Introduction
Combination of the anti-CD38 monoclonal antibody isatuximab with conventional doublet or triplet regimens provides significant benefit to patients across the therapeutic spectrum for multiple myeloma (MM) [ 1 – 5 ]. Isatuximab induces MM cell death through a distinctive mechanism of action that involves multiple tumor-targeting pathways: antibody-mediated effector functions (antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and partly through complement-dependent cytotoxicity), direct induction of cell death, CD38 enzyme inhibition, and immune modulation [ 5 – 8 ]. Isatuximab is approved for intravenous (IV) use in various countries in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of transplant-ineligible patients with newly diagnosed MM (NDMM), and with pomalidomide and dexamethasone (Pd) or carfilzomib and dexamethasone (Kd) for patients with relapsed/refractory multiple myeloma (RRMM) [ 9 , 10 ].
Administration of isatuximab subcutaneously (SC) would offer a more convenient and efficient treatment option by providing an enhanced treatment experience and time savings compared with IV infusion, along with a reduction in the utilization of healthcare resources [ 11 – 16 ]. It has the potential to improve access and facilitate adherence to treatment, particularly for MM patients who need long-term treatment in order to achieve or maintain optimal disease control [ 15 ]. SC administration may also reduce the risk of infusion reactions (IRs), owing to the less abrupt rise to peak concentration, and may provide a suitable option for patients with cardiac or renal impairment due to the low volume administered (10 mL SC versus 250 mL IV). However, SC injections by manual push utilize a visible, 23-25 gauge needle, which may induce patient anxiety and compromise comfort. Furthermore, application of strenuous pressure at a steady rate over several minutes for manual injection may add to the physical burden of healthcare providers (HCPs) [ 17 , 18 ]. Therefore, there is an opportunity to improve practice efficiency and overall treatment experience for patients and HCPs, particularly considering the continued expansion of CD38 antibody use and increased duration of treatment.
The on-body injector (OBI; previously called on-body delivery system or OBDS), is an innovative, wearable injector device applied by a healthcare professional (HCP) that allows hands-free administration of isatuximab SC, in a 10-mL injection volume without hyaluronidase, through a small (30-gauge), hidden needle, at an individualized flow rate based on subcutaneous interstitial pressure [ 15 – 18 ]. A previously reported Phase 1b study demonstrated the efficacy and safety profile for isatuximab administered SC via OBI, infusion pump, or IV in combination with Pd in patients with RRMM, consistent with findings from the randomized Phase 3 ICARIA-MM study with IV administration of isatuximab plus Pd [ 16 , 19 ]. IRAKLIA ( NCT05405166 ) was the first randomized Phase 3 trial to test an OBI in the field of myeloma, and demonstrated comparable efficacy (overall response rate [ORR; 95% CI] = 1.008 [0.903–1.126]) and pharmacokinetics (PK), along with a similar safety profile, for isatuximab in combination with Pd administered SC via OBI or IV in patients with RRMM [ 20 ]. IRAKLIA further demonstrated a substantially lower incidence of IRs with isatuximab OBI versus IV infusion (1.5% vs. 25.0%), with 99.9% of OBI injections completed without interruptions [ 20 ].
Isatuximab administered IV in combination with Kd has shown significant benefit for patients with RRMM after 1 prior therapy in the randomized Phase 3 IKEMA study, which led to its approval for this patient population [ 3 , 9 , 10 ]. In the Phase 2 IZALCO study reported here, we evaluated efficacy, patient preference, safety, and PK for isatuximab administered SC by OBI or manual injection, in combination with Kd, in patients with RRMM.
Methods
Study design, endpoints, and treatment
The primary objective of the randomized, sequential, open-label, Phase 2 IZALCO study ( NCT05704049 ) was to assess the efficacy of isatuximab SC plus Kd in patients with RRMM who had received 1 to 3 prior lines of therapy.
In Part 1 of the study, patients received isatuximab SC injected manually in cycles 1–6. In Part 2, patients were randomized with a 3:1 randomization ratio (using interactive response technology) to isatuximab administered SC by manual injection in cycles 1–3 followed by OBI administration in cycles 4–6 or to isatuximab OBI administration in cycles 1–3 followed by manual injection in cycles 4–6. From cycle 7, in both Parts 1 and 2, patients could choose either treatment modality (Fig. 1 ).
The primary study endpoint was overall response rate (ORR). Patient preference for the modality of isatuximab SC administration—OBI or manual injection—was the key secondary endpoint, evaluated in the randomized cohort in Part 2 of the study. Other secondary endpoints included safety, incidence of IRs, incidence of injection site reactions (ISRs), as well as isatuximab PK and immunogenicity.
Isatuximab was administered SC weekly in cycle 1 (28-day cycles) then biweekly, at the flat dose of 1400 mg. All patients received treatment with intravenous carfilzomib at 20 mg/m 2 on days 1–2, then at 56 mg/m 2 on days 8–9 and 15–16 in cycle 1, and days 1–2, 8–9, and 15–16 of further cycles, and intravenous/oral dexamethasone at 20 mg on days 1–2, 8–9, 15–16, and 22–23. Patients continued treatment until disease progression, unacceptable adverse events (AEs), patient request to discontinue treatment, or any other reason.
The study was approved by the local health authorities and the Institutional Review Board or Independent Ethics Committee at each study center. The study was conducted following the Declaration of Helsinki and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice. All patients provided written informed consent.
Isatuximab SC administration
Isatuximab was given to patients by manual SC administration (over 8 min and then over 6 min in Part 1, and over 6 min in Part 2; Fig. 1 ) using a commercially available syringe and a butterfly infusion set, with injection by manual push (23-gauge needle) at a single site in the periumbilical region. Isatuximab was also administered SC using the OBI (30-gauge needle) applied by an HCP at a single site in the periumbilical region, which was rotated at each administration (Supplementary Fig. S1 ). The isatuximab OBI is a wearable injector, which includes an adhesive backing to secure it to the injection site during administration. At the end of dosing, the injection needle retracts to prevent injuries and the device enters a locked-out state.
Key inclusion/exclusion criteria
Adult patients with RRMM were enrolled in the study if they had measurable disease, had received at least 1 prior line of anti-myeloma therapy, and had adequate hematologic, liver, and renal functions (estimated glomerular filtration rate ≥15 mL/min/1.73 m 2 ).
Patients were not included if they had primary refractory disease, an Eastern Cooperative Oncology Group performance status >2 or a life expectancy ≤3 months, had experienced serious cardiac disease within 6 months prior to start of study treatment, had a left ventricular ejection fraction <40%, had been diagnosed or treated for another malignancy within 3 years prior to study treatment (except for completely resected basal cell carcinoma or squamous cell carcinoma of the skin, in situ malignancies, or low-risk prostate cancer), or were known to have an acquired immunodeficiency syndrome-related illness or HIV+ disease requiring antiviral treatment, active hepatitis A, or active/chronic hepatitis B or C. Furthermore, patients were excluded from the study if they had received prior carfilzomib therapy, had received anti-CD38 therapy less than 9 months prior to study treatment or randomization, were intolerant to anti-CD38 therapy, or had received prior anticancer therapy within 14 days of study treatment start, including dexamethasone.
Assessments
Myeloma response or progression were determined by the Independent Review Committee (IRC) based on central laboratory values, local assessment of radiological images, and local bone marrow assessment (plasma cell infiltration) using the 2016 International Myeloma Working Group (IMWG) criteria.
Patient preference for the method of SC administration, defined as the proportion of patients preferring OBI over manual administration of isatuximab SC at cycle 6/day 15, after the patients had experienced both delivery methods, was assessed using the patient experience and satisfaction questionnaire v.2 (PESQ v.2). HCP preference for OBI or manual administration was assessed through the HCP questionnaire completed at cycle 7/day 1 by the physician or nurse who treated the patient. Health-related quality of life (QoL) was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30). Safety was evaluated in all treated patients and reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
Blood samples were collected for measurement of isatuximab concentrations at prespecified timepoints over the first cycle and then mainly at pre-dose. A robust and high-throughput Gyrolab Platform was used to measure isatuximab levels with a lower limit of quantitation of 5.0 µg/mL [ 21 , 22 ]. PK parameters were assessed and summarized by descriptive statistics for patients in the randomized cohort by non-compartmental analysis (Phoenix version 8.2), from plasma concentrations obtained after isatuximab SC administration (over the first and fourth administration, and over the 4 weekly administrations). Blood samples to assess isatuximab immunogenicity were collected at prespecified pre-administration timepoints as well as 3 months after the last isatuximab administration. A validated polyethylene glycol precipitation and acid dissociation method was used for anti-drug antibody analysis [ 23 , 24 ].
Statistical analysis
The efficacy population included all patients who had taken ≥1 dose of study treatment and had a baseline and ≥1 post-baseline efficacy assessment or disease progression or death from disease progression. For the primary endpoint of ORR, a total sample size of 64 patients would provide a 95% power to reject the null hypothesis of an ORR of 65% against a target ORR of 85%, at a one-sided 2.5% significance level. In absence of confirmed partial response or better, participants were considered as non-responders, including participants with missing or non-evaluable best overall response. The target ORR (alternative hypothesis) was based on the ORR of 86.6% (95% CI 80.7–91.2) observed with Isa-Kd IV treatment in the IKEMA study [ 3 ]. The ORR was summarized with a two-sided 95% confidence interval (CI) using the Clopper-Pearson method.
The patient preference population consisted of all the randomized patients who had taken ≥1 dose of study treatment using both methods (OBI and manual administration), had not discontinued treatment prior to cycle 6/day 15, and had available PESQ v.2 data on preference for method of SC administration for cycle 6/day 15. For the key secondary endpoint of patient preference, it was estimated that approximately 48 participants would be included in the evaluable population. This sample size would provide 83% power to reject the null hypothesis of no preference for the OBI (null rate ≤50%) with a 1-sided 2.5% alpha level and assuming a target rate of 72%, which was based on the expected preference for OBI over manual administration. The patient preference results were summarized as the number and proportion of patients with a preference for OBI versus manual administration, with a two-sided 95% CI using the Clopper-Pearson method and a one-sided p -value based on the binomial test against the null hypothesis of a ≤50% rate.
Results
Patient disposition and baseline characteristics
Patients were enrolled from April 2023 to May 2024. Overall, 74 patients with RRMM were enrolled and treated with isatuximab SC plus Kd at 15 clinical sites across 6 countries (Australia, Brazil, Czech Republic, Greece, Japan, and Portugal): 8 in Part 1 and 66 in the randomized cohort (in Part 2; 42 patients starting with manual injection and 24 starting with OBI administration). The median number of cycles received by patients was 9 (range, 1–16 cycles). Fifty-three (71.6%) patients were still on treatment at the time of the analysis (Supplementary Fig. S2 ). The most frequent reason for discontinuation was disease progression, which occurred in 11 (14.9%) patients.
The patients on study had a median age of 65.0 years (range, 44–85); 56.8%, 32.4%, and 10.8% has ISS stage I, II, or III at study entry, respectively (Table 1 ). The majority (78.4%) had bone disease, with >10 bone lesions in 43.2% of the patients; 16.2% had soft tissue plasmacytoma, and 20.3% had an estimated GFR < 60 mL/min/1.73 m 2 .
Table 1
Patient demographics and baseline characteristics.
d dexamethasone, eGFR estimated glomerular filtration rate (MDRD equation), IMiD immunomodulatory drug, ISS International Staging System, K carfilzomib, MDRD Modification of Diet in Renal Disease, PI proteasome inhibitor, SC subcutaneous. a High risk was defined as the presence of del(17p), and/or t(4;14), and/or t(14;16). Abnormality was defined as ≥30% abnormal plasma cells for t(4;14) and t(14;16), and ≥50% abnormal plasma cells for del(17p).
| Isatuximab SC + Kd All patients N = 74 | |
| Age, median (range), years | 65.0 (44–85) |
| Female—male, n (%) | 33 (44.6)—41 (55.4) |
| Body weight, median (range) kg | 75.9 (40.0–129.0) |
| ≤65 kg, n (%) | 25 (33.8) |
| >65 to ≤85 kg, n (%) | 28 (37.8) |
| >85 kg, n (%) | 21 (28.4) |
| ISS stage at study entry, n (%) | |
| I | 42 (56.8) |
| II | 24 (32.4) |
| III | 8 (10.8) |
| MM subtype at study entry, n (%) | |
| IgG | 47 (63.5) |
| IgA | 15 (20.3) |
| IgM | 1 (1.4) |
| Kappa light chain only | 7 (9.5) |
| Lambda light chain only | 4 (5.4) |
| Bone marrow plasma cells at baseline, (%) median (range) | 13.50 (0–88.0) |
| Soft tissue plasmacytoma, n (%) | 12 (16.2) |
| Bone lesions, n (%) | 58 (78.4) |
| eGFR <60 mL/min/1.73 m 2 | 15 (20.3) |
| Cytogenetic risk, n (%) | |
| High risk a | 12 (16.2) |
| Standard risk | 39 (52.7) |
| Unknown | 23 (31.1) |
| Number of prior lines, median (range) | 1 (1–5) |
| 1, n (%) | 41 (55.4) |
| 2, n (%) | 21 (28.4) |
| 3, n (%) | 10 (13.5) |
| >3, n (%) | 2 (2.7) |
| Refractory to, n (%) | |
| IMiD | 34 (45.9) |
| PI | 31 (41.9) |
| IMiD and PI | 14 (18.9) |
| Prior anti-CD38 therapy | 0 |
The patients had received a median of 1 (1–5) prior line of anti-myeloma therapy; 45.9% were refractory to an immunomodulatory drug, 41.9% to a proteasome inhibitor, and 18.9% to both. None of the patients had previously received treatment with an anti-CD38 antibody.
Efficacy
At a median follow-up of 10.1 months (at the cut-off date of November 8, 2024), the ORR was 79.7% for all patients ( N = 74); 62.2% had a very good partial response or better ( ≥ VGPR) (Fig. 2 ). In the randomized cohort, ORR and ≥VGPR rates were similar between patients starting with manual injections and those starting with OBI administration: 81.0% vs. 79.2% and 66.7% vs. 62.5%, respectively.
Overall, the median time to first response was 1.05 (95% CI, 0.986–1.216) months and 3.81 (95% CI, 2.825–4.632) months to best response (Supplementary Table S1 ). PFS is still immature and the estimated median PFS was not reached in this study (95% CI, 13.14 months to not reached, N = 74).
Patient preference for isatuximab SC administration via OBI versus manual injection
After treatment with both modalities for isatuximab SC administration, significantly more patients, 74.5%, expressed a preference for the OBI rather than manual injection, compared with 17% who preferred manual injection ( p = 0.0004; binomial test against the null hypothesis of a ≤ 50% rate) ( n = 47); 8.5% of patients had no preference for either method (Fig. 3 ). Five of the 8 patients who preferred manual administration received treatment at the same clinical site.
Based on the answers provided to the questionnaire, patients preferred isatuximab SC administration via OBI citing comfort (60.0% of the respondents, 21/35), convenience (34.3%, 12/35), and less pain at the injection site (34.3%, 12/35) as drivers of preference. Forty-seven (90.4%) of the 52 patients who reached cycle 7 after receiving OBI or manual injections in the randomized cohort chose to continue with isatuximab OBI administration from cycle 7 onwards while 5 patients (9.6%) chose manual administration. Further, mean global health status/QoL EORTC-QLQ-C30 scores were stable over time relative to baseline in both arms (Supplementary Fig. S3 ).
HCP preference for isatuximab SC OBI versus manual administration
Of 19 HCPs (16 nurses, 3 physicians) who answered the questionnaire, the majority—78.9%—preferred using the OBI for delivery of isatuximab SC, none preferred manual injection, and 21.1% had no preference for either modality (OBI or manual) (Fig. 3 ). The 4 HCPs who expressed no preference were from the same clinical site where 5 of 8 patients preferred manual administration. All 19 HCPs agreed that using the OBI was a reliable and easy method to administer isatuximab SC.
Treatment exposure and safety
Overall, the median duration of exposure was 34.1 weeks (range, 1–65.6) with a high median relative dose intensity (RDI) of 92.4% for isatuximab (range, 71–106.5) and a median RDI for carfilzomib of 86.9% (49.8–101.6). The median RDI for isatuximab was comparable across the study cohorts (92–94.5%).
The rate of AEs leading to full treatment discontinuation was 8.1% (6/74), due to lower respiratory tract infection, meningitis, acute pulmonary edema, acute respiratory distress syndrome, multiforme erythema, and death. No patient discontinued isatuximab only, while 2 (2.7%) patients permanently discontinued carfilzomib only and 4 (5.4%) permanently discontinued dexamethasone only. Four patients died within 30 days of the last treatment administration due to an AE, including meningitis, acute pulmonary edema, acute respiratory distress syndrome, and sudden death, which were considered not related to study treatment.
Overall, grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients and serious TEAEs in 40.5% of them (Table 2 ; N = 74). The most common TEAEs of any grade (in >10% of patients) were upper respiratory tract infection (37.8%), pneumonia (16.2%), hypertension (13.5%), COVID-19 (12.2%), insomnia (12.2%), diarrhea (10.8%), and pyrexia (10.8%) (Table 3 ). Grade ≥3 non-hematologic TEAEs occurring in more than 2% of patients were pneumonia (9.5%), hypertension (4.1%), and insomnia (2.7%). Less than 10% of patients had hematologic abnormalities of any grade reported as TEAEs. Grade 3–4 neutropenia or grade 3–4 thrombocytopenia were observed as laboratory abnormalities in 15.1% and 19.2% of patients, respectively ( N = 73) (Supplementary Table S2 ). Only 1 patient (1.4%) developed febrile neutropenia. The overall safety was similar across treatment cohorts (Supplementary Table S3 ).
Table 2
Safety summary.
AE adverse event, d dexamethasone, K carfilzomib, SC subcutaneous, TEAE treatment-emergent adverse event. a TEAEs included all AEs occurring during the treatment period up to 30 days after last dose of study treatment (treatment-emergent period).
| Isatuximab SC + Kd All patients N = 74 | |
| n (%) | |
| Any TEAE | 69 (93.2) |
| Grade ≥3 TEAE | 40 (54.1) |
| Treatment-related grade ≥3 TEAE | 26 (35.1) |
| Serious TEAE | 30 (40.5) |
| Fatal TEAE a | 4 (5.4) |
| TEAE leading to permanent full treatment discontinuation | 6 (8.1) |
| TEAE leading to permanent partial treatment discontinuation | 6 (8.1) |
| Isatuximab | 0 |
| Carfilzomib | 2 (2.7) |
| Dexamethasone | 4 (5.4) |
Table 3
Most common TEAEs reported in ≥5% of patients.
AE adverse event, d dexamethasone, K carfilzomib, SC subcutaneous, TEAE treatment-emergent adverse event.
| Isatuximab SC + Kd All patients N = 74 | ||
| n (%) | Any grade | Grade ≥ 3 |
| Any AE | 69 (93.2) | 40 (54.1) |
| Upper respiratory tract infection | 28 (37.8) | 1 (1.4) |
| Pneumonia | 12 (16.2) | 7 (9.5) |
| Hypertension | 10 (13.5) | 3 (4.1) |
| COVID-19 | 9 (12.2) | 0 |
| Insomnia | 9 (12.2) | 2 (2.7) |
| Diarrhea | 8 (10.8) | 0 |
| Pyrexia | 8 (10.8) | 1 (1.4) |
| Fatigue | 7 (9.5) | 0 |
| Neutropenia | 7 (9.5) | 6 (8.1) |
| Thrombocytopenia | 7 (9.5) | 5 (6.8) |
| Dyspnea | 6 (8.1) | 1 (1.4) |
| Headache | 6 (8.1) | 1 (1.4) |
| Nasopharyngitis | 6 (8.1) | 0 |
| Nausea | 6 (8.1) | 0 |
| Respiratory tract infection | 6 (8.1) | 1 (1.4) |
| Vomiting | 6 (8.1) | 0 |
| Anemia | 5 (6.8) | 3 (4.1) |
| Cough | 5 (6.8) | 0 |
| Edema peripheral | 5 (6.8) | 0 |
| Back pain | 4 (5.4) | 0 |
| Bone pain | 4 (5.4) | 1 (1.4) |
| Phlebitis | 4 (5.4) | 0 |
| Rhinitis | 4 (5.4) | 0 |
Two patients (2.7%) experienced a single IR episode (one consisting of grade 1 tachycardia starting 2.9 h after the first dose and one of grade 2 pyrexia, tachycardia, and tremor starting 4.9 h after the first dose), which both occurred with manual injection. No IRs occurred with OBI administration and all isatuximab OBI injections were completed with no interruptions.
Fourteen ISR episodes (all grade 1, except for 1 of grade 2) occurred in 6 (8.1%) patients, with an overall incidence of 1.08% in a total of 1297 manual or OBI injections. The incidence of ISRs was similar between manual injections (8/597; 1.34%) and OBI injections (6/700; 0.86%), with no interruptions in isatuximab SC dosing.
Almost all ISR episodes (13/14; 92.9%) occurred on the day of injection (1 of 14 [7.1%] was observed the day after injection) and most episodes (84.6%) resolved within the same day. Five ISR episodes occurred in cycle 1 and 9 episodes in the subsequent cycles. The ISR manifestations observed in treated patients consisted of 7 erythemas, 4 indurations, 3 swelling, 2 edema, 1 pain, and 1 pruritus, at the injection site. Mild OBI-related ISRs (grade 1) were reported in 1 (1.4%) patient, including erythema and injection site induration at cycle 4, and erythema, pruritus, and injection site induration at cycle 5. All ISRs in this patient resolved on the day of injection with no supportive treatment required.
Pharmacokinetics
Isatuximab was quantifiable in plasma from the first administration. PK analyses showed that comparable PK exposure was achieved with isatuximab SC OBI and manual administration after the first administration and over cycle 1, corresponding to the weekly administration period (Table 4 ). The exposure remained comparable over time (Fig. 4 ). Total variability was generally moderate. In the randomized cohort, mean trough concentration (C trough ) at cycle 6/day 15 was 672.46 µg/mL (SD, 74.8) in SC OBI patients who started with manual injection and 614.76 µg/mL (SD, 65.3) in SC manual patients who started with OBI administration.
Table 4
Isatuximab PK parameters by treatment arm.
AUC last area under the concentration-time curve from time zero to t last (corresponding to C1D8 over 1st administration, or C2D1 over 4th administration and over 4 weekly administrations), C max maximum concentration observed, CV coefficient of variation, h hour, OBI on-body injector, PK pharmacokinetics, SC subcutaneous, SD standard deviation, t max time to reach C max . a Median.
| Cycle 1 | Isatuximab SC | |||||
| Mean ± SD (CV %) | Over 1st administration from C1D1 to C1D8 | Over 4th administration from C1D22 to C2D1 | Over 4 weekly administrations from C1D1 to C2D1 | |||
| Delivery method | OBI | Manual | OBI | Manual | OBI | Manual |
| n | 13 | 16 | 9 | 8 | 6 | 6 |
| C max (µg/mL) | 133 ± 70.7 (53) | 131 ± 40.6 (31) | 471 ± 138 (29) | 499 ± 148 (30) | 525 ± 150 (29) | 465 ± 120 (26) |
| t max a (h) | 165 | 162 | 95.3 | 93.9 | 599 | 598 |
| AUC last (μg h/ml) | 14,700 ± 9030 (62) | 13,600 ± 5000 (37) | 72,900 ± 28,600 (39) | 74,000 ± 21,200 (29) | 203,000 ± 79,000 (39) | 173,000 ± 37,600 (22) |
Immunogenicity
Out of the 72 patients evaluable for immunogenicity, 3 developed an anti-drug antibody response to isatuximab during treatment, resulting in a 4.2% incidence with either SC administration modality.
Discussion
While prior results from the randomized Phase 3 IRAKLIA trial of isatuximab administered SC via OBI versus IV and a Phase 1b study have demonstrated benefit with isatuximab SC in combination with Pd [ 16 , 20 ], in this Phase 2 IZALCO study we evaluated for the first time the efficacy and safety of isatuximab SC administered manually or via an innovative OBI to patients with RRMM in combination with a proteasome inhibitor, carfilzomib, and dexamethasone. The study met its primary endpoint with an ORR of 79.7% in all patients, at a median follow-up of 10.1 months, thus validating the pre-specified efficacy hypothesis. Similar efficacy was achieved regardless of the method used at the start of treatment with isatuximab SC (manual or OBI), supporting treatment with either method as well as the feasibility of transition from manual injection to OBI administration. In addition, this study demonstrated the safety and tolerability of isatuximab SC administered in combination with Kd, either by OBI or manual injection. These efficacy and safety findings are similar to those reported in the Phase 3 study IKEMA of isatuximab infused IV in combination with Kd, which showed an 87% ORR with a manageable safety profile, except for a notable, lower rate of IRs in IZALCO (2.7%) compared with IKEMA (46%) [ 3 ]. The incidence of anti-drug antibodies (4.2%) observed during treatment with either SC administration method was similar to the 4.3% rate reported for isatuximab SC in the IRAKLIA study [ 20 ].
Administration of isatuximab SC by OBI in combination with Kd was very well tolerated with no IRs and only few, mostly mild ISRs (consisting mainly of erythemas resolved within a day), as previously reported with isatuximab SC when given by OBI in combination with Pd [ 16 , 20 ], thus indicating the flexibility of this treatment approach across different combination regimens and the potential to alleviate patient anxiety about treatment delivery [ 17 ].
Of note, 74.5% of patients on this study expressed a preference for receiving isatuximab SC by OBI rather than by manual injection, after receiving both treatment modalities for 3 cycles each in the randomized cohort, and some of them noted that it was more comfortable, convenient, and associated with less pain. The more comfortable experience and less pain reported by patients may be due to the higher-gauge, hidden needle of the OBI compared with manual-push injection and the individualized flow rate of the OBI injections. These findings suggest that availability and access to a preferred treatment modality may increase patient adherence to treatment and thus contribute to optimizing clinical outcomes. Furthermore, these results are in line with the greater patient satisfaction with OBI administration than with IV infusion reported in the IRAKLIA trial [ 20 ] and the preference expressed by nurses in recent surveys for treating patients via OBI rather than IV [ 17 , 18 ]. In the surveys, nurses with clinical experience in using the OBI to administer isatuximab SC noted that patients had a better treatment experience with the OBI versus with IV infusion. In addition, they agreed that use of the OBI provided substantial time savings for both patients and healthcare providers compared with IV administration, thus facilitating a more efficient utilization of healthcare resources [ 17 , 18 ]. Consistently, assessment of the delivery method preferred by HCPs in IZALCO revealed a preference by the majority of HCPs (78.9%) for using the OBI, rather than manual injection, with all the HCPs who answered the questionnaire agreeing on the reliability and ease of use of the OBI, which contributed to eliminating the manual effort required for injection and the risk of repetitive strain injury. Such preference expressed by the HCPs as well as patients for the OBI indicates the possibility to increase practice efficiency and reduce physical burden for HCPs while ensuring patient and HCP satisfaction [ 17 , 18 ]. Nonetheless, the finding that 17% of patients preferred manual injection, 8.5% of patients had no preference, and 21.1% of the HCPs had no preference for either method suggests that administration by manual injection is also a viable option for treatment with isatuximab SC.
While IZALCO included patients with RRMM, further studies are evaluating isatuximab SC administration in NDMM: for the treatment of transplant-eligible patients in combination with bortezomib, lenalidomide, and dexamethasone (VRd) in the Phase 3 GMMG-HD8/DSMM XIX trial ( NCT05804032 ) and as maintenance therapy in combination with iberdomide in the GMMG-HD9 study ( NCT06216158 ). In addition, isatuximab SC is being evaluated in transplant-ineligible NDMM patients in combination with VRd in the multi-center Phase 2 IsaSoCut study ( NCT05889221 ).
There are a few considerations to note while interpreting the data reported here, including the duration of follow-up and sample size. First, a median follow-up time of 10.1 months may be an early readout for fully capturing PFS rates and determining the durability of response. Second, while the analysis was powered for evaluating patient preference between the different administration method groups, the sample size of 47 patients may be insufficiently powered to robustly investigate the preferences within subgroups (age, sex, body weight, etc.) Further research into factors that impact patient preference for methods of administration should be conducted.
In conclusion, our study findings with isatuximab SC plus Kd are consistent with the results of the intravenous isatuximab plus Kd arm of IKEMA, with no new safety signals besides a few low-grade ISRs associated with the SC administration route and a substantially lower rate of IRs. No impact of the SC delivery method—OBI or manual injection—was observed on the efficacy, safety, PK, and immunogenicity of isatuximab given SC in combination with Kd to patients with RRMM, supporting the feasibility of using the OBI as a convenient and preferred method for isatuximab SC administration across treatment regimens.
Supplementary information
Supplementary Information
Acknowledgements
The authors thank the participating patients and their caregivers, the study centers, and the investigators for their contributions to the study. This study was funded by Sanofi. The on-body injector was manufactured by Enable Injections, Inc. Medical writing support was provided by S. Mariani, MD, PhD, of Envision Pharma Group, funded by Sanofi.
Author contributions
GP, CS, DY, FS, and HQ contributed to the conception and design of this study. GP, MC, FS (Seguro), VH, MAD, SD, JM (Minarik), IS, LP, HM, GE, KS, JY, RH, JM (Mihályová), CS, DY, KB, VK, EC, PC, FS (Suzan), and HQ contributed to the analysis and interpretation of the data, and to drafting the paper or revising it critically for intellectual content. All authors GP, MC, FS (Seguro), VH, MAD, SD, JM (Minarik), IS, LP, HM, GE, KS, JY, RH, JM (Mihályová), CS, DY, KB, VK, EC, PC, FS (Suzan), and HQ approved the final manuscript.
Data availability
Qualified researchers may request access to patient-level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.vivli.org/ .
Competing interests
GP: Consulting/advisory role for Janssen and Sanofi. Honoraria from Bristol Myers Squibb and Sanofi. MC: Speaker’s bureau for Amgen, Janssen, and Sanofi. FeS: no competing interests. VH: Honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, Janssen, Sanofi, and Takeda; Support for attending meetings and/or travel from Amgen, Bristol Myers Squibb/Celgene, Janssen, and Sanofi; Participation on a Data Safety Monitoring Board or Advisory Board for Amgen, Bristol Myers Squibb/Celgene, and Janssen. MD: Honoraria from participation in advisory boards and satellite symposia for Amgen, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Menarini-Stemline, Regeneron, Sanofi, and Takeda. SD: Honoraria for advisory boards and satellite symposia Amgen, AOP Pharma, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Sanofi. JM: Consulting fees from Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, and Sanofi. Honoraria for lectures, presentations, and speaker bureaus from Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Pfizer, and Sanofi. Participation on a Data Safety Monitoring Board or advisory board for Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, and Sanofi. IŠ: Consulting fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Sanofi, and Takeda. Honoraria for lectures, presentations, and speaker bureaus from Amgen, Bristol Myers Squibb, Janssen-Cilag, Sanofi, and Takeda. Support for attending meetings and/or travel from Janssen-Cilag, Sanofi, and Takeda. Participation on a Data Safety Monitoring Board or advisory board for Amgen, Janssen-Cilag, Sanofi, and Takeda. LP, HM, GE: no competing interests. KS: Research funding from AbbVie, Beigene, Bristol Myers Squibb, Chugai, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin, Mitsubishi Tanabe, Novartis, ONO, Otsuka, Pfizer, Sanofi; Honoraria from Bristol Myers Squibb, Janssen, Pfizer, and Sanofi. JY: Research funding from AbbVie, Amgen, AstraZeneca, BrightPath Bio, Bristol Myers Squibb, Celaid Therapeutics, Chugai, Daiichi Sankyo, Genmab, Incyte, Janssen, Mitsubishi Tanabe, MSD, Novartis, Sanofi, Sumitomo Pharma, and Takeda. RH: Grants or contracts from Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, and Takeda. Consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, PharmaMar, and Takeda. Honoraria for lectures, presentations, and speaker bureaus: Amgen, Bristol Myers Squibb, Celgene, Janssen, PharmaMar, and Takeda. Support for attending meetings and/or travel from Amgen, Celgene, Janssen, and Takeda. Participation on a Data Safety Monitoring Board or advisory board for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Takeda. CS, DY, PC, EC, and FS: employed by Sanofi; may hold stock and/or stock options in the company. KB and VK: employed by Excelya on behalf of Sanofi; may hold stock and/or stock options in the company. HQ: Research funding from Bristol Myers Squibb, GlaxoSmithKline, Karyopharm, and Sanofi; Consulting/advisory role for Antengene, Beigene, Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Karyopharm, Regeneron, and Sanofi.
Ethics approval and consent to participate
The study was approved by the local health authorities and the Institutional Review Board or Independent Ethics Committee at each study center. The study was conducted following the Declaration of Helsinki and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice. All patients provided written informed consent.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41408-025-01436-0.
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Associated Data
Supplementary Materials
Supplementary Information
Data Availability Statement
Qualified researchers may request access to patient-level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.vivli.org/ .