How Subcutaneous Isatuximab Could Compete With Daratumumab in Multiple Myeloma

On July 9, 2026, the FDA approved subcutaneous isatuximab-irfc (Sarclisa Escena; Sanofi) for use in combination with pomalidomide (Pomalyst; Bristol Myers Squibb) and dexamethasone for adults who have received at least 1 prior line of therapy including lenalidomide (Revlimid; Celgene Corporation) and a proteasome inhibitor; with carfilzomib (Kyprolis; Onyx Pharmaceuticals, Inc) and dexamethasone for adults with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy; and with bortezomib (Velcade; Millennium Pharmaceuticals), lenalidomide, and dexamethasone for adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.¹

The approval introduces a new point of competition within the anti-CD38 monoclonal antibody landscape, offering patients with multiple myeloma an on-body delivery option that may reduce treatment burden and improve practice efficiency.

The agent is administered as a fixed 1400-mg subcutaneous dose using either the CirCLIQ on-body delivery system or a syringe and infusion set for manual administration.^1,2 Its entrance into the market gives practices another subcutaneous anti-CD38 option alongside daratumumab and hyaluronidase-fihj (Darzalex Faspro; Johnson & Johnson), an established therapy with numerous FDA-approved indications and extensive integration into multiple myeloma treatment pathways.³

Subcutaneous isatuximab must therefore demonstrate value in a market already shaped by daratumumab’s clinical familiarity, breadth of supporting evidence, and established purchasing and treatment infrastructure. Its ability to compete may depend not on a direct claim of superior efficacy, but on its delivery system, patient experience, workflow implications, biological characteristics, and the financial realities of adopting another anti-CD38 product.

Anti-CD38 Antibodies Reshape Frontline Treatment

Anti-CD38 monoclonal antibodies have become foundational components of treatment for patients with newly diagnosed and relapsed or refractory multiple myeloma. Daratumumab-based quadruplet regimens have produced deep and durable responses among both transplant-eligible and transplant-ineligible or transplant-deferred populations.^4,5

In the phase 3 PERSEUS trial (NCT03710603), 709 transplant-eligible patients with newly diagnosed multiple myeloma were randomly assigned to receive subcutaneous daratumumab plus bortezomib, lenalidomide, and dexamethasone, followed by daratumumab-lenalidomide maintenance, or bortezomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance alone. The daratumumab-containing regimen produced significant improvements in progression-free survival (PFS), complete response or better, and minimal residual disease negativity.⁴

The phase 3 CEPHEUS trial (NCT03652064) similarly demonstrated that adding subcutaneous daratumumab to bortezomib, lenalidomide, and dexamethasone increased response depth and improved PFS among patients with newly diagnosed multiple myeloma who were transplant ineligible or for whom transplant was not planned as initial therapy.⁵

“The inclusion of anti-CD38 monoclonal antibodies (mAbs) into frontline regimens for patients with newly diagnosed multiple myeloma who are transplant eligible, ineligible, or deferred has led to a marked improvement in outcomes, with modeling of best-fit [median] PFS of 17.1 years for PERSEUS and 8.3 years for CEPHEUS,” Matthew Lei, PharmD, BCOP, a clinical pharmacy specialist in medical oncology and lymphoma, told Pharmacy Times.

Against that established foundation, subcutaneous isatuximab presents another anti-CD38 treatment option with a distinct administration platform and potentially differentiating biological properties. “Isatuximab [subcutaneous on-body injector] would represent another option for patients and was viewed more favorably from patient perspectives in the IRAKLIA and IZALCO studies,” Lei said.

IRAKLIA Establishes Noninferiority of On-Body Administration

The FDA approval of subcutaneous isatuximab was supported primarily by findings from the open-label, phase 3 IRAKLIA trial (NCT05405166), which randomly assigned 531 patients with relapsed or refractory multiple myeloma to receive isatuximab through an on-body injector or as an intravenous (IV) infusion. Both formulations were administered in combination with pomalidomide and dexamethasone.^1,6

The trial met both coprimary end points, demonstrating the noninferiority of subcutaneous isatuximab to IV isatuximab based on overall response rate (ORR) and trough drug concentration at steady state. The ORR was 71.1% in the on-body injector arm and 70.5% in the IV arm.^1,6

Administration-related reactions occurred in approximately 1.5% of patients receiving isatuximab through the on-body injector compared with 25.0% of patients receiving IV isatuximab. Injection-site reactions occurred during 0.4% of on-body injections, all were grade 1 or 2, and 99.9% of injections were completed without interruption.⁶

The subcutaneous formulation contains 1400 mg of isatuximab in a 10-mL solution and does not contain recombinant human hyaluronidase. The CirCLIQ system delivers the dose subcutaneously into the abdomen through a hands-free, battery-free device.²

“[Subcutaneous] isatuximab is hyaluronidase-free and delivered as a 10-mL injection with a 30-gauge needle via a hands-free on-body injector,” Lei explained. “It is battery-free and uses a small amount of pressure—approximately 7 psi—to individualize the flow rate, which is why patients reported less discomfort compared with manual [subcutaneous] injection on trial.”

The phase 2 IZALCO study (NCT05704049) provided additional evidence supporting subcutaneous isatuximab in combination with carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma. The study evaluated efficacy, pharmacokinetics, safety, administration, as well as patient and health care professional experiences with subcutaneous treatment.⁷

Mechanistic Differences May Offer Clinical Rationale

Isatuximab and daratumumab both target CD38, but they are distinct antibodies with differences in their binding and mechanisms of action. Isatuximab binds to a specific epitope on CD38 that is distinct from the daratumumab binding site and induces antimyeloma activity through antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, and direct Fc-independent mechanisms.⁸

“Isatuximab is an anti-CD38 mAb that can induce direct apoptosis of multiple myeloma cells, with less reliance on complement-dependent cytotoxicity, and that binds to a distinct epitope of CD38, inhibiting its enzymatic activity with downstream effects on the immune microenvironment and increasing anti-multiple myeloma drug sensitivity of multiple myeloma cells,” Lei said.

Preclinical evidence indicates that antibody-dependent cellular cytotoxicity may be a dominant effector mechanism for isatuximab, whereas its complement-dependent cytotoxicity occurs under more restricted conditions, including sufficiently high CD38 receptor density and limited expression of complement-regulatory proteins.⁸

These properties have generated interest in whether isatuximab may hold particular value for biologically defined populations, including patients whose disease carries gain or amplification of chromosome 1q. However, this remains a hypothesis derived from mechanistic reasoning and comparisons across separate studies, rather than evidence from a randomized head-to-head trial.

“[Isatuximab] use is pretty low because it doesn’t have a subcutaneous version, and it has benefits of having [a lower risk of] infusion-related reactions and injection-site reactions as it doesn’t engage complement as much and may be more beneficial in patients with 1q gain/amp, as genes on the 1q arm may promote resistance to the mechanism of CDC through upregulation of complement inhibitors,” Lei said.

The new subcutaneous formulation removes one of the practical differences that may previously have favored daratumumab: the availability of a subcutaneous administration option. Nevertheless, the absence of direct comparative data limits conclusions about whether mechanistic differences translate into superior outcomes in specific patient groups.

“There’s not necessarily a direct comparison between isatuximab and daratumumab in patients with 1q, so a lot of the clinical and potentially clinical differences are extrapolated between studies, which isn’t enough for people to shift prescribing from an efficacy standpoint given the financial implications of doing so,” Lei said.

Cross-trial comparisons cannot establish the superiority of either antibody. Treatment selection must instead be based on the evidence supporting the individual regimen in the relevant disease setting, the approved indication, patient characteristics, safety, administration preferences, institutional experience, and access considerations.

Workflow Could Be a Key Differentiator

The on-body delivery system may offer one of subcutaneous isatuximab’s clearest distinctions from subcutaneous daratumumab.

Daratumumab and hyaluronidase-fihj is supplied as a ready-to-use 15-mL solution containing 1800 mg of daratumumab and 30,000 units of hyaluronidase. It is administered manually by a health care professional into the abdomen over approximately 3 to 5 minutes.³

The isatuximab CirCLIQ system is designed to deliver treatment without requiring a nurse to remain actively engaged in manually administering the entire dose.^1,2 This may enable the health care professional to initiate treatment and perform other tasks while the device completes administration.

“Isatuximab subcutaneous on-body injector replaces the manual RN subcutaneous push with a hands-free administration, saving the RN administration time,” Lei said. “The device/drug with a needleless preparation option also may facilitate resource savings for the infusion pharmacy.”

The practical value of those time savings will differ across treatment centers. For high-volume infusion clinics facing staffing constraints, increasing patient numbers, or limited chair capacity, reducing active administration time may create meaningful workflow efficiencies. Other practices may find that the time needed for patient preparation, observation, documentation, or device management limits the overall operational difference.

Pharmacists will play a central role in determining how the product is introduced and used within individual institutions.

“Pharmacists will play an important role in facilitating access to isatuximab subcutaneous on-body injector if approved by the FDA, by engaging with their practices on the storage, preparation, and dispensing of the product, as well as updating treatment plans to include the option for [this formulation],” Lei said.

Although the product has now received FDA approval, those implementation responsibilities remain relevant. Practices currently using IV isatuximab must decide how to incorporate the subcutaneous formulation into existing order sets, inventory systems, electronic treatment plans, policies, and medication-use processes.^1,2

“Furthermore, pharmacists will need to assist in evaluating the line-item extension for isatuximab SC OBI if the practice utilizes isatuximab IV currently, or would need to onboard isatuximab through the formulary status if not done so already,” Lei said. “There will need to be considerations for receipt and storage given the need to facilitate the medication-use process for not just the drug but also the device.”

The on-body system may consequently reduce active administration demands while introducing new considerations related to device inventory, staff education, storage, preparation, troubleshooting, and disposal.²

Contracting May Shape Real-World Adoption

Even when clinical teams recognize potential advantages associated with a new formulation, product selection in oncology is influenced by contracting, reimbursement, purchasing arrangements, inventory requirements, and existing institutional pathways.

Daratumumab’s established market position means many practices already have standardized regimens, order sets, inventory procedures, staff education, and purchasing agreements built around its use.³ Introducing isatuximab may therefore involve more than adding a clinically comparable product to the formulary.

“Sanofi doesn’t really expect to get an incredible amount of the market share compared with Johnson & Johnson, but I presume they want more than they have now and whatever amount they can gain and keep at applicable practices,” Lei said.

These considerations may be particularly important for community and smaller oncology practices that seek to limit inventory complexity and may rely heavily on volume-based agreements.

“From my conversations, it likely will come down to contracting with practices, as it may be too confusing for practices to give daratumumab and isatuximab if they’re community practices or smaller practices, as they have to account for volume-based contracts,” Lei said.

A practice that adds isatuximab may need to divide its anti-CD38 treatment volume between 2 manufacturers. Depending on the terms of its existing purchasing arrangements, that change could affect the financial benefits associated with meeting volume thresholds.

“Even if [the subcutaneous on-body injector] is more advantageous, it has to result in a greater financial delta compared with daratumumab subcutaneous and also the loss in whatever is gained with the volume-based contract,” Lei said.

The amount of operational work required will likely differ among treatment settings. A large academic institution may be better positioned to maintain multiple anti-CD38 products and select among them based on patient, regimen, or workflow considerations. A smaller practice may prefer to standardize its use around a single product to simplify purchasing, inventory, staff education, and administration.

“The sentiment is that people acknowledge the potential advantages, but it’ll be a small to medium to large amount of work depending on the type of center to onboard isatuximab subcutaneous on-body injector, so it has to be worth it and it would need to be used,” Lei said.

Competition Will Extend Beyond Efficacy

Subcutaneous isatuximab is unlikely to compete with daratumumab on the basis of indirect efficacy comparisons alone, particularly in the absence of a randomized head-to-head clinical trial. Instead, its opportunity may rest on a combination of potential advantages: a hyaluronidase-free formulation, a hands-free delivery system, a low rate of administration-related reactions in IRAKLIA, favorable patient and health care professional experiences, and possible reductions in active nursing and pharmacy resource use.^1,2,6,7

Daratumumab retains considerable advantages, including extensive phase 3 evidence, broad clinical familiarity, established treatment protocols, and years of integration into oncology practice.^3-5 Subcutaneous isatuximab must therefore demonstrate sufficient value not only to prescribers and patients, but also to pharmacists, nurses, administrators, formulary committees, and contracting teams.

Regardless, the availability of the on-body injector could change the competitive landscape. Practices are no longer comparing an IV isatuximab regimen with an established subcutaneous daratumumab product. They can now evaluate 2 subcutaneous anti-CD38 options with different delivery systems, formulations, clinical evidence, and operational considerations.^1-3

Whether those distinctions are sufficient to change treatment patterns will likely depend on the needs and infrastructure of each practice. Isatuximab may not need to displace daratumumab broadly to compete successfully; it may instead establish a role in centers where its delivery model, patient experience, workflow benefits, or biological characteristics provide enough value to justify adoption.

REFERENCES

1. US Food and Drug Administration. FDA approves isatuximab-irfc for subcutaneous injection for multiple myeloma indications. Published July 9, 2026. Accessed July 28, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-subcutaneous-injection-multiple-myeloma-indications

2. Sarclisa Escena. Prescribing information. Sanofi-Aventis US LLC; 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761445Orig1s000lbl.pdf

3. Darzalex Faspro. Prescribing information. Janssen Biotech, Inc; 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761145s028lbl.pdf

4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

5. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7

6. Ailawadhi S, Špička I, Spencer A, et al. Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study. J Clin Oncol. 2025;43(22):2527-2537. doi:10.1200/JCO-25-00744

7. Parmar G, Capra M, Seguro F, et al. Efficacy and safety of isatuximab subcutaneous plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma: results of the Phase 2 study IZALCO. Blood Cancer J. 2025;16(1):16. doi:10.1038/s41408-025-01436-0

8. Zhu C, Song Z, Wang A, et al. Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells. Front Immunol. 2020;11:1771. doi:10.3389/fimmu.2020.01771