Infectious complications and NK cell depletion following daratumumab treatment of Multiple Myeloma

Abstract

Treatment with Daratumumab (Dara), a monoclonal anti-CD38 antibody of IgG1 subtype, is effective in patients with multiple myeloma (MM). However, Dara also impairs the cellular immunity, which in turn may lead to higher susceptibility to infections. The exact link between immune impairment and infectious complications is unclear. In this study, we report that nine out of 23 patients (39%) with progressive MM had infectious complications after Dara treatment. Five of these patients had viral infections, two developed with bacterial infections and two with both bacterial and viral infections. Two of the viral infections were exogenous, i.e. acute respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), while five consisted of reactivations, i.e. one herpes simplex (HSV), 1 varicella-zoster (VZV) and three cytomegalovirus (CMV). Infections were solely seen in patients with partial response or worse. Assessment of circulating lymphocytes indicated a selective depletion of NK cells and viral reactivation after Dara treatment, however this finding does not exclude the multiple components of viral immune-surveillance that may get disabled during this monoclonal treatment in this patient cohort. These results suggest that the use of antiviral and antibacterial prophylaxis and screening of the patients should be considered.

Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes

“…We appreciate that our patient was heavily pretreated and post allo-HCT before Dara-containing therapy, which itself put him at risk for PML. An increased risk for reactivated latent infections such as herpes zoster, herpes encephalitis, or hepatitis B during Dara therapy has been described previously and, at least partly, can be attributed to the depletion of NK cells [6]. Possibly, Dara has introduced another type of immunological sequelae highlighted not only by the development of PML but also by concomitant condyloma acuminatum and CMV reactivation.…”

“…Possibly, Dara has introduced another type of immunological sequelae highlighted not only by the development of PML but also by concomitant condyloma acuminatum and CMV reactivation. However, the interplay between innate immunity and T-cell responses during CD38 antibody therapy has yet to be elucidated, and the same holds true for Dara treatment post allo-HCT [6].…”

“…These two cases argue to the potential of T-cell transfers after allo-HCT, although only selected patients will be in a situation where T-cell transfer is an option. Multiple myeloma (MM) patients treated with the anti-CD38 monoclonal antibody daratumumab (Dara) show an increased risk for infectious complications, potentially attributable to the depletion of NK cells [6][7][8].…”

The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors

“…The primary mechanism of action for daratumumab is ADCC, which is largely mediated by the action of NK cells. Elimination of this cell population occurs via CD38+ NK cell apoptosis [72] and, in turn, diminishes daratumumab efficacy [73] and also can increase the risk of infectious complications [74]. Knowledge about CD38-targeting strategies and mechanisms of resistance from these studies in myeloma may prove useful as researchers in the solid tumor field attempt to apply anti-CD38 therapeutic strategies especially for tumor types which have shown to have aberrant and dynamic CD38 activity, which will be described in the next section.…”

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

“…Despite not reaching statistical significance often, the rates of infections (particularly those of viral etiology) have been frequently reported to be increased with the use of MoAb. Indeed, real-world data have registered infectious rates up to 39% in patients treated with daratumumab [119,120]. Long-term observation and future clinical trials should specifically address infection risk in MM patients receiving MoAbs, to develop appropriate guidelines for prophylactic and treatment procedures.…”