Successful Desensitization to Daratumumab After a Severe Life-threatening Reaction in a Patient With Refractory Multiple Myeloma.

Abstract

dexchlorpheniramine (5 mg), and intramuscular epinephrine (0.5 mg) were administered. Nevertheless, the patient’s symptoms progressed, with right oculocephalic deviation, lack of glabellar and menace reflexes, and hypercapnic respiratory acidosis. Therefore, she was admitted to the intensive care unit, where invasive mechanical ventilation and a norepinephrine perfusion were started. The patient’s condition stabilized, and she was successfully extubated after 2 days without neurological sequelae. No tryptase levels were measured. A grade 4 IRR [2] was diagnosed, and the patient was referred to our allergy department. Skin tests with daratumumab (skin prick test at concentrations of 20 mg/mL, 2 mg/mL, and 0.2 mg/mL and an intradermal test at concentrations of 2 mg/mL and 0.2 mg/mL) performed 3 weeks after the reaction yielded negative results [3]. Baseline tryptase was 3.41 ng/mL (normal, <11.5 ng/mL). A basophil activation test (BAT) to daratumumab was performed at different concentrations (0.5 mg/mL, 1 mg/mL, and 2 mg/mL) using the 2 most common markers of activation/degranulation (CD203c and CD63) [4], with negative results for all the concentrations tested. The referring physicians confirmed that daratumumab was the best therapeutic option owing to disease progression and failure of first-line therapy. We assessed the risks for management, and the informed consent was signed. Based on risk stratification for the severe reaction, a 4-bag, 14-step rapid drug desensitization (RDD) protocol was administered [5]. Additional premedication was with montelukast and aspirin, and no breakthrough reactions were recorded (Table). IL-6 levels were measured using high-sensitivity single-molecule array (Simoa) technology [6], which reduces IL-6 levels after desensitization (baseline, 21.85 pg/mL; after desensitization, <2 pg/mL). To date, the patient has tolerated 15 cycles without incident. Disease control is excellent. Hypersensitivity reactions to monoclonal antibodies include infusion-related reactions, cytokine-release reactions (CRRs), type 1 reactions (IgE/non-IgE), type 3 reactions (immune complexes), and delayed type 4 reactions [3]. IRRs and CRRs to monoclonal antibodies can occur at the first infusion. In most cases, the difference between IRRs and CRRs is the self-limiting nature of IRRs on repeat exposure and the response to premedication [5]. Although the patient received premedication according to the summary of product characteristics of daratumumab, she developed a severe lifethreatening reaction. No IgE-mediated hypersensitivity reactions to daratumumab have been reported to date. Polysorbate 20 and mannitol are excipients of daratumumab. Cases of anaphylaxis due to sensitization to mannitol and polysorbate (mainly polysorbate 80) have been reported [7,8]. Since no IgE-mediated mechanism was demonstrated in the present case following skin tests and BAT, and given that the patient developed a severe life-threatening reaction despite receiving adequate premedication following the summary of product characteristics, we considered CRRs to be a possible underlying mechanism of the severe reaction and thought that the patient could benefit from an RDD protocol for administration of daratumumab [3]. Given the negative skin test results with daratumumab, further studies with mannitol and polysorbate 20 were not performed. Desensitization by expert allergists is a powerful tool that is both safe and effective for maintaining treatment in patients Successful Desensitization to Daratumumab After a Severe Life-threatening Reaction in a Patient With Refractory Multiple Myeloma