SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity.
Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.
Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails.
With prevalence of multiple myeloma expected to climb further, disparities in care delivery remain a concern, often linked to treatment access, infusion-center capacity, and patient convenience. Advances in drug delivery technology, particularly subcutaneous (SC) administration, offer an opportunity to bridge these gaps. Compared with intravenous (IV) therapy, SC approaches can shorten administration time, improve comfort, and reduce healthcare resource demands.
However, conventional SC delivery of large-volume biologics can be challenging, often requiring high manual pressure over several minutes and the use of larger needles, both of which may cause discomfort and anxiety for patients and increase the physical burden for nurses. The IRAKLIA trial is the first Phase III study in multiple myeloma to evaluate an On-Body Injector (OBI) for delivering SC Isatuximab (Isa) in combination with Pomalidomide and Dexamethasone (Pd) in Relapsed/Refractory MM (RRMM).
Study Design
IRAKLIA was a global, open-label, randomized, noninferiority Phase III trial enrolling adults with 1 or more prior lines of therapy, including Lenalidomide and a Proteasome Inhibitor. A total of 531 patients were randomized (OBI, N=263; IV, N=268). Participants were assigned 1:1 to receive either:
- Isa OBI: 1,400 mg SC via an OBI device (Enable Injections, Inc.)
- Isa IV: 10 mg/kg IV infusion once weekly during cycle 1, then on days 1 and 15 of subsequent cycles.
Both arms received Pomalidomide 4 mg orally, days 1–21 and Dexamethasone 40 mg orally weekly and 20 mg if 75 years or older. Baseline characteristics were generally balanced, although the OBI group had slightly more patients ≥75 years, with higher rates of advanced disease features (soft-tissue plasmacytomas, ISS stage III, reduced renal function, and Lenalidomide-refractory status).
Key coPrimary endpoints were Overall Response Rate (ORR) and steady-state trough concentration (Ctrough) at cycle 6 day 1. The trial also assessed ≥Very Good Partial Response (≥VGPR) rate, pharmacokinetics at week 4, incidence of Infusion-related Reactions (IRs), and patient-reported satisfaction.
Efficacy after 12 Month Median Follow-Up
- ORR: 71.1% (OBI) vs 70.5% (IV); noninferiority demonstrated (RR 1.008; 95% CI, 0.903–1.126).
- Ctrough: Higher with OBI (geometric mean ratio 1.532; 90% CI, 1.316–1.784), meeting noninferiority criteria.
- ≥VGPR rate: Comparable-46.4% (OBI) vs 45.9% (IV).
- Results were consistent across most subgroups, with a lower response in patients ≥75 years in the OBI arm, likely due to baseline disease imbalances.
Safety
- Grade ≥3 treatment-emergent adverse events occurred in 81.7% (OBI) vs 76.1% (IV).
- Infusion-related Reactions were dramatically reduced with OBI (1.5%) compared with IV (25%).
- Injection site reactions with OBI were rare (0.4%, all grade 1–2).
- No unexpected safety signals emerged; the profile aligned with prior Isa studies.
Patient Experience
- Satisfaction rates were higher with OBI (70.0%) than IV (53.4%).
- Nearly all OBI doses (99.9%) were completed without interruption.
Clinical Implications
Reduced Infusion Reactions and Improved Workflow
The marked drop in Infusion-related Reactions incidence with OBI is likely related to slower systemic absorption from interstitial tissue compared with rapid IV exposure. This improvement not only enhances patient comfort but also reduces infusion chair time and the need for monitoring, potentially enabling at-home administration by healthcare professionals in select patients.
Efficiency for Nursing Staff
OBI eliminates the sustained manual pressure required for large-volume SC pushes and replaces large-bore needles with a smaller, hidden 30-gauge needle. This reduces nurse fatigue, frees up clinical resources, and may lower patient anxiety during injections.
Potential for Home Administration and Broader Access
Given the convenience and safety profile, OBI administration could be extended beyond the infusion center. This aligns with ongoing efforts to decentralize cancer care, expand access to anti-CD38 therapy, and improve treatment adherence in multiple myeloma.
Future Directions
Isa OBI is being further evaluated in other multiple myeloma settings, including:
- IZALCO: Isa-Kd in RRMM (NCT05704049)
- IsaSoCut: Isa-VRd in transplant-ineligible NDMM (NCT05889221)
- GMMG-HD8: Isa-VRd in NDMM (NCT05804032)
Upcoming analyses from IRAKLIA will also explore the feasibility of at-home dosing.
Conclusion
The Phase III IRAKLIA trial demonstrates that Isa SC delivered via OBI is noninferior to IV administration in RRMM, with equivalent efficacy, favorable pharmacokinetics, and a significantly lower Infusion-related reaction rate. This hands-free delivery method offers a practical, patient-preferred, and resource-efficient alternative to standard IV infusion, potentially transforming anti-CD38 therapy administration in multiple myeloma.
Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study. Ailawadhi S, Špička I, Spencer A, et al. J Clin Oncol. 2025;43:2527-2537.
