Listeria Susceptibility in Patients With Multiple Myeloma Receiving Daratumumab-Based Therapy

Daratumumab is a human immunoglobulin G1κ monoclonal antibody directed against cluster of differentiation (CD) 38 that received US Food and Drug Administration approval in 2017 as multiple myeloma therapy. While CD38 is highly expressed by myeloma cells, it is also expressed by activated macrophages and appears to play an important role in Listeria defense, inhibiting the infection of the macrophage cytoplasm by phagocytosed bacilli and preventing macrophage-based dissemination.¹ In mice, CD38 inactivation causes a marked susceptibility to Listeria monocytogenes. As CD38 is also induced on human macrophages, identical mechanisms may underlie human Listeria protection.²

Clinical trials have characterized daratumumab’s safety profile and demonstrated only a mild infection risk.³ However, because preclinical models of CD38 inactivation are associated with increased L monocytogenes susceptibility, we assessed the risk of listeriosis in patients receiving anti-CD38 daratumumab therapy.

We performed a nested case-control study examining the risk of L monocytogenes among patients receiving daratumumab amid an outbreak at a commercial eatery in a tertiary cancer center in Toronto, Ontario, Canada, over 9 months in 2018. Patients or next of kin provided written informed consent and institutional review board approval was waived by the University Health Network. The cancer center services 364 clinics per week and 284 500 outpatient visits per year. The term cases was used to refer to patients who acquired listeriosis from the eatery based on clinical and molecular data. Controls were defined as outpatients attending the cancer center during the outbreak. Restaurant patronage was assumed to be equal across cancer subtypes. We compared the odds of developing listeriosis among patients receiving daratumumab with control populations not exposed to the drug. Odds ratios were adjusted according to patient visits, and P values were calculated according to Altman.⁴ Statistical significance was set at α = .05.

Seven people with listeriosis that was associated with patronage at the eatery were identified, and all had cancer (Table). Four (57%) had multiple myeloma. Of these, 1 (14%) had recently undergone autologous stem cell transplant (following bortezomib induction) and 3 (43%) were receiving daratumumab-based therapy (together with pomalidomide and dexamethasone). During the exposure period, there were 85 301 patient visits at the hospital. Patients with myeloma receiving daratumumab (n = 40) accounted for fewer than 0.3% of potentially exposed individuals yet comprised 43% of cases. After adjusting for hospital visits, patients with myeloma receiving daratumumab were found to have a 340-fold increased risk (95% CI, 68-1693; P < .001) of developing listeriosis compared with other patients with cancer based on small numbers (Figure). Moreover, patients treated with daratumumab experienced a 75-fold listeriosis risk (95% CI, 8-726; P < .001) 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.

Treatment with daratumumab for patients with myeloma appears to be associated with a substantive increase in Listeria risk, consistent with the strong preclinical evidence of enhanced Listeria susceptibility in CD38 knockout mice. Although these patients received daratumumab together with pomalidomide and dexamethasone, increased Listeria risk has not been reported with pomalidomide. While use of corticosteroids may increase Listeria susceptibility,⁵ no cases occurred in patients with myeloma who were receiving corticosteroids without daratumumab, despite their greater number. Thus, daratumumab was the likely critical driver of Listeria susceptibility in this population.

Notably, listeriosis risk is rarely ascertained from phase 1 to 3 studies because of low exposure rates. Nevertheless, during clinical trials of daratumumab-Rd, an individual treated with daratumumab developed grade 3 to 4 listeriosis, whereas no cases occurred in the Rd arm (NCT02076009), supporting the findings reported in this article.

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 sulfamethoxazole/trimethoprim, which has activity against Listeria and is routinely indicated for pneumocystis pneumonia prophylaxis with corticosteroid use. 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.

Corresponding Author: Rodger E. Tiedemann, MBChB, PhD, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 101 College St, Princess Margaret Cancer Research Tower, Ste 12-306, Toronto, ON M5G 1L7, Canada (rodger.tiedemann@uhn.ca).

Published Online: November 27, 2019. doi:10.1001/jamaoncol.2019.5098

Author Contributions: Dr Tiedemann had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Khan, Vaisman, Hota, Tiedemann.

Acquisition, analysis, or interpretation of data: Khan, Bennett, Hota, Reece, Trudel, Tiedemann.

Drafting of the manuscript: Khan, Vaisman, Hota, Tiedemann.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Vaisman, Tiedemann.

Obtained funding: Tiedemann.

Administrative, technical, or material support: Khan, Bennett, Hota, Trudel.

Supervision: Hota, Reece, Tiedemann.

Conflict of Interest Disclosures: Dr Reece reported grants and personal fees from Janssen, Celgene, Amgen, and Takeda; personal fees from Karyopharm; and grants from Otsuka, Merck, and Bristol-Myers Squibb. Dr Trudel reported grants and personal fees from Janssen, Celgene, Amgen, and GlaxoSmithKline; personal fees from Sanofi and Karyopharm; and grants from Genentech. Dr Tiedemann reported grants from Terry Fox Research Institute and personal fees from Janssen, Amgen, Roche, Celgene, and Takeda. No other disclosures were reported.

Funding/Support: Funding for this study was provided in part by the Terry Fox Research Institute.

Role of the Funder/Sponsor: The Terry Fox Research Institute had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the National Microbiology Lab and the Public Health Ontario Laboratory for contributing public health–level information and the myeloma clinical trials team at Princess Margaret Cancer Centre for providing visit data. We thank the Terry Fox Research Institute for support (Pan-Canadian Myeloma Program Project grant to Drs Tiedemann and Trudel).