Dr Leleu on SC Isatuximab via On-Body Injector in R/R Multiple Myeloma
Explore the innovative subcutaneous delivery of isatuximab for multiple myeloma, enhancing patient experience and treatment efficiency in the IRAKLIA study.
Abnormal plasma cell or B-cell in multiple myeloma emitting paraprotein, 3D illustration: © LASZLO - stock.adobe.com
In an interview with Targeted OncologyTM, Xavier Leleu, MD, PhD, discussed the clinical and practical implications of subcutaneous (SC) administration of isatuximab-irfc (Sarclisa) via an on-body injector (OBI) in relapsed/refractory (R/R) multiple myeloma. The conversation emphasized how this novel approach addresses long-standing challenges in patient burden, treatment convenience, and resource utilization in the multiple myeloma care landscape.
Leleu, head of the Department of Hematology and the Myeloma Clinic at Hôpital La Mileterie, in Poitiers, France, highlighted the unmet need for less burdensome delivery methods in multiple myeloma, especially given the long treatment durations and frequent clinic visits required for intravenous (IV) and manual SC regimens. "Many patients are on treatment for years—up to 96 months—with hundreds of needle punctures,” he explained. “Far too many stop treatment due to frustration with the burden.”
The phase 3 IRAKLIA study (NCT05405166) demonstrated noninferiority of SC isatuximab via OBI compared with IV isatuximab in combination with pomalidomide (Pomalyst) and dexamethasone (Pd), with similar efficacy and safety. Specifically, data presented during the 2025 EHA Congress showed that noninferiority was reached for the co-primary end point of objective response rate (ORR), meeting the noninferiority margin of 0.839. The ORR achieved with SC isatuximab OBI plus Pd (n = 263) was 71.1% vs 70.5% with IV isatuximab plus Pd (n = 268; relative risk, 1.008; 95% CI. 0.903-1.126; P =.0006).
Notably, noninferiority of the co-primary end point of Ctrough of isatuximab at steady state (predose at day 1 cycle 6) was also reached, with there being a lower CI of the geometric mean ratio (GMR) above the noninferiority margin of 0.8. The GMR was 1.532 (90% CI, 1.316-1.784). Another key secondary end point was met with noninferiority shown for the GMR of Ctrough of isatuximab at 4 weeks (day 1 cycle 2 predose), with the lower CI above the noninferiority margin of 0.8. Specifically, the GMR was 1.302 (95% CI, 1.158-1.465).
From a clinical workflow perspective, Leleu pointed out the potential for increased efficiency, with reduced nurse burden and minimized preparation time. Surveys of healthcare professionals supported this, with 94% of nurses and 100% of pharmacists reporting expected workflow improvements with OBI use.
In the interview, Leleu further discussed the significance of isatuximab in this space and the implications from the IRAKLIA trial for oncologists treating patients with R/R multiple myeloma.
Targeted OncologyTM: Given the current treatment landscape for relapsed/refractory multiple myeloma, how significant is the unmet need addressed by a subcutaneous formulation of isatuximab?
Multiple myeloma remains incurable, often involving time-consuming intravenous or manual subcutaneous injections, which can pose a considerable strain on patients and health care providers. Many current standards of care regimens administered via IV can take up to 75 minutes per infusion. Administering large-volume medicines via manual SC injections can present significant challenges, including a labor-intensive process for nurses, risk of strain and needlestick injuries, and potential need for larger needles that may compromise patient comfort and increase anxiety.
CD38 monoclonal antibody-based regimens have emerged as a standard of care for patients, but these regimens can often entail years of lengthy, burdensome lab visits. For instance, I have several patients who will be on treatment for up to 96 months. This means at least 96 trips to the clinic and 96 needle punctures. When factoring in labs, the latter number can easily grow to 200. Despite the improved long-term outcomes associated with these regimens, far too many patients stop treatment due to frustration with the long duration. There is an unmet need for improved formulations that can help alleviate the quality-of-life impact on patients.
SC administration via an OBI has the potential to improve the overall patient experience for all patients [with multiple myeloma]. In clinical studies, the OBI shortened treatment time to minutes. Recent studies and surveys have suggested the use of an OBI may be associated with greater convenience, flexibility and patient satisfaction compared to IV or manual SC administration methods. In addition, an OBI may also streamline the administration process for providers, potentially reducing the physical burden on nurses and enabling them to possibly move freely through the use of a hands-free device while monitoring the patient during injection.
The IRAKLIA study established non-inferiority for isatuximab SC-Pd vs IV-Pd in ORR and Ctrough. What were your key considerations regarding the trial design?
Our primary goal was to evaluate the use of isatuximab administered subcutaneously via an OBI compared to isatuximab IV infusion in a combination that is approved, reimbursed, and standard of care in its specific indication. For this reason, we chose isatuximab in combination with pomalidomide and dexamethasone in adult patients with R/R multiple myeloma who have received at least 1 prior line of treatment. Overall, the IRAKLIA phase 3 study was run as expected, including the statistical methodology for inferiority definition. Of note, isatuximab SC administration via an OBI is also being evaluated in several other combinations and lines of therapy, including several studies in the frontline treatment setting.
The observed isatuximab mean Ctrough was higher with SC-Pd compared to IV-Pd, yet efficacy was noninferior. Can you elaborate on the potential clinical implications of this pharmacokinetic profile for an oncologist?
In the IRAKLIA study, we wanted to evaluate the performance of isatuximab SC administered via an OBI at a fixed dose in combination with Pd. We view the fixed dose as a significant advancement for patient and provider convenience in addition to the OBI. With a fixed dose, it's important to understand the variations in drug exposure [C-trough] across different patient weights, specifically, verifying higher serum residual concentrations in lower weight subgroups show no potential safety concerns, and verifying that lower serum residual concentrations in higher weight subgroups show no loss of efficacy.
A critical aspect of the IRAKLIA study's design was to assess these potential variations to understand any safety or efficacy implications across weight groups. While a higher mean Ctrough at steady state was observed in the IRAKLIA study, it still fell within the threshold of noninferiority defined by the study parameters. We do not believe it poses any cause for concern. In fact, it reinforces that patients will potentially benefit fully from the fixed dose.
The IZALCO study [NCT05704049] demonstrated a strong patient preference for the OBI over manual SC injection. How might this preference translate into improved adherence, quality of life, and overall treatment outcomes for your patients?
The IZALCO study did not specifically evaluate the correlation between patient preference and other outcomes, such as adherence or quality of life, but the findings reinforce the potential of the OBI to improve the overall patient experience in MM treatment. The OBI used in the IZALCO study uses a 30-gauge, hidden, and retractable needle that is smaller compared to some of the commonly used large-volume SC injection needles, which may support patient comfort. By comparison, larger needles have the potential to compromise patient comfort and increase anxiety. Given the high volume of injections patients may receive across different medications over the course of their treatment, a hidden, smaller needle could have a significant impact on their treatment experience.
In a recent survey of nurses with direct experience in administering certain large-volume SC medicines, 94.4% of hematology and oncology respondents believed that the thinner needles would improve needle phobia for patients and reduce patient chair time. While not studied, we could hypothesize that adherence to isatuximab-based regimens could be improved due to the benefits of the OBI over manual push. In addition to the patient experience, there are also several potential practice efficiencies that may be attributed to the OBI.
In a similar survey of pharmacists, 100% believed an OBI would improve efficiency due to the single-step, hands-free preparation process, and 90% believed an OBI would reduce preparation errors. As mentioned previously, an OBI may also streamline the administration process for providers, potentially reducing the physical burden on nurses and enabling them to possibly move freely through the use of a hands-free device while monitoring the patient during injection. The shortened treatment time compared to IV infusion could also be a significant benefit.
Considering both the efficacy/safety data from IRAKLIA and the patient preference from IZALCO, what are the most significant implications of subcutaneous isatuximab via OBI for the daily management of relapsed/refractory multiple myeloma patients in your clinic? How might this impact treatment sequencing or choice?
Collectively, data from the IRAKLIA and IZALCO studies demonstrated that isatuximab SC administered via an investigational OBI shortened treatment time to minutes with similar efficacy and safety compared with IV infusion. Further, both studies reinforced the potential value of the OBI for patients, as shown by the higher patient satisfaction and preference scores for the OBI, compared to IV and manual SC administration, respectively. We believe this represents a significant innovation, which is novel for [multiple myeloma] treatment, and has the potential to improve and streamline the administration process for both patients and providers. While patients may still require IV or manual SC injections for other aspects of their treatment regimen, easing even just part of the treatment burden could make a meaningful difference for patients.
Could you expand on any specific safety considerations for patient education points that oncologists should be particularly aware of when transitioning patients from IV to SC isatuximab?
The overall safety profile of isatuximab SC in combination with Pd observed in this study was consistent with the established safety profile of isatuximab IV-Pd, but with a notably lower rate of systemic infusion reactions. No new safety concerns were observed, except for low-grade injection site reactions [ISRs] associated with SC administration via OBI that occurred at with a low incidence of 0.4%. Nearly all ISRs were grade 1, except for 1 episode of grade 2. Given the high volume of injections patients may receive across different medications over the course of their treatment, the low rate of ISRs is significant.
Additionally, 99.9% of isatuximab SC OBI injections were successfully delivered with no significant safety concerns related to the OBI. If the OBI were to be available in another capacity in the future, there may be additional education needed for patients or caregivers.
Looking ahead, what further real-world evidence or comparative effectiveness studies would you like to see to fully optimize the integration of subcutaneous isatuximab via OBI into routine oncology practice?
Based on findings from the IRAKLIA and IZALCO studies, I don’t believe there are any specific populations where further research would be needed, nor do I believe there is any further real-world evidence or comparative effectiveness studies required.
If you had one key takeaway message about the isatuximab SC OBI data for your oncology colleagues, what would it be and why is it important for them to understand?
Given the OBI’s potential to improve the overall patient experience in multiple myeloma treatment, I believe it’s critical for my colleagues to fully understand the key insights from these data. The OBI represents a significant innovation for the multiple myeloma community that has the potential to improve and streamline the administration process for both patients and providers. While other therapies may be administered subcutaneously, the IRAKLIA phase 3 study was the first to incorporate the use of an OBI in the treatment of multiple myeloma and demonstrate noninferiority to IV. While there are several steps yet ahead to make this innovation available, I feel confident that the reception will be positive amongst multiple myeloma patients and providers.
