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Daratumumab Increases Listeria Susceptibility

Listeria monocytogenes.

Patients with multiple myeloma who are receiving daratumumab (Darzalex®, Janssen) have an increased susceptibility to listeriosis, a potentially deadly infection by Listeria monocytogenes, a gram-positive bacterium to which individuals with weakened immune systems are susceptible.

Daratumumab, a CD38 monoclonal antibody, is effective against multiple myeloma because CD38 is strongly expressed in multiple myeloma cells. However, activated macrophages also express CD38. It seems to be an important part of the body's line of defense against infection with listeria, inhibiting the infection of the macrophage cytoplasm and preventing macrophage-based dissemination by phagocytosed bacilli. This hypothesis has been borne out by the fact that CD38 inactivation in mice causes a susceptibility to listeria infection.

For this reason, researchers at the Princess Margaret Cancer Centre and the Department of Infection Prevention and Control of the University Health Network in Toronto, Canada, examined the risk of listeriosis among patients treated with daratumumab at a tertiary community cancer center during a listeria outbreak at a commercial eatery in Toronto over the course of a nine-month span in 2018. The results of their nested case-control study have been published today in a research letter in JAMA Oncology.

Of 7 people with listeriosis acquired at the eatery, all had cancer, and 4 (57%) had multiple myeloma. Three of the patients with multiple myeloma––43% of the patients diagnosed with listeriosis––were receiving a daratumumab-based therapy (daratumumab/pomalidomide/dexamethasone); the fourth multiple myeloma patient with listeria had recently undergone autologous stem cell transplant following bortezomib induction therapy. The 40 patients receiving daratumumab for multiple myeloma at the cancer center comprised fewer than 0.3% of all potentially exposed individuals who visited the cancer center, yet they represented 43% of the listeriosis cases.

''Patients with myeloma receiving daratumumab were found to have a 340-fold increased risk… of developing listeriosis compared with other patients with cancer based on small numbers," write the investigators, led by first author Sahar Khan, MBChB, and senior author Rodger E. Tiedemann, MBChB, PhD, both of the Princess Margaret Cancer Centre's Department of Medical Oncology and Hematology. "Moreover, patients treated with daratumumab experienced a 75-fold listeriosis risk… compared with all other patients with myeloma despite the latter group at the tertiary cancer center including at-risk patients undergoing stem cell transplant or experimental therapies for relapsed-refractory disease."

Clinical trials of daratumumab demonstrated only a mild risk of listeria infection, a fact which the authors of the research letter attribute to low exposure rates. Even so, they note, during clinical trials of daratumumab/lenalidomide/dexamethasone, an individual treated with the daratumumab-containing regimen did develop grade 3/4 listeriosis, while there were no listeriosis cases in the lenalidomide/dexamethasone arm.

"We suggest that patients receiving daratumumab be provided with dietary advice to avoid unpasteurized dairy products, undercooked meats, or unwashed vegetables. Antibiotic prophylaxis should be considered using sulfa-methoxazole/trimethoprim, which has activity against Listeria and is routinely indicated for pneumocystis pneumonia prophylaxis with corticosteroid use," write Dr. Khan and colleagues. "Lastly, clinicians should be vigilant for listeriosis in this population, particularly when patients develop gastroenteritis, unexplained sepsis, or neurological findings. As daratumumab use continues to rise, these simple measures may reduce treatment-associated Listeria risk."

For More Information

Khan S, Vaisman A, Hota SS, et al (2019). Listeria susceptibility in patients with multiple myeloma receiving daratumumab-based therapy. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2019.5098

​Image credit: James Folsom

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