An evaluation of isatuximab, pomalidomide and dexamethasone for adult patients with relapsed and refractory multiple myeloma

Anna Piggin & H. Miles Prince

To cite this article: Anna Piggin & H. Miles Prince (2021) An evaluation of isatuximab, pomalidomide and dexamethasone for adult patients with relapsed and refractory multiple myeloma, Expert Review of Hematology, 14:5, 419-427, DOI: 10.1080/17474086.2021.1924052
To link to this article: https://doi.org/10.1080/17474086.2021.1924052

Published online: 16 May 2021.

Submit your article to this journal

Article views: 90
View related articles View Crossmark data

Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierr20

EXPERT REVIEW OF HEMATOLOGY 2021, VOL. 14, NO. 5, 419–427

https://doi.org/10.1080/17474086.2021.1924052

DRUG PROFILE
An evaluation of isatuximab, pomalidomide and dexamethasone for adult patients with relapsed and refractory multiple myeloma
Anna Piggina,b and H. Miles Princea,b
aMolecular Oncology and Cancer Immunology, Epworth Healthcare, Melbourne, Australia; bDepartment of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia

ARTICLE HISTORY
Received 3 February 2021
Accepted 26 April 2021
KEYWORDS
Isatuximab; pomalidomide; relapsed myeloma; refractory myeloma; multiple myeloma

1. Introduction
Despite therapeutic advances, myeloma remains an essen- tially incurable disease, with relapse inevitable and a median survival of approximately 8 − 10 years [1]. Most patients receive at least four lines of therapy during their disease course [2], and the majority will develop disease that is refractory to immunomodulatory agents (IMiDs) such as lenalidomide and pomalidomide, and proteasome inhibitors (PIs) including bortezomib, carfilzomib and ixa- zomib. Consequently, treatment regimens containing drugs with different mechanisms of action are necessary. This unmet clinical need is highlighted by the fact that patients with myeloma refractory to lenalidomide and PIs have an approximate survival of only 15 months [3].
Isatuximab is one such novel drug, a monoclonal anti- body (MoAb) targeting CD38, and is the second drug in this class after daratumumab. This paper will consider the current role for isatuximab with pomalidomide and dexa- methasone for the treatment of relapsed/refractory mye- loma (RRMM). Evidence for the use of daratumumab in RRMM patients, as well as in the up-front setting, will also be discussed, as a current important consideration is where to place isatuximab in the treatment algorithm in the face of increasing numbers of patients exposed to anti- CD38 therapy.

1.1. Treatment approach in relapsed/refractory myeloma
Treatment options for RRMM are broad. Treatment decisions need to balance factors such as kinetics of relapse, presence of comorbidities, performance status, nature and tolerance of prior therapies, high risk biological features (in particular, high-risk cytogenetic features as well as other poor prognostic indicators such as renal failure and extramedullary myeloma), and patient preference. Regional regulatory approval is another necessary consideration with many countries parti- cularly limiting combinations of high-cost drugs. Close mon- itoring may be the most appropriate option for biochemically relapsed disease which is asymptomatic, progressing slowly, and which is not in the early post-transplant/initial therapy period [2], while clinically relapsed disease generally warrants therapy.
Triplet therapy, generally defined as a combination of two biological agents (IMiD, PI or MoAb) plus a steroid (typically dexamethasone), is generally utilized at first relapse in patients who are able to tolerate this, with improved clinical outcomes demonstrated in multiple clinical trials and meta-analyses [2]. The best choice and sequencing of regimens with subse- quent relapses is not clearly defined, and in the absence of randomized controlled trial data, the general approach has been to prescribe various regimens sequentially based on

© 2021 Informa UK Limited, trading as Taylor & Francis Group

and dexamethasone; and ixazomib, lenalidomide and dex- amethasone [5].
At the time of publication of van Beurden’s [5] systema- tic review, isatuximab phase III trial data was not available for inclusion. ICARIA-MM is the first such phase III trial, and compared isatuximab, pomalidomide and dexamethasone to pomalidomide and dexamethasone alone in heavily pre- treated patients with RRMM [6]. Although no direct com- parative trials exist between therapies, particularly between isatuximab- and daratumumab-based therapies, the most appropriate place for such regimens in the sequence of treatments for RRMM needs to be considered.

factors including availability, prior therapies, and toxicity pro- files. For example, patients initially treated with a lenalidomide-based regimen can be effectively treated at first relapse with PI-based therapy, and conversely those who relapse after PI-based therapy can receive an IMiD-based regi- men [4].
Overall, given the large number of possible therapeutic agents and regimens, and lack of direct comparison of these in the RRMM setting, clinicians are faced with diffi- cult choices when managing patients with RRMM. A systematic review and network meta-analysis by van Beurden and colleagues [5] in 2017 aimed to compare and rank all available therapies for RRMM at that time with available evidence from phase III randomized con- trolled trials, in order to guide evidence-based decision- making in this setting. In total, 17 randomized controlled trials of 18 treatment regimens were included. The median age of patients included in these studies ranged from 59 to 71 years, and had received a median of 2 (range 1–11) prior therapies. A network meta-analysis using hazard ratios (HRs) for progression-free survival (PFS) was per- formed, with comparisons made between novel treatment regimens against dexamethasone alone, lenalidomide and dexamethasone, and bortezomib and dexamethasone. Considerations of adverse event profiles and quality of life measurements were not included in this meta- analysis. This study identified daratumumab, lenalidomide and dexamethasone triple therapy as the most favorable treatment in the RRMM setting in terms of PFS (HR 0.13; 95% CI 0.09–0.19), in comparison with dexamethasone alone based on the POLLUX study (see below). A further
4 treatment regimens were categorized as being equal ‘second-best’ options after daratumumab, lenalidomide and dexamethasone, and were, in random order; daratu- mumab, bortezomib and dexamethasone; carfilzomib, lena- lidomide and dexamethasone; elotuzumab, lenalidomide

2. Introduction to isatuximab
2.1. Pharmacodynamics
CD38 is a type II transmembrane glycoprotein, widely expressed on human tissues, including plasma cells, NK cells, and other subsets of lymphoid and myeloid cells, as well as on malignant plasma cells in patients with mye- loma [7,8].
Isatuximab is a chimeric immunoglobulin (Ig) IgG kappa MoAb which targets a specific epitope of CD38, distinct from the epitope targeted by daratumumab. Isatuximab has multi- ple mechanisms of action for killing plasma cells, including antibody-dependent cellular cytotoxicity and phagocytosis, complement-dependent cytotoxicity and tumor cell apoptosis. CD38 is also a multifunctional ectoenzyme, with catabolic substrates including nicotinamide adenine dinucleotide (NAD
+) and nicotinamide adenine dinucleotide phosphate (NADP) [8]. Inhibition of these enzymatic activities results in increased intracellular NAD+, which may have anti-myeloma activity in conjunction with other therapies such as bortezomib, and may also contribute to autophagic cell death [9].

2.2. Pharmacokinetics and metabolism
Pharmacokinetic modeling in the early stage of drug devel- opment for isatuximab demonstrated a clearance pattern common in IgG therapeutic MoAbs, with a two- compartment model with parallel linear and non-linear elimination from the central compartment [10]. The clear- ance mechanism for isatuximab is likely to be via protein catabolic pathways, with minimal contribution from renal or hepatic clearance [11]. Following administration at the recommended dose and schedule, the maximum predicted plasma concentration (Cmax) at steady state is 351 μg/ml (36%), and area under the plasma concentration–time curve (AUC) 72,600 μg.h/mL (51.7%). The mean predicted total volume of distribution is 8.13 L. The median time to reach steady state is approximately 8 weeks, and the time to near complete (≥99%) elimination after the last dose predicted to be approximately 8 weeks also [11].

Fau et al. [10] performed comprehensive population phar- macokinetic modelling based on early phase studies of isatux- imab, including single-agent phase I/II studies, as well as phase I, Ib and III studies with isatuximab plus pomalidomide and dexamethasone in patients with RRMM. The linear clear- ance in a typical patient was demonstrated to decrease over time, with an approximately 50% reduction in clearance between treatment start date, and 6 weeks into treatment. Variables such as age, renal or liver function, body weight, sex, Asian race, β2-microglobulin level, and prior lines of therapy appeared not to significantly affect the elimination models. The most influential variable in the pharmacokinetic modelling with respect to drug elimination was M-protein Ig isotype, specifically IgG vs. non-IgG isotype; patients with IgG M-protein demonstrated an almost twofold higher clearance rate of isatuximab compared to patients with non-IgG M-protein. Consequently, patients with non-IgG M-proteins were predicted to have approximately twofold higher drug exposure at steady state compared to patients with IgG M-protein [10].

2.3. Laboratory test interference
An important consideration with the use of anti-CD38 MoAbs in the treatment of myeloma is the interference with two common laboratory assays, namely 1) serological pre-transfusion testing, and 2) serum protein electrophor- esis in disease response assessments.
CD38 is expressed on red blood cells, and a consequent class effect of anti-CD38 MoAbs is interference with sero- logical pre-transfusion testing [12]. Neither isatuximab nor daratumumab interfere with ABO/RhD typing, but can cause false-positive results in indirect antiglobulin testing (indirect Coombs test), and antibody screening and identi- fication panels. Current recommended practice is to per- form extended red cell antigen phenotyping and consider genotyping in patients prior to commencing therapy with anti-CD38 MoAbs, to allow the issue of phenotype– or genotype-matched blood products [13]. In addition, anti- body screening can be performed if required with the use of dithiotreitol-treated red cell panels. Good communica- tion between the clinical team and transfusion laboratory is essential, ideally prior to commencing therapy, allowing formal documentation that the patient is to receive anti- CD38 MoAb therapy, and to allow necessary testing as outlined above. Patients should also receive an ‘alert card’ to carry, informing treating healthcare practitioners that they are receiving anti-CD38 therapy.
Isatuximab, like other IgG MoAbs, can be detected in serum protein electrophoresis and immunofixation assays used to assess M-protein levels in patients with myeloma, in some cases causing false positives or making the quantification of M-protein difficult. Unpublished data indicates that isatuximab interference in electrophoresis and immunofixation in the ICARIA-MM study resulted in under-estimation of complete response in 10.8% of patients in the isatuximab arm. Techniques to overcome this interference, including high-

resolution mass spectrometry assays, are being investigated but are not yet widely applied [14].

3. Clinical efficacy of isatuximab
3.1. Phase I/II studies
Preclinical studies demonstrated potent anti-tumor activity of isatuximab in tumor models, including xenografts [15], provid- ing a rationale for clinical studies. Jiang and colleagues [16] also demonstrated that combining isatuximab with pomalido- mide in vitro augmented the direct and effector-cell mediated anti-tumor effects of isatuximab.
Early-phase clinical trials confirmed single-agent efficacy in patients with RRMM. Ninety-seven patients were treated with isatuximab monotherapy in a phase II dose-finding study [17], with an overall response rate (ORR) of 29.2% at the dose of 10 mg/kg every 2 weeks. These patients had received a median of 5 prior lines of therapy (range 2–14), with 85% being refractory to both IMiDs and PIs. An ORR of 40.9% (9/22 patients) was seen in those with high-risk cytogenetics.
A phase Ib dose–escalation study evaluated isatuximab (at 5 mg/kg, 10 mg/kg or 20 mg/kg) weekly for 4 weeks then ongoing every 2 weeks, in combination with pomalidomide and dexamethasone, in patients with RRMM who had received
≥2 prior therapies [18]. Forty-five patients were enrolled, with a median of 3 (range 1–10) prior therapies, and high rates of refractoriness (82% lenalidomide-refractory, and 84% PI- refractory). In this heavily pre-treated group, an encouraging ORR of 62% was achieved, with a median PFS of 17.6 months. Importantly, the toxicities were manageable, with fatigue (62%), dyspnea (40%), upper respiratory tract infections (42%) and infu- sion reactions (42%) being the most common adverse events, and mostly Grade 1–2. The most common ≥Grade 3 adverse event was pneumonia, which was seen in 17.8% of patients [18].

3.2. Phase III studies
3.2.1. ICARIA-MM; isatuximab, pomalidomide and dexamethasone
ICARIA-MM is the first phase III study which has shown a PFS benefit for an anti-CD38 therapy, specifically isatuximab, com- bined with pomalidomide and dexamethasone (Isa-Pd), versus pomalidomide and dexamethasone (Pd) alone. This is a multi- center, open-label randomized controlled trial, which recruited adult patients with RRMM who had received ≥2 prior therapies including lenalidomide and a PI. Patients were excluded if they had previously received, and were refractory to, an anti-CD38 therapy [6].
All patients were treated on a 28-day cycle, with pomalido- mide 4 mg orally administered on days 1–21 plus dexametha- sone 40 mg (20 mg in patients ≥75 years old) intravenously or orally on days 1, 8, 15 and 22. Patients randomized to the Isa- Pd arm also received isatuximab 10 mg/kg intravenously weekly (days 1, 8, 15, 22) in the first cycle, and every 2 weeks for subsequent cycles. Randomization also stratified patients by number of lines of treatment (2–3 versus >3) and

Table 1. Efficacy outcomes for ICARIA-MM phase III trial.
Isatuximab plus

56 in the Pd arm, HR 0.68 [95% CI 0.461–1.023]). The median was not reached in either group. Analysis of event-free survival

pomalidomide plus dexamethasone (n = 154)

Pomalidomide plus dexamethasone
(n = 153) Statistical significance

demonstrated an early and sustained separation of the Kaplan–Meier curves, demonstrating a 40% decrease in the risk of death or disease progression at 12 months in the Isa-Pd

Progression- free survival

11.5 months (95% CI 8.9–13.9)

6.5 months (95% CI 4.5–8.3)

HR 0.596 (95% CI
0.44–0.81); p = 0.001

group compared with the Pd group.
A prespecified subgroup analysis of ICARIA-MM examined efficacy in patients with renal impairment [19]. Unlike lenali-

Overall
response rate (n [%])
Very good partial response or better

93 (60%) 54 (35%) OR 2.795 (95% CI
1.75–4.56);
p = <0.0001

49 (32%) 13 (9%) OR 5.026 (95% CI
2.514–10.586);
p = <0.0001

domide, the metabolism of pomalidomide is not substan- tially affected by renal impairment. ICARIA-MM allowed inclusion of patients with mild or moderate renal impair- ment, with a cutoff eGFR of ≥30 mL/min/1.73 m2; 38.7%
and 33.8% of patients enrolled in ICARIA-MM in the Isa-Pd and Pd arms, respectively, had renal impairment. Overall, the

CI = confidence interval, HR = hazard ratio, OR = odds ratio

age (<75 years versus ≥75 years). Treatment was continued until progression, unacceptable toxicity, or consent withdra- wal. Dose reductions for toxicity were permitted for pomali- domide and dexamethasone, but not for isatuximab.
Between January 2017 and February 2018, 307 patients were recruited, with 154 randomized to Isa-Pd and 153 to Pd only. Median age was 67 years (interquartile range, IQR, 60–73) and median prior lines of therapy was 3 (IQR 2–4). All patients had previously received both lenalidomide and a PI. On recruitment, 93% were refractory to lenalidomide, and 76% to at least one PI [6].
Table 1 outlines the efficacy data at a median follow-up of
11.6 months. The primary endpoint of PFS based on an intention- to-treat analysis was a median 11.5 months (95% CI 8.9–-
13.9 months) for the Isa-Pd arm, and 6.5 months (4.5–8.3 months) in the Pd arm, with a HR 0.596 (95% CI 0.44–0.81; p = 0.001).
Importantly, the PFS benefit seen in the overall cohort occurred in all pre-specified subgroups, including age ≥ 75 years (HR 0.48 [95% CI 0.24–0.95]); those with >3 lines of prior therapy (HR 0.59 [0.36–0.98]); patients refractory to PIs (HR 0.58 [0.41–0.82]), lenalidomide (HR 0.59 [0.43–0.82]) or to
both PIs and lenalidomide (HR 0.58 [0.40–0.84]). Patients with highrisk cytogenetic markers of del(17p), t(4;14) and t(14;16), also demonstrated a trend toward improved PFS but this was not statistically significant (HR 0.66 [0.33–1.28]).
Secondary endpoints studied in ICARIA-MM were ORR, and OS (overall survival). Responses were assessed in the intention- to-treat population, by an independent central committee which was blinded to treatment allocation. ORR in the Isa-Pd arm was significantly higher, with 60% of patients achieving any response compared to 35% in Pd alone, with an odds ratio (OR) of 2.795 (95% CI 1.75–4.56). Very good partial response (VGPR) or better was achieved in 32% in the Isa-Pd arm compared with 9% in Pd alone (OR 5.026 [95% CI 2.514–- 10.586]). Eight patients (5%) in the Isa-Pd arm, versus none in the Pd arm, achieved minimal residual disease (MRD) nega- tivity by next-generation sequencing (NGS) molecular assay at a sensitivity level of 10−5.
An interim analysis of OS was performed at 12 months, at which time 99 deaths had occurred (43 in the Isa-Pd arm and

efficacy findings in patients with renal impairment were consistent with the findings in the study population as a whole. Median PFS in those with renal impairment was
9.5 months with Isa-Pd and 3.7 months with Pd alone (HR
0.50 [95% CI 0.30–0.85]). Median OS in patients with renal impairment was not reached in the Isa-Pd arm, and
11.6 months in the Pd arm (HR 0.53 [95% CI 0.30–0.96]). Patients with renal impairment had an ORR of 56.4% in the Isa-Pd arm, and 24.5% in the Pd arm (OR 3.98 [95% CI 1.60–- 10.17]). Isa-Pd also induced a complete renal response, according to IMWG criteria, in 71.9% of patients, versus 38.1% of those in the Pd arm. These are important findings given that renal impairment affects up to 50% of patients with myeloma [19], and that this cohort of patients are often excluded from clinical trials.

3.3. Safety and tolerability
Isa-Pd was well tolerated overall in the ICARIA-MM study [6], with the most frequent adverse events of any grade in the Isa- Pd versus Pd alone groups being infusion reactions (38% vs. 0%), diarrhea (26% vs. 20%) and upper respiratory tract infec- tions (28% vs.17%) (see Table 2).
Neutropenia occurred frequently in both groups (96% and 93% of patients in the Isa-Pd and Pd arms, respectively, but was more severe in the Isa-Pd arm, with 61% of patients experiencing Grade 4 neutropenia compared with 31% of patients in the Pd arm. Rates of anemia and thrombocytope- nia were similar between the groups.
The overall incidence of serious adverse events was 54% in the Pd arm and 62% in the Isa-Pd arm, and when adjusted for difference in treatment exposure, the event rate per patient year was not significantly different, being
1.30 and 1.36 in the Pd and Isa-Pd arms, respectively. One death due to a treatment-related adverse event was reported in the Isa-Pd arm (sepsis), and 2 in the Pd arm (pneumonia and urinary tract infection). In patients with renal impairment, the toxicity profile of Isa-Pd was similarly manageable; when adjusted for difference in exposure time, the rates of serious adverse events were similar in the Isa-Pd arm (1.90 per patient year) and the Pd arm (1.94 per patient-year) [19].

Table 2. Safety outcomes in ICARIA-MM phase III trial.
Isatuximab plus pomalidomide plus dexamethasone (n = 152) Pomalidomide plus dexamethasone (n = 149)
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
Most common adverse events
Infusion reaction 56 (38%) 2 (1%) 2 (1%) 0 0 0
Upper respiratory tract infection 43 (28%) 5 (3%) 0 26 (17%) 1 (<1%) 0
Diarrhea 39 (26%) 3 (2%) 0 29 (20%) 1 (<1%) 0
Bronchitis 36 (24%) 5 (3%) 0 13 (9%) 1 (<1%) 0
Pneumonia 31 (20%) 23 (15%) 2 (1%) 26 (17%) 20 (13%) 2 (1%)
Fatigue 26 (17%) 6 (4%) 0 32 (22%) 0 0
Back pain 25 (16%) 3 (2%) 0 22 (15%) 2 (1%) 0
Constipation 24 (16%) 0 0 26 (17%) 0 0
Asthenia 23 (15%) 5 (3%) 0 27 (18%) 4 (3%) 0
Dyspnea 23 (15%) 6 (4%) 0 15 (10%) 2 (1%) 0
Nausea 23 (1%) 0 0 14 (9%) 0 0
Hematological laboratory abnormalities (worst grade in evaluable patients)
Anemia 151/152 (99%) 48/152 (32%) 0 145/147 (99%) 41/147 (28%) 0
Neutropenia 146/152 (96%) 37/152 (24%) 92/152 (61%) 137/147 (93%) 57/147 (39%) 46/147 (31%)
Thrombocytopenia 127/152 (84%) 22/152 (15%) 25/152 (16%) 118/147 (80%) 14/147 (10%) 22/147 (15%)

To date, based on the results of the ICARIA-MM study, isatuximab is approved in multiple countries including USA, Europe, Canada, Australia, Japan and Russia, for use with pomalidomide plus dexamethasone in RRMM in adults who have received at least two prior therapies.

4. Daratumumab use in myeloma
Daratumumab was the first anti-CD38 MoAb developed. It is a monoclonal IgG kappa immunoglobulin, with mechanisms of action including antibody-dependent cellular cytotoxicity and phagocytosis, complement-dependent cytotoxicity, tumor cell apoptosis and modulation of CD38 enzymatic activ- ity. Daratumumab also has immunomodulatory effects such as enhancement of function of CD38+ tumor suppressor cells, and modulation of function of regulatory T and B cells [20,21]. The epitope targeted by daratumumab is slightly different to that targeted by isatuximab [22].
Daratumumab has clinical data supporting its use in both the relapsed and, increasingly, front-line setting, in combina- tion with various other therapies.

4.1. Daratumumab in relapsed/refractory myeloma
4.1.1. Daratumumab with pomalidomide and dexamethasone
Daratumumab has been evaluated in combination with poma- lidomide and dexamethasone in patients with RRMM. The EQUULEUS/MMY1001 trial is a multi-arm phase Ib study eval- uating daratumumab with various backbone therapies, includ- ing pomalidomide and dexamethasone (D-Pd) [22]. Eligible patients had received ≥2 prior lines of therapy, including ≥2 consecutive cycles with bortezomib and lenalidomide; were pomalidomide-naïve; and with a creatinine clearance ≥45 ml/ min. Daratumumab was given at a dose of 16 mg/kg on a standard intravenous schedule (weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks thereafter). 103 patients were recruited, with a median age of 64, including

22% of patients with high cytogenetic risk. Median prior lines of therapy was 4 (range 1–13). Overall, the study found that D-Pd was well tolerated, with a similar toxicity profile to Pd alone. The most common Grade 3 adverse events were neu- tropenia (78.6%), anemia (28%) and leukopenia (24%). At a median follow up of 28.1 months, ORR was 66% (95% CI 55.5–75.4%), including 13% stringent complete response (sCR) and 10% complete response (CR). VGPR or better was achieved in 48% of patients. MRD negativity at 10−5 sensitivity was achieved in 7% of patients. Median PFS was 9.9 months, and median OS 25.1 months.
The phase II MM-014 trial examined D-Pd in patients with relapsed/refractory disease after lenalidomide in first or second line treatment [23]. The ORR was 76% in lenalido- mide-refractory patients at a median follow up of 17.2 months, and the median PFS was not reached. The treatment was overall well-tolerated although 13% of patients experienced Grade 3/4 pneumonia. An important conclusion of this study was that pomalidomide is a well-tolerated and effective treat- ment option, even in those recently refractory to lenalidomide. Based on this promising early-phase clinical trial data, the phase III open-label, randomized multicenter APOLLO trial evaluated subcutaneous D-Pd versus Pd alone in RRMM patients who had received ≥1 prior line of therapy, including lenalidomide and a PI [24]. Patients with exposure to prior anti-CD38 therapy, or to pomali- domide, were excluded, as were patients with a creatinine clearance ≤30 ml/min. Patients with chronic obstructive pulmonary disease (COPD) were also excluded if their forced expiratory volume in 1 second
(FEV1) was <50% of predicted normal [25].
All patients received treatment on a 28-day cycle, with weekly dexamethasone 40 mg and pomalidomide 4 mg on days 1–21. Those in the daratumumab arm, after protocol amendment, also received subcutaneous daratumumab 1800 mg weekly for cycles 1–2, every 2 weeks for cycles 3–6 and every 4 weeks thereafter. 304 patients were recruited (151 to D-Pd and 153 to Pd alone), with a median age of 67 (range

35–90 years), and a median of 2 prior lines of therapy (range 1–5). 35% of patients had high cytogenetic risk factors. Almost 80% of patients were refractory to lenalidomide.
The study met its primary endpoint of improved PFS, with a HR of 0.63 (95% CI 0.47–0.85) for progression or death in those patients receiving D-Pd versus Pd alone, at a median follow up of 16.9 months. Median PFS for D-Pd was 12.4 months, versus 6.9 months in the Pd arm, although overall survival data is still awaited. Higher response rates were observed in the D-Pd arm than the Pd arm, with ≥CR in 24.5% versus 3.9%%, respectively and
≥VGPR rates of 51% versus 19.6% respectively.
The D-Pd combination was well tolerated overall, but with a higher observed incidence of Grade 3 neutrope- nia (68% versus 51% in Pd alone), febrile neutropenia (9% versus 3%) and pneumonia (13% versus 7%) than Pd alone. Data on secondary endpoints of MRD negativity rates, as well as subgroup evaluation (ffor example,those in high cytogenetic risk groups) are yet to be reported.

4.1.2. POLLUX; daratumumab, lenalidomide and dexamethasone
The POLLUX study is a phase III randomized, open-label multi- center study comparing daratumumab plus lenalidomide and dexamethasone (D-Rd) to lenalidomide and dexamethasone alone (Rd) in RRMM [26]. In POLLUX, adult patients with RRMM received Rd (lenalidomide 25 mg orally on days 1–21 and dexamethasone 40 mg orally weekly) either with or without daratumumab on a standard intravenous schedule until pro- gression. Patients with lenalidomide-refractory disease were excluded [26].
POLLUX recruited 569 patients, with 286 assigned to D-Rd and 283 to Rd alone. The median age was 65 years (range 34 to 89), and the median number of prior therapies was 1 (range 1–11). Prior PI and IMiD exposure was noted in approximately 85% and 55% of ppatients, respectively with around 44% of patients having received both a PI and an IMiD. Approximately 20% of patients were refractory to bortezomib; 28% of patients in the D-Rd arm, and 26.9% in the Rd arm, were refractory to their last line of therapy [26].
A recently published extended follow-up analysis of the POLLUX intention-to-treat populations, with a median follow- up of 44.3 months [27], demonstrated a PFS advantage in the D-Rd arm compared with Rd; median PFS in the D-Rd and Rd arms, respectively, were 44.5 months (95% CI 34.1-not estim- able) and 17.5 months (13.9–20.8; HR 0.44; 95% CI 0.35–0.55;
P < 0.0001). The PFS survival benefit was maintained in various analyzed subgroups including age > 75 years, high- risk cytogenetic status, ISS disease stage, Eastern Cooperative Oncology Group performance status score, prior treatment exposure and refractory status [27].
ORR was significantly higher in the D-Rd arm compared with Rd alone (92.9% vs 76.4%; P < 0.0001), as were rates of CR or better (56.6% vs 23.3%; P < 0.0001) and VGPR or better (80.4% vs 49.3%; P < 0.0001). MRD negativity by NGS at a sensitivity of 10−5 was achieved in 30.4% and 5.3% of

patients in the D-Rd and Rd arms, respectively, at a median follow up of >3 years [27].
In the POLLUX study [26,27], D-Rd was well tolerated, with the most common treatment-related adverse effect being neutropenia (63.3% vs 48% in D-Rd vs Rd alone). The most common non-hematological adverse events were diarrhea (58.3% vs 37.4% in D-Rd vs Rd); upper respiratory tract infec- tion (42.8% vs. 27.8%), fatigue (38.9% vs 31%) and cough (35% vs 14.9%). Treatment discontinuation due to adverse events was similar between D-Rd and Rd arms (14.8% vs 14.6% respectively)%, respectively.

4.1.3. Daratumumab with bortezomib and dexamethasone
The combination of daratumumab, bortezomib and dexa- methasone (D-Vd) versus bortezomib and dexamethasone (Vd) alone has been evaluated in the phase III open-label, randomized multicentre CASTOR trial [28]. 498 patients with RRMM were randomized, with a median age of 64 years, and a median of 2 prior lines of therapy.
At a median follow up of 40 months, D-Vd prolonged median PFS compared with Vd alone (16.7 months versus
7.1 months), HR for progression or death 0.31 (95% CI 0.25–- 0.40). ORR was 85% in the D-Vd arm and 63% in the Vd arm, and CR achieved in 30% versus 10%. Significantly higher rates of MRD negativity at the 10−5 level were achieved in the D-Vd group (15%) versus the Vd group (2%). These trends were seen both in standard and high cytogenetic risk groups.

4.2. Daratumumab in newly diagnosed myeloma
In addition to the RRMM setting, daratumumab is now being applied in newly diagnosed patients. Several large clinical trials utilizing daratumumab for front-line induction therapy in trans- plant-eligible patients have led to the recent recommendation to consider this in high-risk patient groups, in particular those with adverse cytogenetic features such as del(17p), t(4;14), t(14;16), t (14;20), gain 1q, or p53 mutation [29,30]. The CASSIOPOEIA [29] trial is a phase III, open-label, randomized controlled trial which studied the combination of bortezomib, thalidomide and dexa- methasone (VTd) with or without daratumumab (D-VTd) in newly diagnosed transplant-eligible patients. Four induction cycles of treatment were given prior to autologous stem cell transplant, and two consolidation cycles post-transplant. 1085 patients were enrolled; 542 in VTd group and 543 in D-VTd group. At 100 days post-transplant, the primary endpoint of sCR was attained in 29% and 20% of patients in the D-VTd and VTd arms, respectively (OR 1.60, 95% CI 1.21–2.12, p = 0 · 0010). MRD, assessed by multi- parametric flow cytometry, was achieved in 64% in the D-VTd arm versus 44% in the VTd arm (p < 0.0001). The daratumumab combination therapy was overall well tolerated with no signifi- cant safety concerns.
The GRIFFIN trial, another phase III randomized trial for transplant-eligible patients, examined the addition of daratumumab (D-RVd) to bortezomib, lenalidomide and dexamethasone (RVd) [30]. The trial recruited 207

patients and at a median follow-up of 22.1 months, the primary endpoint of sCR was achieved in 62.6% versus 45.4% patients in the D-RVd and RVd arms, respectively (p = 0.177). MRD negativity at the 10−5 threshold was seen in 51% of patients in the D-RVd arm and 20.4% in the RVd arm (p < 0.0001).
Daratumumab has also been applied front-line in the transplant-ineligible group. The MAIA trial enrolled 737 newly-diagnosed transplant-ineligible patients and com- pared daratumumab, lenalidomide and dexamethasone (D-Rd) to lenalidomide and dexamethasone alone (Rd), and found a significant improvement in OS and PFS with the addition of daratumumab [31]. At 30 months of follow up, 70.6% versus 55.6% of patients in the D-Rd and Rd arms, respectively were alive and free of disease progression (HR 0.56; 95% CI, 0.43 to 0.73; P < 0.001).

5. Future directions for isatuximab
Isatuximab is currently only available in intravenous formula- tion, although a clinical trial examining the safety and efficacy of a subcutaneous formulation (with pomalidomide) is cur- rently recruiting [32]. Several recent studies [33–35] have examined a subcutaneous formulation of daratumumab, which can be administered over 5 minutes, as opposed to the median infusion time of approximately 3 hours for the intravenous preparation. Overall, these studies have found similar or improved tolerability with fewer infusion reactions, and demonstrated non-inferiority with the intravenous formu- lation, leading to the recent approval of subcutaneous formu- lation of daratumumab by the Food and Drug Administration (FDA) in the United States.
Trials investigating isatuximab in combination with other therapies are currently under way. IKEMA [36] is an ongoing phase III trial investigating the efficacy and safety of isatux- imab in combination with carfilzomib and dexamethasone, compared to carfilzomib and dexamethasone only, in patients with RRMM. A prespecified interim analysis has demonstrated significantly improved PFS rates for the isatuximab combina- tion, with no new safety concerns [37]. Significantly higher MRD negativity rates were also reported in the isatuximab arm at a median follow-up of 20.7 months compared with carfilzomib and dexamethasone alone (30% vs. 13%, p = 0.0004) [38], although this was assessed in patients attain- ing ≥VPGR, rather than in those achieving ≥CR or sCR as in ICARIA-MM.
A trial investigating isatuximab in combination with carfil- zomib, lenalidomide and dexamethasone up-front in newly diagnosed transplant-eligible patients is also currently recruit- ing [39].

6. Conclusion
Isatuximab is a novel anti-CD38 therapeutic monoclonal anti- body that has demonstrated efficacy and tolerability both as a single agent and in combination therapy in RRMM. In parti-

cular, isatuximab in combination with pomalidomide and dex- amethasone offers a new treatment option for those patients with RRMM who are refractory to PIs and lenalidomide, a patient group with poor prognosis and unmet clinical need.

7. Expert opinion
There is no doubt that currently, and in the immediate future, clinicians will want to incorporate anti-CD38 therapy early in the treatment of patients with myeloma. It will only be the agents that target BCMA (B cell maturation antigen) that will challenge the anti-CD38 antibodies. So the obvious question is – how do the two anti-CD38 antibodies compare? We have three studies that have evaluated anti-CD38 MoAbs in rando- mized trials. However, in the absence of direct comparative data, conclusions cannot be drawn about the superiority or otherwise of the regimens studied in ICARIA-MM (Isa-Pd), APOLLO (D-Pd), POLLUX (D-Rd) and the myriad other treat- ment options available in RRMM. Isa-Pd, D-Pd and D-Rd are all well-tolerated regimens with demonstrated efficacy. Patient- specific factors including prior therapies, as well as practical- ities such as cost and reimbursement factors, will play a key part in driving patterns of use.
Specifically, with respect to the combination of Isa-Pd, this combination is clearly efficacious in patients with RRMM who are naïve to anti-CD38 MoAbs but its use in patients already exposed to anti-CD38 therapy requires assessment. This will represent an increasingly large group of patients as daratu- mumab moves into established front-line treatment regimens. Nonetheless, given the slightly different targeted epitope and mechanism of action of isatuximab, it may represent an effec- tive treatment option in relapsed patients previously exposed to daratumumab. A retrospective analysis of 9 patients treated with isatuximab after receiving daratumumab in prior lines of therapy found a best ORR of partial response in the majority (89%) of patients [40]. Further studies investigating this are urgently required.
A major benefit of the Isa-Pd regimen is the ability to use it in patients with substantial renal impairment. A specific sub- group analysis in ICARIA-MM examined Isa-Pd in patients with moderate to severe renal impairment, demonstrating excellent efficacy and tolerability in this population, makes it an attrac- tive option in such patients. Additionally, the combination with pomalidomide supports this, given its minimal renal excretion as opposed to lenalidomide which requires dose- reduction in those with significant renal impairment. The APOLLO study also allowed enrolment of patients with mod- erate renal impairment, and specific outcomes of D-Pd in this group are awaited.
An important treatment goal for both up-front and relapsed myeloma is the attainment of MRD negativity; it is notable that approximately 30% of patients in the daratumumab arm in POLLUX, and 5% in the isatuximab arm in ICARIA-MM attained MRD negativity as assessed by NGS. This difference is likely largely due to the more heavily treated patients in the ICARIA- MM study, although direct comparisons would be valuable to

evaluate any efficacy differences between these anti-CD38 MoAbs. MRD negativity data is awaited for the APOLLO study.
Recent approval of the subcutaneous formulation of dara- tumumab will no doubt improve the patient experience on this drug. Data on the subcutaneous formulation of isatuxi- mab is eagerly awaited.
Overall, the combination therapy of Isa-Pd has demon- strated efficacy and a definite role in the treatment of RRMM, although clinicians still face a challenge in deciding where it is best placed in the treatment algorithm.

Funding
This paper was not funded

Declaration of interest
HM Prince has received honoraria and on advisory boards for Janssen, Sanofi, Celgene and Bristol Myer Squibb. He has received research funding from Celgene and Bristol Myer Squibb.
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 disclosure
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

References
1. Annamaria Gulla KCA. Multiple myeloma: the (r) evolution of cur- rent therapy and a glance into the future. haematologica. 2020;105 (10):10.
2. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol. 2019;37(14):1228–1263.
3. Kumar S, Dimopoulos M, Kastritis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31(11):2443–2448.
4. Van De Donk NW. Sequencing multiple myeloma therapies with and after antibody therapies. In: Hematology 2014, the american society of hematology education program book. Hematology Am Soc Hematol Educ Program. 2020;Vol. 2020:248–258. 1.
5. Van Beurden-tan CH, Franken MG, Blommestein HM, et al. Systematic literature review and network meta-analysis of treat- ment outcomes in relapsed and/or refractory multiple myeloma. J Clin Oncol. 2017;35(12):1312–1319.
6. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus poma- lidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096–2107.
7. Moreno L, Perez C, Zabaleta A, et al. The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clin Cancer Res. 2019;25(10):3176–3187.
8. Van De Donk NW, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131(1):13–29.
9. Cagnetta A, Cea M, Calimeri T, et al. Intracellular NAD+ depletion enhances bortezomib-induced anti-myeloma activity. Blood. 2013;122(7):1243–1255.

10. Fau JB, El-Cheikh R, Brillac C, et al. Drug-disease interaction and time-dependent population pharmacokinetics of isatuximab in relapsed/refractory multiple myeloma patients. CPT Pharmacometrics Syst Pharmacol. 2020;9(11):649–658.
11. Sanofi-Aventis. Sarclisa© Full Prescribing Information. Reference ID. 4568826. In: New Jersey, USA. 2020.
12. Mei Z, Wool GD. Impact of novel monoclonal antibody therapeutics on blood bank pretransfusion testing. Hematol/Oncol Clin. 2019;33 (5):797–811.
13. Quach H, Benson S, Haysom H, et al. Considerations for pre-trans- fusion immunohaematology testing in patients receiving the anti- CD38 monoclonal antibody daratumumab for the treatment of multiple myeloma. Intern Med J. 2018;48(2):210–220.
14. Mills JR, Kohlhagen MC, Willrich MA, et al. A universal solution for eliminating false positives in myeloma due to therapeutic mono- clonal antibody interference. blood. 2018;132(6):670–672.
15. Deckert J, Wetzel M-C, Bartle LM, et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent anti- tumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res. 2014;20 (17):4574–4583.
16. Jiang H, Acharya C, An G, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic path- ways, which is further enhanced by pomalidomide. Leukemia. 2016;30(2):399–408.
17. Mikhael J, Richter J, Vij R, et al. A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma. InLeukemia. 2020;34(12):3298–3309.
18. Mikhael J, Richardson P, Usmani SZ, et al. A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refrac- tory multiple myeloma. Blood J Am Soc Hematol. 2019;134 (2):123–133.
19. Dimopoulos MA, Leleu X, Moreau P, et al. Isatuximab plus pomali- domide and dexamethasone in relapsed/refractory multiple mye- loma patients with renal impairment: ICARIA-MM subgroup analysis. Leukemia. 2021;35(2):562–572.
20. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384–394.
21. Adams III HC, Stevenaert F, Krejcik J, et al. High-parameter mass cytometry evaluation of relapsed/refractory multiple myeloma patients treated with daratumumab demonstrates immune mod- ulation as a novel mechanism of action. Cytometry Part A. 2019;95 (3):279–289.
22. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus poma- lidomide and dexamethasone in relapsed and/or refractory multi- ple myeloma. Blood. 2017;130(8):974–981.
23. Siegel DS, Schiller GJ, Samaras C, et al. Pomalidomide, dexa- methasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment. Leukemia. 2020;34 (12):3286–3297.
24. Dimopoulos M, editor APOLLO: Phase 3 randomized study of sub- cutaneous daratumumab plus pomalidomide and dexamethasone (D-pd) versus pomalidomide and dexamethasone (pd) alone in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Abstract.
25. ClinicalTrials.gov. Comparison of pomalidomide and dexametha- sone with or without daratumumab in subjects with relapsed or refractory multiple myeloma previously treated with lenalidomide and a proteasome inhibitor daratumumab/pomalidomide/dexa- methasone vs pomalidomide/dexamethasone (EMN14). NCT03180736. [cited 2021 Jan 20]. Available from: https://clinical trials.gov/ct2/show/NCT03180736.
26. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalido- mide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319–1331.
27. Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple

myeloma: Extended follow-up of POLLUX, a randomized, open- label, phase 3 study. Leukemia. 2020;34(7):1875–1884.
28. Weisel K, Spencer A, Lentzsch S, et al. Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hematol Oncol. 2020;13 (1):1–11.
29. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29–38.
30. Voorhees PM, Kaufman JL, Laubach JP, et al.Daratumumab, lenalido- mide, bortezomib, & dexamethasone for transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Blood. 2020;136(8):936–945.
31. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104–2115.
32. ClinicalTrials.gov. Multi-center, open-label, phase 1b study in patients with relapsed/refractory multiple myeloma (RRMM). [cited 2021 Jan 25]. Available from: https://clinicaltrials.gov/ct2/ show/NCT04045795
33. Usmani SZ, Nahi H, Mateos M-V, et al. Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma. Blood. 2019;134(8):668–677.
34. San-Miguel J, Usmani SZ, Mateos M-V, et al. Subcutaneous daratu- mumab in patients with relapsed or refractory multiple myeloma:

Part 2 of the open-label, multicenter, dose-escalation phase 1b study (PAVO). Haematologica. 2020. DOI: 10.3324/ haematol.2019.243790.
35. Mateos M-V, Nahi H, Legiec W, et al. Subcutaneous versus intrave- nous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. The lancet haematology. 2020;7(5): e370–e380.
36. ClinicalTrials.gov. Multinational clinical study comparing isatuximab, carfilzomib and dexamethasone to carfilzomib and dexamethasone in relapse and/or refractory multiple myeloma patients (IKEMA).
37. Thomas Martin JM, Hajek R, Kim K, et al. Depth of response and response kinetics of isatuximab plus carfilzomib and dexametha- sone in relapsed multiple myeloma: ikema interim analysis. Blood. 2020;136(Supplement 1):7–8.
38. Moreau P, Dimopoulos M, Mikhael J, et al. Isatuximab plus carfilzo- mib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3 randomized, open-label study. Hematol Transfus Cell Ther. 2020;42:262–263.
39. ClinicalTrials.gov. KRDI in transplant-eligible MM.
40. Becnel MR, Horowitz SB, Thomas SK, et al. Descriptive analysis of isatuximab use following prior daratumumab in patients with relapsed/refractory multiple myeloma. In: . BLOOD. WASHINGTON, DC 20036 USA: 2020:136 (Supplement 1): 20–21.