Subcutaneous Isatuximab Delivery Is Noninferior to IV Administration in Multiple Myeloma

Subcutaneous delivery of isatuximab-irfc (Sarclisa) via an on-body injector (OBI; Isa SC OBI) resulted in noninferior responses, equivalent pharmacokinetics (PK), and a comparable safety profile to that of intravenously administered isatuximab (Isa IV) among patients with multiple myeloma, according to findings from the phase 3 IRAKLIA trial (NCT05405166).¹

Primary data presented during the 22nd Annual International Myeloma Society Meeting and Exposition showed that Isa SC OBI successfully met the study’s predefined noninferiority margin of 0.839 for its co-primary end point of overall response rate (ORR). The ORR for Isa SC OBI combined with pomalidomide (Pomalyst) and dexamethasone (Pd; n = 263) was 71.1%. This included a 24.7% partial response (PR) rate, a 28.5% very good PR (VGPR) rate, and a 17.9% stringent complete response (sCR) or complete response (CR) rate. Similarly, the ORR was 70.5% with Isa IV plus Pd (n = 268), yielding a relative risk of 1.008 (95% CI, 0.903-1.126; P = .0006). Corresponding rates of PR, VGPR, and sCR or CR were 24.6%, 25.4%, and 20.5%.

Noninferiority was also confirmed for the co-primary PK end point of isatuximab C_trough at steady state (predose on day 1 of cycle 6), as the lower CI of the geometric mean ratio (GMR), which was 1.532 (90% CI, 1.316-1.784), exceeded the noninferiority margin of 0.8. Furthermore, noninferiority was shown for the GMR of isatuximab C_trough at 4 weeks (predose on day 1 of cycle 2), a key secondary end point. The lower CI of this specific GMR, which was 1.302 (95% CI, 1.158-1.465), also remained above the 0.8 noninferiority margin.

“IRAKLIA is the first multiple myeloma phase 3 study to incorporate this innovative, hands-free OBI technology to maximize practice efficiency and patient convenience,” Xavier P. Leleu, MD, PhD, head of the Myeloma Clinic and Department of Haematology at Hospital La Mileterie, Poitiers, France, stated in a presentation of the data. “These data support OBI as a standard of care administration for patients with multiple myeloma.”

What Clinical Need Does Isa SC OBI Address in Multiple Myeloma?

IRAKLIA was initiated to evaluate the use of an advanced OBI for Isa SC delivery. The OBI is a sterile, single-use, user-filled wearable injector capable of automatically administering agents such as isatuximab subcutaneously without the reliance on batteries or electronic components. This opens the potential for at-home Isa SC administration.

“OBI is a round device that you stick to your skin and on the belly, and it’s hand-free,” Leleu explained. “It has a needle which is hidden to patients and retracted in the hand. It’s a very tiny needle of [approximately] 30 gauge that is much [smaller] than those we usually use for SC, man-made formulations. It’s also totally individualized to the thickness of [the patient’s] abdomen. [The patient] can see on the window that the product is going through, that it’s empty, and then it’s retracted. [Patients can then] take it out and trash it, and are good to go.”

Prior data from a phase 1b study (NCT04045795) indicated that administration of Isa SC via an on-body delivery system (OBDS) had a safety profile similar to that of IV administration, showing local tolerability and zero infusion reactions.² The rate of grade 3 or 4 treatment-related, treatment-emergent adverse effects (TEAEs) when using OBDS (n = 22) was 77.3%. Furthermore, the efficacy observed in the SC cohorts was comparable to findings from the phase 3 ICARIA-MM trial (NCT02990338). Specifically, for patients in the OBDS cohort (n = 32) treated with Isa SC plus Pd at the recommended phase 2 dose, the ORR was 78.1%, with a VGPR or better rate of 40.6%.

What Was the Design of the IRAKLIA Trial?

IRAKLIA enrolled 531 patients with relapsed or refractory multiple myeloma who were at least 18 years of age and had received 1 or more prior lines of therapy.¹ Patients were stratified by multiple myeloma isotype, body weight, and the number of prior lines of therapy.

Upon enrollment, eligible patients were randomly assigned 1:1 to receive Isa IV plus Pd or Isa SC OBI plus Pd in the following dosing schedules:

• Cycle 1
  • Isa IV: 10 mg/kg on days 1, 8, 15, and 22.
  • Isa SC OBI: 1400 mg on days 1, 8, 15, and 22.
  • Pomalidomide: 4 mg on days 1 to 21.
  • Dexamethasone: 40 mg on days 1, 8, 15, and 22.
• Cycle 2 and onward:
  • Isa IV: 10 mg/kg on days 1 and 15.
  • Isa SC OBI: 1400 mg on days 1 and 15.
  • Pomalidomide: 4 mg on days 1 to 21.
  • Dexamethasone: 40 mg on days 1, 8, 15, and 22.

Treatment continued until disease progression, intolerable toxicity, patient withdrawal, or another reason.

The study’s co-primary end points were ORR and C_trough (predose at day 1 cycle 6). VGPR or better, C_trough (predose at day 1 cycle 2), infusion reaction incidence rate, and patient satisfaction measured via PESQ on day 15 cycle 5, served as key secondary end points.

Were Patient Characteristics Balanced Between the SC and IV Arms at Baseline?

All patients on the Isa SC OBI arm (n = 263) initiated treatment vs 98.5% (n = 264) of patients in the Isa IV arm (n = 268). At the data cutoff of November 6, 2024, 56.7% of patients in the Isa SC OBI arm and 55.6% of those in the Isa IV arm remained on treatment. In the Isa SC OBI arm, the leading cause of treatment discontinuation was disease progression (30.8%), followed by adverse effects (AE; 8.4%), other reasons (3.0%), and patient request (1.1%). The median duration of follow-up was 12 months.

Baseline characteristics were generally well balanced between treatment arms. The median age was 66 years in both the Isa SC OBI arm (range, 36-86) and Isa IV arm (range, 31-85). Most patients were White (70% with Isa SC OBI vs 69% with Isa IV), male (70%; 69%), had an ECOG performance status of 0 (53%; 58%), had stage I disease at study entry (56%; 63%), and had standard cytogenetic risk (59%; 55%). In the Isa SC OBI arm, 29% of patients received 1 prior line of therapy, 35% had 2 prior lines, and 36% had 3 or more prior lines. All patients in this arm had been previously exposed to a proteasome inhibitor and an immunomodulatory drug, and 85% of patients were refractory to lenalidomide (Revlimid).

What Were the Additional PK and Efficacy Data With Isa SC OBI?

The rates of VGPR or better were 46.4% for Isa SC OBI plus Pd vs 45.9% for Isa IV plus Pd (relative risk, 1.011; 95% CI, 0.841-1.215; P < .0001). Noninferiority was also achieved for this secondary end point, with the lower CI being above the 0.6312 noninferiority margin.

The use of a flat dose of Isa SC OBI resulted in a sustained ORR across different body weight classifications. This consistency was seen in patients weighing up to 65 kg (relative risk, 0.928; 95% CI, 0.748-1.444), those over 65 kg up to 85 kg (relative risk, 1.009; 95% CI, 0.850- 1.197), and those heavier than 85 kg (relative risk, 1.115; 95% CI, 0.915-1.372). Based on the C_trough measurement at cycle 2, day 1, the flat dose of Isa SC OBI provided sufficient exposure for every body weight subgroup.

Overall, 99.9% of 5145 Isa SC administrations using the OBI were completed without interruption. The median duration of OBI injection was 13 minutes, and 97.9% were completed in under 20 minutes.

“Because it’s automated, [injection time varies from] patient to patient, but everyone will have completed [infusion] by 20 minutes,” Leleu affirmed. “Again, it is very, very easy to do.”

How Did This Novel Delivery System Affect Patient Satisfaction?

Notably, the study also assessed patient satisfaction with the delivery method of isatuximab at cycle 5 day 15. In the intention-to-treat population, patient satisfaction was significantly higher for Isa SC OBI (70.0%) vs Isa IV (53.4%; OR, 2.036; 95% CI, 1.425-2.908; P = .0001). Furthermore, of those who finished the questionnaire in the Isa SC OBI group (n = 190), 47.9% reported satisfaction and 48.9% reported being very satisfied. In the Isa IV group (n = 202), 52.5% were satisfied and 18.3% were very satisfied.

Leleu and colleagues stated that this finding validates the positive effect of this innovative administration method on patient experience.

Was the Safety Profile of Isa SC OBI Consistent With Prior Findings in This Patient Population?

The incidence of any-grade TEAEs was 97.0% in the Isa SC OBI arm vs 96.6% in the Isa IV arm, with grade 3 or higher TEAEs observed in 81.7% and 76.1% of patients, respectively. Treatment-related TEAEs of grade 3 or higher affected 65.8% of patients in the Isa SC OBI group vs 64.4% of those in the Isa IV group. Serious TEAEs and serious treatment-related TEAEs occurred in 52.9% and 27.0% of patients in the SC arm, respectively; comparative rates in the IV arm were 48.1% and 29.5%. Grade 5 TEAEs were reported in 6.8% and 7.2% of patients in the Isa SC OBI and Isa IV groups, respectively.

Infusion reactions were substantially lower with Isa SC OBI (1.5%) vs Isa IV (25.0%; relative risk, 0.061; 95% CI, 0.022-0.164). Local injection site reactions (ISRs) were rare, occurring in only 0.4% of Isa SC OBI injections. Of the 19 recorded ISRs, 18 were grade 1, and one was grade 2. The majority of ISRs (78.9%) appeared on the day of injection and resolved on the same day.

In the Isa SC OBI arm, the most frequently observed non-hematologic AEs were upper respiratory tract infection (22.8% all grade; 1.5% grade ≥3), diarrhea (19.8%; 1.5%), fatigue (19.4%; 3.8%), pneumonia (19.4%; 14.8%), insomnia (14.8%; 2.7%), constipation (14.4%; 0%), COVID-19 (12.5%; 2.7%), peripheral edema (8.4%; 0%), and infusion-related reactions (1.9%; 0.4%). The most common hematologic laboratory abnormalities in this group included neutropenia (98.1%; 84.7%), thrombocytopenia (85.1%; 26.1%), and anemia (96.2%; 17.6%).

Permanent full treatment cessation due to TEAEs occurred in 8.4% of patients in the Isa SC OBI cohort vs 8.7% of patients in the Isa IV cohort. In the SC arm, TEAEs caused permanent partial discontinuation of isatuximab (0%), pomalidomide (3.4%), and dexamethasone (4.9%). Corresponding rates for the IV arm were 0%, 5.3%, and 2.7%.

“This excellent local tolerability of the OBI and infrequent ISRs [that were] low grade, demonstrates that Isa SC OBI [at a] flat dose is a very interesting, new way of using isatuximab,” Leleu concluded.

References

1. Ailawadhi S, Spicka I, Lu J, et al. Isatuximab subcutaneous via an on-body delivery system versus isatuximab intravenous, plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma: the randomized phase 3 IRAKLIA study. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-58.
2. Quach H, Parmar G, Ocio E, et al. Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): interim phase 1b study results. J Clin Oncol. 2022;40(suppl 16):8025. doi:10.1200/JCO.2022.40.16_suppl.8025