What's changed: SC delivery is now proven, not just promising
For years, CD38 antibodies like daratumumab and isatuximab were given intravenously (IV), requiring hours in a clinic and carrying a risk of infusion reactions. Recent trials have overturned that assumption, showing that subcutaneous (SC) injection—under the skin—is just as effective and much more convenient. In the phase 3 AQUILA trial, SC daratumumab monotherapy reduced the risk of progression or death by 51% compared to active monitoring in high-risk smoldering myeloma (hazard ratio 0.49), with 5-year progression-free survival of 63.1% vs 40.8% [1]. This wasn't just about efficacy; it demonstrated that SC delivery could be used as a standalone treatment, not just an add-on.
Similarly, the phase 3 IRAKLIA trial in relapsed/refractory myeloma found that SC isatuximab given via an on-body injector (a small device worn on the body) was non-inferior to IV isatuximab: overall response rates were 71.1% vs 70.5%, and drug levels in the blood were actually higher with SC (geometric mean ratio 1.53) [2]. This means patients get the same benefit with a much less invasive administration method.
How SC delivery cuts the burden: fewer reactions, less chair time, better experience
The biggest practical win is the dramatic drop in infusion-related reactions. In IRAKLIA, infusion reactions occurred in only 1.5% of patients on SC isatuximab versus 25% on IV [2]. This is because SC delivery bypasses the rapid bloodstream exposure that triggers these reactions, and it means patients need less pre-medication and monitoring. A separate study of switching from IV to SC daratumumab found no administration reactions in 35 of 36 patients, even when the switch happened after a gap of up to a year [5].
SC delivery also saves time and improves the experience for both patients and nurses. A nurse survey reported that the on-body injector was easy to learn and administer, reduced clinic time, and was preferred over IV by all 12 nurses surveyed [6]. Patients benefit from no needle visibility, shorter treatment duration, and a painless injection [6]. This isn't just a minor convenience—it can transform the treatment experience, making it easier for patients to maintain their normal lives while undergoing therapy.
What to keep in mind: not all patients, not all settings
While the evidence is strong, there are caveats. The trials showing SC efficacy were in specific populations: high-risk smoldering myeloma [1] and relapsed/refractory disease [2]. For newly diagnosed, transplant-eligible patients, the phase 3 PERSEUS trial used SC daratumumab combined with standard therapy and found a significant progression-free survival benefit (84.3% vs 67.7% at 4 years) [3], but this was in combination, not as monotherapy. So SC delivery is proven across the disease spectrum, but the exact regimen matters.
Also, the on-body injector is a device that patients must wear for a period, which may not suit everyone. The nurse survey noted that while most patients were satisfied, the device requires some training and comfort with wearing it [6]. Finally, while SC delivery reduces infusion reactions, it doesn't eliminate all side effects—grade 3 or 4 adverse events were still common in the trials (e.g., neutropenia in 62.1% with D-VRd) [3]. So the burden is reduced, not eliminated.
About These Sources
This answer is built on 6 peer-reviewed studies — published from 2022 to 2025, 4 from 2024 or later, 5 in Q1 journals, collectively cited 513 times — selected as the most relevant from 6 studies that passed quality screening, drawn from 52 papers retrieved from a database of over 500 million.
Sources used in this answer
Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma
In a phase 3 trial of 390 patients with high-risk smoldering myeloma, subcutaneous daratumumab monotherapy reduced the risk of progression or death by 51% versus active monitoring (hazard ratio 0.49), with 5-year progression-free survival of 63.1% vs 40.8%.
Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study
In the phase 3 IRAKLIA trial of 531 patients with relapsed/refractory myeloma, subcutaneous isatuximab via on-body injector was non-inferior to IV on response rate (71.1% vs 70.5%) and drug levels, with infusion reactions in only 1.5% vs 25%.
Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma
In the phase 3 PERSEUS trial of 709 transplant-eligible newly diagnosed myeloma patients, subcutaneous daratumumab added to standard therapy improved 4-year progression-free survival to 84.3% vs 67.7% (hazard ratio 0.42).
Recent Developments in Convenience of Administration of the Anti-CD38 Antibody Isatuximab: Subcutaneous Delivery and Fast Intravenous Infusion in Patients With Multiple Myeloma
A review of isatuximab development reports that subcutaneous administration via on-body delivery system and fast 30-minute IV infusions are safe and effective, with patient-reported outcomes indicating confidence and satisfaction with SC delivery.
Safety of Subcutaneous Daratumumab/ Hyaluronidase after Intravenous Daratumumab for Patients with Multiple Myeloma
In a single-center study of 36 patients switching from IV to subcutaneous daratumumab, only one grade 2 administration reaction occurred (in a patient with a 448-day gap), suggesting safe switching with low reaction rates.
Subcutaneous administration of isatuximab in patients with multiple myeloma by an on-body delivery system: results of a nurse survey
A nurse survey (N=12) found unanimous agreement that on-body injector administration improved efficiency, was easy to learn, reduced clinic time, and was preferred over IV, with benefits including no needle visibility and painless injection.