Isatuximab (Sarclisa) and Daratumumab (Darzalex) represent a major advancement in the treatment of multiple myeloma, a cancer of the plasma cells. Both medications are monoclonal antibodies, a type of targeted therapy designed to harness the body’s immune system to fight cancer. They belong to the drug class known as CD38 inhibitors, which target a protein highly expressed on the surface of myeloma cells. While they share the same primary molecular target, subtle but significant differences in their design lead to distinct mechanisms of action, clinical applications, and administration logistics.
Understanding the CD38 Target
The CD38 molecule is a multifunctional glycoprotein found in high numbers on the surface of multiple myeloma cells. This high and uniform expression on malignant plasma cells, coupled with limited expression on most healthy tissues, makes CD38 an ideal molecular target for therapy. CD38 acts as both a receptor and an ectoenzyme, meaning it can facilitate cell signaling and catalyze metabolic reactions outside the cell.
Targeting this molecule with monoclonal antibodies triggers multiple ways to destroy the cancer cell. The primary shared mechanism is Antibody-Dependent Cell-mediated Cytotoxicity (ADCC), where the antibody flags the cancer cell for destruction by natural killer (NK) cells. Another shared mechanism is Antibody-Dependent Cellular Phagocytosis (ADCP), where macrophages engulf the flagged tumor cell. By binding to CD38, both drugs also modulate the tumor microenvironment, which can help reverse the immunosuppression that typically protects the cancer.
Distinct Mechanisms of Action
Despite targeting the same CD38 molecule, Isatuximab and Daratumumab differ at a molecular level because they bind to distinct, non-overlapping regions, or epitopes, on the protein. This difference in binding site has functional consequences that distinguish their activity against myeloma cells. Daratumumab was initially selected for its robust ability to induce Complement-Dependent Cytotoxicity (CDC), a mechanism where the antibody binding triggers a cascade of proteins that directly punctures the cancer cell membrane.
Isatuximab appears to be a more potent inducer of CDC in some in vitro models, a characteristic related to the specific epitope it binds. The binding of Isatuximab also uniquely induces direct apoptosis, a form of programmed cell death in myeloma cells, which Daratumumab is generally unable to trigger alone. Furthermore, the two drugs differ in their effect on CD38 internalization, the process where the cell absorbs the drug-target complex from the surface. Isatuximab induces more efficient clustering and subsequent internalization of CD38, potentially leading to a more profound depletion of the target protein from the cell surface.
Comparative Clinical Efficacy
Daratumumab was the first-in-class CD38 inhibitor approved, leading to its extensive integration across multiple lines of therapy, from newly diagnosed to relapsed/refractory multiple myeloma. For newly diagnosed, transplant-eligible patients, the addition of Daratumumab to standard regimens like bortezomib, thalidomide, and dexamethasone (Dara-VTd) in the CASSIOPEIA trial led to improved rates of minimal residual disease (MRD) negativity. In the relapsed setting, Daratumumab has established efficacy in combinations like Daratumumab with lenalidomide and dexamethasone (Dara-Rd) in the POLLUX trial.
Isatuximab gained approval later and is primarily used in the relapsed/refractory setting, often in combination with pomalidomide and dexamethasone (Isa-Pd), based on the results of the ICARIA-MM trial. It is also approved in combination with carfilzomib and dexamethasone (Isa-Kd), a regimen that demonstrated improved progression-free survival (PFS) in the IKEMA trial. While direct head-to-head trials are lacking, analyses suggest comparable overall response rates and PFS when the two drugs are used in similar combinations and patient populations. The choice between the two often depends on prior treatments, as Daratumumab has a broader range of established indications and is a standard component of many first-line regimens.
Differences in Administration and Safety
A significant practical difference for patients is the route of administration, as Daratumumab is available in both an intravenous (IV) and a subcutaneous (SC) formulation. The SC formulation, Darzalex Faspro, is a rapid injection that can be administered in about five minutes, greatly enhancing patient convenience compared to the multi-hour IV infusions. Isatuximab is currently only available as an IV formulation, which typically requires a longer infusion time.
Both drugs carry a risk of infusion-related reactions (IRRs), which are common with all CD38 antibodies and can include symptoms like chills, shortness of breath, and cough. The incidence of IRRs is generally higher with Daratumumab, ranging up to 50% in initial studies, compared to Isatuximab, which has been reported to have an IRR rate around 38%. To manage this risk, both require premedication before each infusion, including:
- Corticosteroids.
- Antihistamines.
- Fever reducers.
The most common serious non-infusion-related side effect for both drugs in combination regimens is hematologic toxicity, particularly neutropenia (a low white blood cell count).