenalidomide and a PI. The efficacy of isatuximab in combination with other MM drugs, such as bortezomib, thalidomide, and selinexor, is under evaluation with a number of studies planned or underway.

More data are also required regarding the efficacy and safety of isatuximab therapy as first-line treatment. Data are needed for patients with NDMM who are eligible and not eligible for ASCT. Table 3 shows ongoing isatuximab trials in NDMM patients, and we will discuss the Phase III trials in more detail. Specifically, the IMROZ study (ClinicalTrials.gov identifier: NCT03319667) is evaluating isatuximab in combination with bortezomib/lenalidomide/dexamethasone in transplant-ineligible patients with NDMM. An investigator-sponsored trial (University of Heidelberg Medical Center), the GMMG HD7 study (ClinicalTrials.gov identifier: NCT03617731), is examining isatuximab in combination with bortezomib/lenalidomide/dexamethasone in transplant-eligible patients with NDMM. The ITHACA study (ClinicalTrials.gov identifier: NCT04270409) is investigating isatuximab combined with lenalidomide/dexamethasone in patients with high-risk smoldering MM. Finally, the recently opened IsKia trial (ClinicalTrials.gov identifier: NCT04483739), sponsored by the European Myeloma Network, was designed to evaluate the combination of isatuximab with carfilzomib/lenalidomide/dexamethasone in NDMM patients eligible for autologous stem cell transplantation (Table 3).

Table 3. Ongoing clinical studies assessing isatuximab in previously untreated MM patients

Clinical trial	Phase	Patients	Treatment	Objectives
NCT02513186	I	NDMM ineligible for transplant	Isatuximab + VCd; Isatuximab + VRd	To determine MTD and recommended dose of isatuximab when given in combination with VCd. To assess ORR and CRR of isatuximab + VCd and +VRd
NCT02960555^a	II	High-risk smoldering myeloma	Isatuximab monotherapy	Determine the rate of response according to IMWG criteria of isatuximab monotherapy
NCT03104842^b	II	NDMM with HRCA	Isatuximab + KRd	To determine MRD negativity (~1 year from 1^st administration)
NCT03319667(IMROZ)	III	NDMM ineligible for transplant	Isatuximab + VRd vs VRd	To demonstrate the benefit of isatuximab + VRd in prolonging PFS compared with VRd
NCT03617731^c (GMMG HD7)	III	NDMM eligible for transplant	Isatuximab + VRd vs VRd, then maintenance with Isatuximab + R vs R	To demonstrate the benefit of isatuximab + VRd in terms of MRD negativity and PFS
NCT04270409 (ITHACA)	III	High-risk smoldering myeloma	Isatuximab + Rd vs Rd	To confirm the recommended dose of isatuximab when given in combination with Rd and to demonstrate the clinical benefit of isatuximab + Rd in high-risk smoldering MM
NCT04483739 (IsKia)^d	III	NDMM eligible for transplant	Isatuximab + KRd vs KRd	To demonstrate the benefit of isatuximab + KRd in terms of MRD negativity after ASCT consolidation

^aInvestigator-sponsored trial (M.D. Anderson Cancer Center in collaboration with the National Cancer Institute). ^bInvestigator-sponsored trial (University Hospital Tuebingen). ^cInvestigator-sponsored trial (University of Heidelberg Medical Center). ^dInvestigator-sponsored trial (European Myeloma Network).

ASCT – autologous stem cell transplantation; C – cyclophosphamide; CRR – complete response rate; d – low-dose dexamethasone; HRCA – high-risk cytogenetic abnormalities; IMWG – International Myeloma Working Group; K – carfilzomib; NDMM – newly diagnosed multiple myeloma; MRD – minimal residual disease; MTD – maximum tolerated dose; MM – multiple myeloma; ORR – overall response rate; PFS – progression-free survival; R – lenalidomide; V – bortezomib.

The use of isatuximab as maintenance therapy following treatment with Isa-Pd in both the NDMM and RRMM settings would be welcome. Data from real-world clinical settings would also be very useful to assess the effectiveness and tolerability of isatuximab in clinical practice, with current Phase 3 results suggesting translation from clinical studies to community practice will be robust, but this will require confirmation [64]. To this end, the IONA-MM trial (ClinicalTrials.gov identifier: NCT04458831) is a prospective, non-interventional, observational study of RRMM patients treated with isatuximab in routine clinical practice. This study will enroll approximately 1100 RRMM patients across 100–125 sites in Asia, Europe, Latin, and North America.

In the near future, the results of Phase III randomized trials will further the importance of isatuximab combination therapy with other anti-MM agents for the treatment of late- and early-line MM patients. These data should in turn inform how to best position this potent mAb after prior CD38-targeting therapy and in the context of later salvage, as part of combination approaches to improve patient outcome.

Box 1. Drug summary

Table

Drug name:	Isatuximab
Phase:	Launched
Indication:	Relapsed/refractory multiple myeloma
Pharmacology description/mechanism of action:	A CD38 targeted monoclonal antibody
Route of administration:	Intravenous
Pivotal trial:	Phase III ICARIA-MM study: isatuximab in combination with pomalidomide/dexamethasone [47]

Article highlights

• The monoclonal antibody isatuximab binds to a specific epitope on CD38 and induces multiple myeloma cell death by various mechanisms.

• In this indication, isatuximab can be administered as a 250 mL fixed-volume infusion with a median infusion time of 75 minutes for the third and subsequent infusions.

• The Phase III IKEMA study showed superior efficacy of isatuximab in combination with carfilzomib/dexamethasone vs carfilzomib/dexamethasone alone in patients with relapsed multiple myeloma who have been previously treated with 1–3 lines of therapy.

• Isatuximab is well tolerated. Infusion reactions are the most common adverse event, but the majority are Grade 1 or 2, occur during the first infusion, and can be managed with premedication.

• In the near future, the results of Phase III randomized trials will further the importance of isatuximab combination therapy with other anti-myeloma agents for the treatment of late- and early-line multiple myeloma patients, and how to best position this potent monoclonal antibody after prior CD38-targeting therapy and in the context of later salvage as part of these combination approaches.This box summarizes key points contained in the article.

Declaration of interest

PG Richardson: research funding from Bristol Myers Squibb, Celgene, Oncopeptides, and Takeda; honoraria from Celgene, Janssen, Karyopharm, Oncopeptides, Sanofi and Takeda. M Beksaç: honoraria from Amgen, Celgene, Janssen, and Takeda. I Špička: honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, Sanofi, and Takeda. J Mikhael: honoraria from Amgen, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Acknowledgments

Medical writing support was provided by Camile Semighini Grubor, PhD of Elevate Medical Affairs, contracted by Sanofi Genzyme for publication support services.

Additional information

Funding

This paper was funded by Sanofi Genzyme.