Isatuximab (Sarclisa) and daratumumab (Darzalex) are monoclonal antibody drugs used to treat multiple myeloma, a cancer affecting plasma cells in the bone marrow. These therapies represent advancements in managing this complex blood cancer. This article explores their shared mechanisms, clinical outcomes, safety profiles, and factors guiding their use.
Shared Mechanism of Action
Both isatuximab and daratumumab are monoclonal antibodies that specifically target the CD38 protein, a molecule found abundantly on the surface of multiple myeloma cells. CD38 is a transmembrane glycoprotein involved in cell function. Its high expression on myeloma cells makes it an attractive target for therapeutic intervention.
By binding to CD38, these antibodies trigger several mechanisms to eliminate myeloma cells. One method is antibody-dependent cellular cytotoxicity (ADCC), where immune effector cells like natural killer (NK) cells destroy antibody-coated cancer cells. Another is complement-dependent cytotoxicity (CDC), which activates the complement system to directly lyse target cells. Antibody-dependent cellular phagocytosis (ADCP) also contributes, with macrophages engulfing antibody-bound myeloma cells. Both drugs can also induce programmed cell death (apoptosis) in myeloma cells and modulate CD38’s enzymatic activity.
Comparing Clinical Outcomes and Safety
Both isatuximab and daratumumab have demonstrated efficacy in treating multiple myeloma, though their clinical profiles present distinctions. Isatuximab is approved for relapsed or refractory multiple myeloma, often in combination with pomalidomide and dexamethasone, or carfilzomib and dexamethasone, after patients have received prior therapies. Daratumumab has broader indications, including use in newly diagnosed patients and those with relapsed or refractory disease, both as monotherapy and in various combination regimens.
Direct head-to-head trials are limited, but indirect comparisons offer insights into efficacy. In relapsed/refractory multiple myeloma, isatuximab with pomalidomide and dexamethasone showed an overall response rate (ORR) of approximately 60%, with a median progression-free survival (PFS) of 11.5 months. Daratumumab in a similar setting also achieved an ORR of about 60%, with a median PFS of 8.8 months, though differences in patient populations may influence these figures. A matching-adjusted indirect comparison (MAIC) suggested Isa-Kd might offer a better PFS compared to Dara-Rd in relapsed patients, though overall survival showed a non-significant improvement favoring Isa-Kd.
Both drugs share common side effects, including infusion-related reactions, cytopenias (low blood cell counts, particularly neutropenia), and increased risk of infections. Infusion reactions are common, with reported rates of around 38% for isatuximab and 50% for daratumumab in some studies. Neutropenia is a frequently observed hematologic toxicity for both. Isatuximab has been associated with pneumonia and upper respiratory tract infections, while daratumumab may also cause thrombocytopenia, fatigue, and nausea.
Both are given intravenously. Initial infusions can be lengthy; isatuximab’s initial infusion is approximately 3 hours, shorter than daratumumab’s 3.9 hours or longer. Subsequent infusions may be shorter. Daratumumab also has a subcutaneous formulation available, which offers a quicker administration time of about 3 to 5 minutes. Daratumumab was initially approved as a monotherapy in November 2015 for heavily pre-treated patients, and its indications have expanded to various combinations for newly diagnosed and relapsed/refractory settings. Isatuximab received its initial U.S. FDA approval in March 2020 in combination with pomalidomide and dexamethasone for relapsed/refractory patients, with further approvals in March 2021 (carfilzomib and dexamethasone) and September 2024 (bortezomib, lenalidomide, and dexamethasone for newly diagnosed patients).
Guiding Treatment Decisions
The selection between isatuximab and daratumumab is an individualized process, influenced by patient-specific and disease-related factors. A patient’s prior treatment history, including responses to other therapies and refractoriness to specific drug classes, plays a significant role. Myeloma characteristics, such as aggressiveness or genetic features, also influence the decision.
A patient’s overall health status and presence of other medical conditions (comorbidities) are important considerations. Some patients may have conditions that make them more susceptible to certain side effects, influencing which drug might be better tolerated. Tolerance to potential side effects is also a factor, as safety profiles, while similar, do have subtle differences in incidence or severity of specific adverse events.
Convenience of administration, including infusion time and frequency, impacts patient preference and quality of life. While both are typically given intravenously, daratumumab’s subcutaneous formulation offers a more convenient option for some patients. Combination therapy considerations are also a factor, as both drugs are often used in multi-drug regimens, and the choice may depend on which other agents are being used or are planned for combination. Ultimately, the decision is made in consultation with a healthcare professional, considering clinical evidence, patient-specific needs, and logistical aspects.