Isatuximab: A Review in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.

Digital Features for this Adis Drug Evaluation can be found at 10.6084/m9.figshare.30462479.

Isatuximab: clinical considerations in transplant-ineligible newly diagnosed multiple myeloma

Anti-CD38 monoclonal antibody Prolongs PFS and generally induces deeper responses when added to bortezomib, lenalidomide and dexamethasone Neutropenia, pneumonia, cataract and thrombocytopenia are the most common grade ≥ 3 treatment-emergent adverse events

Introduction

Multiple myeloma (MM) is a plasma cell malignancy that primarily affects older individuals (who are at increased risk of frailty; Sect. 7 ); at diagnosis, the median age of patients is 69 years and approximately one-third of patients are aged ≥ 75 years [ 1 ]. MM is characterized by multiple remissions and relapses, resulting in high attrition rates for first- and subsequent lines of therapy [ 1 – 3 ]. In addition, age negatively affects both progression-free survival (PFS) and overall survival (OS), which also decline with each additional line of therapy, and treatment outcomes in older patients are frequently compromised by comorbidities and an increased susceptibility to treatment-related adverse events (AEs). Thus, patients with MM benefit most when efficacious regimens are used early in the treatment process [ 1 – 3 ].

The therapeutic approach for newly diagnosed MM (NDMM) is determined by a patient’s eligibility for autologous stem cell transplantation (ASCT; which is affected by their age, performance status and comorbidities) and their risk stratification (standard risk vs high risk) [ 3 ]. Patients at an increased risk of treatment-related toxicities due to older age, poor performance status or high comorbidity burden are considered to be transplant ineligible [ 4 , 5 ]. According to a previous retrospective analysis of real-world data from the USA [ 2 ], attrition rates across all lines of therapy were high for both transplant-eligible and -ineligible patients with NDMM. However, while treatment duration was consistent across the lines of therapy in patients with transplant-eligible NDMM, it decreased by line of therapy for those with transplant-ineligible NDMM. Beyond the first line of therapy in patients with transplant-ineligible NDMM, an older age at diagnosis, cardiovascular disorders, pulmonary circulation disorders and renal impairment are associated with higher attrition rates [ 2 ].

Several drug classes have demonstrated activity against MM and are used clinically [ 3 ]. These include alkylating agents, corticosteroids, immunomodulatory drugs and proteasome inhibitors [ 3 ]. Anti-CD38 monoclonal antibodies [e.g. daratumumab [ 6 ] and isatuximab (isatuximab-irfc; SARCLISA ® ) [ 7 , 8 ]] are a recent addition to the arsenal of treatments available for patients with MM [ 3 ]. These antibodies target CD38, a transmembrane glycoprotein that functions as a receptor (with CD31 acting as a ligand), an adhesion molecule and a multifunctional ectoenzyme (being involved in the catabolism of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, which results in the generation of potent intracellular Ca 2+ -mobilizing compounds, and the production of adenosine) [ 9 , 10 ]. CD38 is highly and uniformly expressed on MM cells while also being expressed at lower levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin [ 9 ].

Owing to the heterogeneous nature of MM, combination therapy with agents with synergistic mechanisms of action and overlapping toxicities has been shown to be a successful strategy for improving clinical outcomes, with anti-CD38 monoclonal antibodies considered an attractive component given their distinct mechanisms of action, efficacy, favourable toxicity profile and single-agent activity [ 9 ]. The current European Hematology Association (EHA)–European Myeloma Network (EMN) evidence-based guidelines [ 11 ] recommend two standard of care regimens for patients with NDMM aged < 80 years who are ineligible for ASCT and have an International Myeloma Working Group (IMWG) frailty score (FS) of < 2: daratumumab in combination with bortezomib, lenalidomide and dexamethasone; and isatuximab in combination with bortezomib, lenalidomide and dexamethasone. These regimens are also recommended by the current National Comprehensive Cancer Network (NCCN) guidelines for multiple myeloma [ 12 ] as preferred regimens (category 1) for the primary treatment of patients aged < 80 years who are not frail and for whom haematopoietic cell transplant (HCT) is deferred or not indicated. Daratumumab–lenalidomide–dexamethasone is recommended as a preferred regimen (category 1) for patients for whom HCT is deferred or not indicated [ 12 ].

The anti-CD38 IgG1κ-derived monoclonal antibody isatuximab has been previously approved in the EU [ 7 ] and the USA [ 8 ] for use in combination with pomalidomide and dexamethasone in adults with relapsed and refractory MM who have received ≥ 2 prior therapies (including lenalidomide and a proteasome inhibitor) [ 8 ] and have demonstrated disease progression on the last therapy [ 7 ]; and in combination with carfilzomib and dexamethasone in adults with MM who have received ≥ 1 [ 7 ] or 1–3 [ 8 ] prior therapies [ 13 , 14 ]. Recently, isatuximab has also been approved in the EU [ 7 ] for use in combination with bortezomib, lenalidomide and dexamethasone for the induction treatment of adults with newly diagnosed MM (NDMM) who are eligible for ASCT based on the results from the GMMG-HD7 study [ 15 ]. This article reviews the efficacy and tolerability of isatuximab in combination with bortezomib, lenalidomide and dexamethasone in adults with NDMM who are ineligible for ASCT, and provides a brief overview of the pharmacological properties of isatuximab.

Pharmacodynamic Properties of Isatuximab

Isatuximab binds to a specific extracellular epitope on the CD38 receptor, a binding site that is distinct from those used by other anti-CD38 monoclonal antibodies, including daratumumab (a first-in-class anti-CD38 monoclonal antibody) [ 6 – 8 , 16 ].

Isatuximab induces tumour cell apoptosis via Fc-dependent mechanisms [e.g. antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement dependent cytotoxicity (CDC)] and Fc-independent mechanisms (e.g. direct cytotoxicity) [ 7 , 8 , 16 – 18 ]. However, evidence suggests that isatuximab-induced CDC occurs only in the presence of high CD38 receptor density (compared with daratumumab, for which CDC appears to be a more prominent effector mechanism) [ 19 ]. Isatuximab also inhibits the enzymatic activity of CD38, activates natural killer (NK) cells in the absence of CD38-positive target tumour cells, and suppresses CD38-positive T-regulatory cells (Tregs; which actively suppress immune responses) by reducing the number of Tregs, blocking their trafficking, and inhibiting immunosuppressive cytokines [ 7 , 8 , 16 – 18 ]. The blockade of Tregs by isatuximab restores CD4 + CD25 – conventional T cell levels and stimulates cytotoxic T and NK cell-mediated MM cell cytolysis, which immunomodulatory drugs can further enhance [ 17 ]. ADCC and ADCP appear to be the predominant immune effector mechanisms for isatuximab in MM cells, with their activation by isatuximab dependent upon the expression level of CD38 [ 16 ]. Indeed, isatuximab shows a preferential cytotoxic effect toward high CD38-expressing tumour cells, while low CD38-expressing cells in normal tissues are spared [ 16 ].

Isatuximab in combination with pomalidomide enhanced cell lysis via ADCC and direct cytotoxicity mechanisms versus isatuximab alone in CD38-expressing MM cells, and enhanced antitumor activity versus isatuximab or pomalidomide alone in a human MM xenograft model [ 7 , 8 ].

Reductions in the absolute counts of total NK cells (including inflammatory CD16 + , low CD56 + bright and cytotoxic CD16 + , bright CD56 +dim NK cells) and CD19 + B cells were seen in the peripheral blood of patients with MM treated with isatuximab, pomalidomide and dexamethasone [ 8 ].

Like daratumumab, isatuximab may be incidentally detected on serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) assays used to clinically monitor disease monoclonal immunoglobulins (M-protein), thereby interfering with accurate response classification [ 7 , 8 , 20 ]. In patients with a persistent very good partial response and suspected isatuximab interference, clinicians should consider using a validated isatuximab-specific IFE assay to inform their assessment of a complete response [ 7 , 8 , 20 ].

The binding of isatuximab to CD38 on red blood cells (RBCs) may result in a false positive indirect antiglobulin test (indirect Coombs test) in recipients for ≥ 6 months following the last infusion of isatuximab [ 7 , 8 ] (Sect. 6 ). Potential false positive reactions may also be seen in antibody detection (screening) tests, antibody identification panels and antihuman globulin crossmatches [ 7 , 8 ]. Among interference mitigation measures is the treatment of reagent RBCs with dithiothreitol (DTT; which denatures CD38) [ 7 , 8 , 21 ]; see local prescribing information for further details, including the effect of DTT on the Kell blood group system.

At twofold the recommended dose, isatuximab did not prolong the QT interval to a clinically relevant extent [ 8 ].

Pharmacokinetic Properties of Isatuximab

Owing to its binding to the CD38 receptor, isatuximab displays nonlinear pharmacokinetics with target-mediated drug disposition in patients with MM [ 7 ]. Following the administration of isatuximab 10 mg/kg every week for 4 weeks followed by every 2 weeks, the median time to steady state was 18 weeks with a 3.1-fold accumulation [ 7 , 8 ].

As it is a large protein, isatuximab is expected to be metabolized into small peptides by non-saturable proteolytic catabolism processes [ 7 , 8 ]. Isatuximab is eliminated by two parallel pathways: a nonlinear target-mediated pathway that dominates at low concentrations and a nonspecific linear pathway that dominates at higher concentrations [ 7 ]. In the therapeutic plasma isatuximab concentration range, the linear pathway predominates and decreases by 50% over time to a steady state value of 9.55 mL/h (0.229 L/day). This is associated with a terminal half-life of 28 days [ 7 ]. At steady state, the elimination of almost all (≥ 99%) isatuximab from plasma is predicted to occur in ≈ 2 months after the last dose [ 8 ]. The elimination of isatuximab was similar when given as a single agent or as combination therapy [ 8 ].

According to population pharmacokinetic analyses, age (36–85 years), sex, race, renal impairment and mild hepatic impairment [total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or total bilirubin > 1 to 1.5 × ULN and any AST) have no clinically relevant effect on isatuximab exposure [ 7 , 8 ]. However, isatuximab clearance increases with increasing body weight, necessitating body weight-based dosing (Sect. 6 ). The effect of moderate (total bilirubin > 1.5 to 3 × ULN and any AST) and severe (total bilirubin > 3 × ULN and any AST) hepatic impairment on the pharmacokinetics of isatuximab is not yet known [ 7 , 8 ].

Isatuximab has no impact on the pharmacokinetics of bortezomib, carfilzomib, lenalidomide or pomalidomide, with each of these drugs having no impact on the pharmacokinetics of isatuximab [ 7 ].

Therapeutic Efficacy of Isatuximab

The preliminary efficacy of adding isatuximab to a regimen consisting of bortezomib, lenalidomide and dexamethasone in adults with measurable NDMM ineligible or with no immediate intent for ASCT was demonstrated in an open-label, multicentre, phase 1b study [ 22 ]. In this study, 56.3% of 71 patients achieved a complete response (CR) or better (primary endpoint) following induction treatment with four 42-day cycles of isatuximab–bortezomib–lenalidomide–dexamethasone and then maintenance treatment with 28-day cycles of isatuximab–lenalidomide–dexamethasone until disease progression, unacceptable toxicity or patient withdrawal [ 22 ]. This was followed by a noncomparative, multicentre phase II study (REST) in adults with NDMM ineligible for high-dose melphalan and ASCT [ 23 ] and a randomized phase III study (BENEFIT) in adults with NDMM ineligible for ASCT [ 24 , 25 ]. Both REST [ 23 ] and BENEFIT [ 24 , 25 ] utilized weekly bortezomib and sparing dexamethasone administration schedules and thus are not discussed further.

This section focuses on the results of IMROZ, a randomized, open-label, multinational phase III study evaluating the efficacy of isatuximab in combination with bortezomib, lenalidomide and dexamethasone in adults with NDMM ineligible for ASCT [ 26 ]. The active comparator in this study was combination therapy with bortezomib, lenalidomide and dexamethasone. IMROZ enrolled patients aged 18–80 years with symptomatic previously untreated myeloma (as per IMWG criteria) and measurable disease (defined as serum M-protein ≥ 1.0 g/dL and/or urine M-protein ≥ 200 mg/24 h and/or serum free light chain MM without measurable disease in serum or urine as per previous criteria). Patients who were newly diagnosed and not considered for high-dose chemotherapy due to either age ≥ 65 years, or age < 65 years with important comorbidities likely to have a negative impact on the tolerability of high-dose chemotherapy with ASCT, were also eligible. Among the exclusion criteria were age > 80 years, an Eastern Cooperative Oncology Group performance status score of > 2 (scores assessed on a 5-point scale, with higher scores indicating greater disability) and estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m 2 . Randomization to isatuximab–bortezomib–lenalidomide–dexamethasone or bortezomib–lenalidomide–dexamethasone was stratified by country (not China vs China), age (< 70 vs ≥ 70 years) and Revised International Staging System disease stage (stage I or II vs III vs not classified) [ 26 ].

The study medications were administered over four 42-day cycles (induction) followed by 28-day cycles (maintenance) that continued until disease progression, an unacceptable AE, or other discontinuation criteria [ 26 ]. During the induction treatment period, patients in both groups received subcutaneous bortezomib (1.3 mg/m 2 on days 1, 4, 8, 11, 22, 25, 29 and 32), oral lenalidomide [25 mg/day (or 10 mg/day if the patient’s eGFR was 30 to < 60 mL/min/1.73 m 2 ) on days 1–14 and 22–35] and oral or intravenous dexamethasone [20 mg/day on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32 and 33 (or on days 1, 4, 8, 11, 15, 22, 25, 29 and 32 in patients aged ≥ 75 years)]. Patients in the isatuximab–bortezomib–lenalidomide–dexamethasone group also received intravenous isatuximab (10 mg/kg of body weight once weekly in cycle 1, with subsequent cycles occurring every 2 weeks). Antibacterial prophylactic treatment was recommended for all patients during the induction period. During the maintenance treatment period, patients in both groups received oral lenalidomide [25 mg/day (or 10 mg/day if the patient’s eGFR was 30 to < 60 mL/min/1.73 m 2 ) on days 1 to 21] and dexamethasone (20 mg/day once weekly). Patients in the isatuximab–bortezomib–lenalidomide–dexamethasone group also received intravenous isatuximab (10 mg/kg every 2 weeks, with monthly administration starting with cycle 18) while those in the bortezomib–lenalidomide–dexamethasone group with biochemical or clinical progression were permitted to crossover to the isatuximab–bortezomib–lenalidomide–dexamethasone group at the investigator’s discretion. Patients receiving isatuximab–bortezomib–lenalidomide–dexamethasone at any point during the study received premedication [acetaminophen, dexamethasone, diphenhydramine and ranitidine (or equivalent)] directly prior to isatuximab infusion. Those not experiencing an infusion reaction following four consecutive administrations of isatuximab could have their need for subsequent premedication reconsidered at the investigator’s discretion [ 26 ].

The primary endpoint in IMROZ was PFS [defined as the time from randomization to first documented disease progression (as assessed by an independent review committee; IRC) or death, whichever occurred first] [ 26 ]. Three interim and one final PFS analyses were planned [ 27 ]. The three interim PFS analyses were to be performed after 133, 167 and 189 events of disease progression or death had occurred (which were 60%, 75% and 85%, respectively, of the 222 events specified for the planned final analysis) [ 27 ]. Key secondary endpoints (assessed in a hierarchical manner) were CR or better [defined as a CR or stringent CR (i.e. a CR plus a normal free light-chain ratio and an absence of clonal plasma cells)]; minimal residual disease (MRD)-negative status (assessed using next-generation sequencing with a sensitivity threshold of 1 in 10 5 nucleated cells [ 27 ]; strongly predicts a favourable prognosis and correlates with improved PFS and OS in patients receiving first-line therapy [ 11 ]) in patients with a CR or better; a very good partial response (VGPR) or better (defined as the proportion of patients with CR and VGPR); and OS (defined as the time from randomization to death from any cause) [ 26 ]. OS analyses were planned to be conducted at the time of the four PFS analyses, with the final OS analysis intended for when ≈ 202 deaths had been observed [ 27 ]. The confidence intervals for the primary and key secondary endpoints were adjusted for multiplicity [ 26 ]. Other secondary endpoints included overall response (defined as a partial response or better), time to disease progression, time to first response, time to best response, duration of response, PFS according to MRD status, sustained MRD-negative status for ≥ 12 months, PFS2 (defined as time from randomization to second progression or death, whichever occurred first) and health-related quality of life (HR-QOL) [ 26 ].

Amongst the 446 enrolled patients, baseline demographic and disease characteristics were balanced across the isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone groups ( n = 265 and 181) [ 26 ]. Patients were aged 55–80 years (median 72 years); 16.6% of 446 patients had high-risk cytogenetic features, 37.0% had a chromosomal 1q21+ abnormality (≥ 3 copies of 1q21) and 28.7% had an eGFR of < 60 mL/min/1.73 m 2 [ 26 ]. Using the simplified IMWG FS [a modification of the IMWG FS calculated based on age (≤ 75 vs 76–80 years), Eastern Cooperative Oncology Group performance status and a modified Charlson Comorbidity Index (which uses baseline medical history); scores of 0 or 1, or ≥ 2 were considered non-frail and frail, respectively], 119 (26.7%) of 446 patients were classified as frail and 321 (72.0%) as non-frail [ 28 ].

Data from the second prespecified interim PFS analysis (data cutoff date 26 September 2023; median follow-up 59.7 months) of the intention-to-treat population (defined as all the patients who underwent randomization) are discussed [ 26 ]. At this timepoint, 162 events [84 and 78 in the isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone groups ( n = 265 and 181)] of disease progression or death and 128 events (69 and 59 in the respective groups) of death had occurred; the median treatment duration was 53.2 and 31.3 months and 47.2% and 24.3% of patients were continuing treatment [ 26 , 27 ]. In frail patients, the median treatment duration in the respective treatment groups was 31.2 and 19.2 months [ 28 ].

The addition of isatuximab to bortezomib–lenalidomide–dexamethasone was associated with a significant 40% lower risk of disease progression or death relative to bortezomib–lenalidomide–dexamethasone [ 26 , 27 ]. Kaplan–Meier IRC-assessed estimated PFS rates were 63.2% and 45.2% for recipients in the respective groups [hazard ratio (HR) 0.60 (98.5% 0.41–0.88); p < 0.001]. At this timepoint, median PFS had not been reached in the isatuximab–bortezomib–lenalidomide–dexamethasone group (and was 54.3 months in the bortezomib–lenalidomide–dexamethasone group) (Table 1 ). An investigator assessment was consistent with this finding, with the risk of disease progression or death reduced by 49% [Kaplan–Meier estimated PFS rate 64.0% vs 35.0%; HR 0.51 (98.5% CI 0.36–0.73); one-sided p = 0.007] with isatuximab combination therapy versus bortezomib–lenalidomide–dexamethasone [ 26 ]. Table 1 Efficacy of isatuximab added to bortezomib, lenalidomide and dexamethasone in adults with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant Endpoint Isa-VRd [ n = 265] VRd [ n = 181] OR (95% CI) Median PFS [mo] (95% CI) a NR (NR, NR) 54.3 (45.2, NR) ≥ CR [% of pts] 74.7 64.1 1.66 (1.10–2.50)* MRD-negative status b [% of pts] 55.5 40.9 1.80 (1.23–2.65)* ≥ VGPR [% of pts] 89.1 82.9 1.73 (0.99–3.01) c Median OS [mo] (95% CI) NR (NR, NR) NR (NR, NR) Results of the second prespecified interim PFS analysis (data cutoff date 26 September 2023; median follow-up 59.7 mo) from IMROZ [ 26 ]. Additional information has been obtained from the European Medicines Agency assessment report [ 27 ] ≥ CR complete response or better, d dexamethasone, Isa isatuximab, mo months, MRD minimal residual disease, NR not reached, OR odds ratio, OS overall survival, PFS progression-free survival, pts patients, R lenalidomide, V bortezomib, ≥ VGPR very good partial response or better * p ≤ 0.008 vs VRd a Primary endpoint b Assessed in patients who achieved ≥ CR c Not significant owing to an efficacy p value boundary of 0.025

Prespecified subgroup analyses for the primary endpoint significantly (95% CIs < 1) favoured isatuximab combination therapy over bortezomib–lenalidomide–dexamethasone regardless of age (< 70 vs ≥ 70 years) and the presence or absence of baseline extramedullary disease [ 26 ]. In other subgroup analyses, the PFS benefits with isatuximab–bortezomib–lenalidomide–dexamethasone versus bortezomib–lenalidomide–dexamethasone in a subgroup of Chinese patients [ 29 ] and in subgroups of patients with 1q21+ status with or without high-risk chromosomal abnormalities, and isolated 1q21+ status [ 30 ] were consistent with that seen in the overall population. However, among patients with plasmacytoma, including extramedullary disease, the benefit in PFS did not significantly differ between the isatuximab combination therapy and bortezomib–lenalidomide–dexamethasone groups [ 31 ]. In a post hoc subgroup analysis, a PFS benefit significantly favouring isatuximab–bortezomib–lenalidomide–dexamethasone over bortezomib–lenalidomide–dexamethasone was seen regardless of patient frailty status, with 48% and 38% reductions in the risk of disease progression or death observed in frail (HR 0.52; 95% CI 0.29–0.91) and non-frail (HR 0.62; 95% CI 0.42–0.90) patients [ 28 ].

At a median follow-up of 59.7 months, the odds of achieving a CR or better (key secondary endpoint) were significantly higher with isatuximab–bortezomib–lenalidomide–dexamethasone than with bortezomib–lenalidomide–dexamethasone, as were the odds of achieving an MRD-negative status in patients with a CR or better (key secondary endpoint) (Table 1 ). However, the odds ratio for VGPR or better (key secondary endpoint) did not significantly differ between the isatuximab combination therapy and bortezomib–lenalidomide–dexamethasone groups (Table 1 ). OS data were immature at the time of the second prespecified interim analysis, but median OS (key secondary endpoint) had not been reached in either treatment group (Table 1 ). At this timepoint, 26.0% of isatuximab–bortezomib–lenalidomide–dexamethasone recipients and 32.6% of bortezomib–lenalidomide–dexamethasone recipients had died [HR 0.78 (99.97% CI 0.41–1.48)] [ 27 ]. In the subgroup of frail patients, the odds of achieving an MRD-negative status [odds ratio (OR) 3.25; 95% CI 1.43–7.37] and an MRD-negative status in patients with a CR or better [OR 3.46; 95% CI 1.50–8.01) were significantly higher with isatuximab combination therapy than with bortezomib–lenalidomide–dexamethasone (post hoc subgroup analysis) [ 28 ].

In terms of other secondary endpoints, the median time to disease progression had not been reached in the isatuximab combination therapy group and was 59.70 months in the bortezomib–lenalidomide–dexamethasone group [ 26 , 27 ]. Kaplan–Meier IRC-assessed estimated time to progression rates were 75.2% and 49.9% for recipients in the respective groups (HR 0.41; 95% CI 0.29–0.60) [ 26 ]. In the isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone groups, respectively, 91.3% and 92.3% of patients had achieved an overall response, the median time to first response was 1.15 and 1.48 months, the median time to best response was 6.51 and 5.59 months, and the median duration of response was not reached and 58.25 months. The proportion of patients with an MRD-negative status was 58.1% in the isatuximab–bortezomib–lenalidomide–dexamethasone group and 43.6% in the bortezomib–lenalidomide–dexamethasone group; 46.8% and 24.3% of patients had an MRD-negative status for ≥ 12 months at any point during the study. In patients with an MRD-negative status, a significant PFS benefit was seen in both the isatuximab combination therapy (HR 0.22; 95% CI 0.14–0.35) and bortezomib–lenalidomide–dexamethasone (HR 0.31; 95% CI 0.19–0.52) groups. Patients who had a sustained MRD-negative status for ≥ 12 months had a PFS benefit comparable to that in patients who had an MRD-negative status for < 12 months [ 26 ]. Further analyses of MRD negativity dynamics over up to 60 months demonstrated deeper responses in isatuximab–bortezomib–lenalidomide–dexamethasone recipients compared with bortezomib–lenalidomide–dexamethasone recipients [ 32 ]. In the isatuximab combination therapy and bortezomib–lenalidomide–dexamethasone groups, respectively, rates of MRD negativity were 49.7% and 41.1% during the 6-month induction treatment period and 76.1% and 40.0% by month 60 of the maintenance treatment period. Moreover, in the respective treatment groups, rates of MRD negativity in patients with a CR were 48.2% and 38.4% during the 6-month induction treatment period and 73.9% and 40.0% by month 60 of the maintenance treatment period [ 32 ].

As of the data cutoff date, 25 bortezomib–lenalidomide–dexamethasone recipients had received confirmation of a first disease progression and crossed over to receive isatuximab in addition to their current treatment regimen; 12 of these patients had died by the data cutoff date [ 26 ]. The mean time from disease progression to the first subsequent therapy was 12.0 weeks [ 27 ]. Overall, 19.6% of 265 isatuximab–bortezomib–lenalidomide–dexamethasone recipients and 44.2% of 181 bortezomib–lenalidomide–dexamethasone recipients underwent further antimyeloma (e.g. alkylating, anti-CD38, immunomodulatory, proteasome inhibitor) therapy [ 26 ]. PFS2 rates at a median 59.7 months of follow-up were 65.4% and 54.9% in the isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone groups (HR 0.70; 95% CI 0.51–0.95) [ 26 ].

HR-QOL, as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC-QLQ-C30) global health status domain score, was maintained over the treatment period in and did not significantly differ between the isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone groups [ 26 , 33 ]. According to a post hoc subgroup analysis, the EORTC-QLQ-C30 global health status domain score remained stable over the treatment period in both frail and non-frail patients [ 28 ]. Isatuximab combination therapy was associated with clinically meaningful better physical functioning (overall least-squares mean difference 5.92; 95% CI 2.76–9.08; p = 0.0003) and significantly delayed the time to first deterioration in the pain subscale (HR 0.75; 95% CI 0.59–0.94; p = 0.0146) than bortezomib–lenalidomide–dexamethasone [ 33 ].

Tolerability of Isatuximab

In adults with transplant-ineligible NDMM participating in IMROZ [ 26 ], the combination of isatuximab with bortezomib, lenalidomide and dexamethasone resulted in a safety profile consistent with that seen in adults with transplant-eligible NDMM participating in the phase III GMMG-HD7 study [ 34 ] and in patients with NDMM, or relapsed or refractory MM receiving different isatuximab-based combination therapy in clinical studies (pooled safety data) [ 27 ].

At the data cutoff (26 September 2023) in IMROZ, median exposure duration in the isatuximab combination therapy and bortezomib–lenalidomide–dexamethasone groups was 53.2 and 31.3 months [ 27 ]. Almost all patients experienced treatment-emergent AEs (TEAEs) of any grade [99.6% of 263 isatuximab–bortezomib–lenalidomide–dexamethasone recipients and 98.3% of 181 bortezomib–lenalidomide–dexamethasone recipients; exposure-adjusted event rates (EAER) were 13.386 and 12.691 events per patient–year (PY)] [ 26 , 27 ]. Grade ≥ 3 TEAEs occurred in 91.6% and 84.0% of patients (EAER 1.171 and 0.986 events/PY) in the respective groups. The primary system organ classes with a grade ≥ 3 TEAE incidence of > 15% in the isatuximab combination therapy and bortezomib–lenalidomide–dexamethasone groups were infections and infestations (44.9% and 38.1% of patients) and blood and lymphatic system disorders (38.4% and 33.1%). Notably, the incidence of grade ≥ 3 infections and infestations was lower with versus without antibiotic prophylaxis (which started at induction) in both patients receiving isatuximab–bortezomib–lenalidomide–dexamethasone (43.5% and 51.0%) and those receiving bortezomib–lenalidomide–dexamethasone (35.2% and 48.7%) [ 26 , 27 ]. The most frequently reported grade ≥ 3 TEAEs are presented in Fig. 1 . Grade 5 TEAEs occurred in 11.0% and 5.5% of patients (EAER 0.031 and 0.019 events/PY) in the isatuximab combination therapy and bortezomib–lenalidomide–dexamethasone groups and mainly resulted from infection (in 6.5% and 3.9% of patients), including COVID-19 (in 3.0% and 1.1%) [ 26 ]. No Grade 5 TEAEs were reported in patients aged < 65 years: they were observed in 10.7% and 13.2% of patients aged 65–74 years and ≥ 75 years [ 7 ]. Fig. 1 The most common (incidence ≥ 10% in either treatment group) grade ≥ 3 treatment-emergent adverse events in adults with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant in IMROZ [ 27 ]. d dexamethasone, Isa isatuximab, R lenalidomide, V bortezomib

Treatment-related (i.e. related to ≥ 1 drug) TEAEs of any grade were seen in 97.7% and 96.7% of isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone recipients [ 26 , 27 ]. Neutropenia (occurring in 29.3% vs 21.0% of patients), fatigue (24.7% vs 22.1%), infusion-related reactions (IRRs; 23.2% vs 0%) and cataract (20.9% vs 13.8%) were the most commonly observed (incidence > 20.0% in either group) treatment-related TEAEs of any grade reported more frequently with isatuximab combination therapy than bortezomib–lenalidomide–dexamethasone [ 27 ]. Treatment-related grade ≥ 3 TEAEs occurred in 76.8% and 68.0% of patients, with peripheral sensory neuropathy (7.2% vs 6.1%) and neutropenia (29.3% vs 19.9%) being the most common and reported more frequently with isatuximab combination therapy than with bortezomib–lenalidomide–dexamethasone [ 27 ].

Serious TEAEs were reported in 70.7% and 67.4% of patients in the isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone groups, with grade ≥ 3 serious TEAEs occurring in 65.0% and 58.0% of patients [ 26 , 27 ]. Infections and infestations were the most frequently reported serious TEAE (in 44.1% and 36.5% of patients, respectively) and grade ≥ 3 serious TEAE (in 40.7% and 33.1% of patients, respectively) by primary system organ class [ 26 , 27 ]. Pneumonia was the most frequently reported severe infection: grade 3, 4 and 5 pneumonia, respectively, occurred in 17.5%, 1.1% and 1.5% of isatuximab combination therapy recipients and 8.8%, 2.8% and 1.1% of bortezomib–lenalidomide–dexamethasone recipients [ 26 ]. Approximately one-third (33.1% and 32.0%) of patients (EAER 0.375 and 0.435 events/PY) in the respective groups experienced serious treatment-related TEAEs [ 26 ].

Four (1.5%) patients in the isatuximab–bortezomib–lenalidomide–dexamethasone group and one (0.6%) patient in the bortezomib–lenalidomide–dexamethasone group died within 60 days following receipt of the first dose [ 26 ]. The difference between the groups was in part driven by their different treatment exposures. At 6 months, ten (3.8%) and eight (4.4%) patients in the isatuximab combination therapy and bortezomib–lenalidomide–dexamethasone groups had died; the deaths of six (2.3%) and four (2.2%) patients were due to AEs [ 26 ].

In terms of haematological laboratory abnormalities that occurred during the treatment period, the incidences of grade ≥ 3 anaemia, lymphopenia, neutropenia, leukopenia and thrombocytopenia, respectively, were 17.5%, 60.1%, 54.4%, 31.6% and 30.3% with isatuximab combination therapy and 16.0%, 53.0%, 37.0%, 16.6% and 27.6% with bortezomib–lenalidomide–dexamethasone [ 26 ].

Treatment-emergent anti-drug antibodies (ADAs) were detected in 22 (8.7%) of 253 evaluable patients, with 21 and 1 patient(s) considered to have a transient or indeterminate ADA response [ 8 ]. Neutralizing antibodies were detected in 13 of the 22 ADA-positive patients (i.e. 5.1% of the evaluable patient population). Among patients who tested positive for ADAs to isatuximab, there was no meaningful impact on efficacy [ 8 ].

Adverse Events of Special Interest

AEs of special interest (AESIs) included a grade ≥ 3 infusion reaction, a symptomatic overdose with the study treatment or a non-investigational medicinal product, the presence of a second primary cancer, and pregnancy (in either a patient or partner) [ 26 , 27 ]. In IMROZ, AESIs occurred in 13.7% of isatuximab–bortezomib–lenalidomide–dexamethasone recipients and 7.2% of bortezomib–lenalidomide–dexamethasone recipients [ 27 ]. Any grade of invasive solid tumour secondary primary cancer occurred in 22 (8.4%) and 8 (4.4%) of patients, respectively [ 26 ]. Most of the solid tumours were nonmelanoma skin cancers. Haematological cancer was infrequently reported in the isatuximab–bortezomib–lenalidomide–dexamethasone and bortezomib–lenalidomide–dexamethasone groups (1.1% and 1.1%) [ 26 ]. Two (0.8%) patients receiving isatuximab–bortezomib–lenalidomide–dexamethasone experienced a grade ≥ 3 infusion reaction (vs 0% of patients receiving bortezomib–lenalidomide–dexamethasone) [ 27 ]. TEAEs resulting in definitive treatment discontinuation were reported in 22.8% of isatuximab combination therapy recipients and 26.0% of bortezomib–lenalidomide–dexamethasone recipients (EAER 0.066 and 0.090 events/PY) [ 26 ]. Grade ≥ 3 TEAEs resulting in definitive treatment discontinuation occurred in 1.7% and 20.4% of patients in the respective groups [ 26 ].

Dosage and Administration of Isatuximab

When used in combination with bortezomib, lenalidomide and dexamethasone, the recommended dose of isatuximab is 10 mg/kg body weight, administered as an intravenous infusion, on days 1, 8, 15, 22 and 29 of the first 42-day treatment cycle, days 1, 15 and 29 (i.e. every 2 weeks) of the second, third and fourth 42-day treatment cycles, days 1 and 15 (i.e. every 2 weeks) of the fifth to seventeenth 28-day treatment cycles, and day 1 (i.e. every 4 weeks) of the eighteenth and subsequent 28-day treatment cycles [ 7 , 8 ]. Treatment is continued until disease progression or unacceptable toxicity. A fixed volume of 250 mL of isatuximab is administered at each infusion, with an infusion rate of 25, 50 and 200 mL/h used for the first, second and all subsequent infusions, respectively [ 7 , 8 ]. Incremental escalation of the infusion rate should be considered only in the absence of IRRs [ 8 ], with administration adjustments made if IRRs occur [ 7 ].

To reduce the risk and severity of IRRs, patients should receive premedication 15–60 min prior to an infusion of isatuximab that should also incorporate the dexamethasone component of bortezomib–lenalidomide–dexamethasone [ 7 , 8 ]. Patients who do not experience an IRR upon their first four administrations of isatuximab may have their need for subsequent premedication reconsidered [ 7 ]. To avoid potential RBC transfusion issues, patients receiving isatuximab should undergo blood type and screen tests before the first infusion [ 7 , 8 ].

Local prescribing information should be consulted in the first instance and for detailed information regarding the preparation, dosage and administration of isatuximab, recommended premedication agents, serum protein electrophoresis and immunofixation testing, serological testing, use in special patient populations, contraindications and warning and precautions.

Place of Isatuximab in the Management of Transplant-Ineligible Newly Diagnosed Multiple Myeloma

The management of patients with transplant-ineligible NDMM is associated with several unmet clinical needs [ 35 ]. Eligibility for ASCT and access to both treatments and monitoring tools vary globally, particularly in elderly and/or frail patients [ 11 , 35 ]. Moreover, comorbidities and decreased organ function may contribute to an increased vulnerability to AEs and treatment adherence, and frail and high-risk patients are underrepresented in clinical trials [ 35 ].

In current EHA–EMN evidence-based guidelines, isatuximab in combination with bortezomib, lenalidomide and dexamethasone (I, A for level of evidence and grade of recommendation) is recommended as a first-line option for the treatment of patients aged < 80 years with NDMM who are ineligible for ASCT and have an IMWG FS of < 2 [ 11 ]. The combination of isatuximab with bortezomib, lenalidomide and dexamethasone is also recommended as a preferred regimen (category 1) for the primary treatment of patients aged < 80 years with MM who are not frail and for whom haematopoietic cell transplant is deferred or not indicated in the latest NCCN guidelines for multiple myeloma [ 12 ]. The current American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) joint clinical practice guideline [ 36 ] was published prior to the EU and US approval of isatuximab as combination therapy in this setting.

The EU [ 7 ] and US [ 8 ] approvals for isatuximab in combination with bortezomib, lenalidomide and dexamethasone for the treatment of adults with NDMM who are ineligible for ASCT were based on data from the phase III IMROZ study. In this study, isatuximab–bortezomib–lenalidomide–dexamethasone significantly prolonged PFS (with median PFS not reached after a median follow-up of 59.7 months) versus bortezomib–lenalidomide–dexamethasone (Sect. 4 ). Isatuximab–bortezomib–lenalidomide–dexamethasone was also generally associated with deeper responses. At a median follow-up of 59.7 months, OS data were immature, but median OS had not been reached. Adding isatuximab to bortezomib–lenalidomide–dexamethasone did not affect HR-QOL (Sect. 4 ).

Frailty is described as a reduction in physiological function accompanied by a susceptibility to stressors and a high risk of poor health-related conditions (e.g. infections) that leads to increased morbidity and mortality [ 11 ]. Frail patients with MM are harder to treat than fit patients as they are less likely to tolerate MM therapeutic regimens [ 28 ]. Such patients have exhibited worse outcomes than non-frail patients: they have higher rates of dose reductions and treatment discontinuations, which result in shorter PFS and OS [ 28 ]. In a post hoc subgroup analysis in IMROZ, isatuximab combination therapy demonstrated benefits in PFS and MRD rates over bortezomib–lenalidomide–dexamethasone regardless of patient frailty status (Sect. 4 ).

Among the recognized limitations of anti-CD38 monoclonal antibodies are interference with laboratory tests such as SPEP and IFE (which potentially confounds response evaluation) and blood transfusion tests (which may complicate blood compatibility assessments), autoimmune AEs, infections and IRRs [ 9 ]. Effective communication between clinicians and laboratory/blood bank staff is required when assessing therapeutic responses [with a validated isatuximab-specific IFE assay also available [ 20 ] (Sect. 2 )] and to minimize delays in providing RBCs, and pre- and post-infusion medications are recommended to prevent IRR development [ 9 ]; see Sect. 2 and local prescribing information for details.

In IMROZ, isatuximab combination therapy had a safety profile consistent with that previously established for isatuximab (Sect. 5 ). A slightly higher toxicity (notably IRRs, pneumonia, severe neutropenia, and secondary primary cancer, which are all known safety concerns associated with other isatuximab-containing treatment regimens) resulted from the addition of isatuximab to bortezomib–lenalidomide–dexamethasone [ 27 ]. Infection (e.g. pneumonia, upper respiratory tract infection) is a frequent and substantial complication of MM [ 37 ]. With the risk of pneumonia amplified by the profound immune dysfunction associated with the disease and worsened by therapy, routine infection control measures (e.g. antimicrobial prophylaxis, vaccination, and close monitoring by both the clinician and the patient) are necessary in patients with MM undergoing treatment to mitigate the risk of pneumonia [ 37 , 38 ]. Patient education on reducing infection exposure via handwashing, social distancing and vaccinations is vital [ 38 ].

Patients receiving isatuximab–bortezomib–lenalidomide–dexamethasone experienced numerically slightly higher incidences of treatment-related TEAEs, grade ≥ 3 TEAEs and serious TEAEs than those receiving bortezomib–lenalidomide–dexamethasone (Sect. 5 ). These between-group differences may have been influenced by the length of exposure (53.2 months vs 31.3 months in the respective groups), given that some of the differences were less pronounced following adjustment for exposure. However, the incidences of grade ≥ 3 TEAEs and IRRs were numerically higher with isatuximab combination therapy than bortezomib–lenalidomide–dexamethasone following adjustment for exposure, with the IRR result expected given that isatuximab is the only treatment drug in the study administered via infusion. The incidence of both serious TEAEs and TEAEs resulting in definitive treatment discontinuation was generally similar between the groups (Sect. 5 ).

An acknowledged limitation of IMROZ was that black patients were underrepresented [ 26 ]. Efficacy, HR-QOL and tolerability data from the remaining interim and final PFS and OS analyses of data from this study are awaited with interest. Real-world data and robust cost effectiveness analyses would further elucidate the role of isatuximab combination therapy in adults with NDMM who are ineligible for ASCT, and a head-to-head comparison of isatuximab- and daratumumab-containing regimens would be of interest.

Although beyond the scope of this review, it is worth noting that a subcutaneous formulation of isatuximab, delivered via an on-body injector, in combination with bortezomib, lenalidomide and dexamethasone is currently being evaluated in adults with NDMM who are ineligible for ASCT in a multicentre phase II study (ISASOCUT) [ 39 ].

In conclusion, although further interim and final PFS and OS data are awaited, current evidence indicates that isatuximab in combination with bortezomib, lenalidomide and dexamethasone is a useful addition to the treatment options available for adults with NDMM who are ineligible for ASCT.

Data Selection Isatuximab: 116 records identified

Duplicates removed 8 Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial) 37 Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials) 32 Cited efficacy/tolerability articles 12 Cited articles not efficacy/tolerability 27 Search Strategy: Cochrane Library, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were isatuximab, Sarclisa, SAR650984, multiple myeloma. Records were limited to those in English language. Searches last updated 30 March 2026.

Supplementary Information

Below is the link to the electronic supplementary material. Supplementary file1 (PDF 210 kb)

The manuscript was reviewed by : F. Malavasi , Lab of Immunogenetics, Department of Medical Sciences, University of Torino and Fondazione Ricerca Molinette Ets, Torino, Italy; T. Martin , Division of Hematology-Oncology, University of California San Francisco, San Francisco, CA, USA; J. Vela-Ojeda , Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico.

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Change history

8/13/2026

This article was originally published under the subscription model but it is now published under an Open Access license.

Acknowledgements

During the peer review process, the manufacturer of isatuximab was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Funding

The preparation of this review was not supported by any external funding. After publication, Sanofi requested that the article be made Open Choice and funded post-publication open access.

Declarations

Authorship and Conflict of interest

Sheridan M. Hoy is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.

Ethics Approval, Consent to Participate, Consent to Publish, Availability of Data and Material, Code Availability

Not applicable.

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