Cytomegalovirus reactivation in patients with multiple myeloma administered daratumumab-combination regimens

Abstract

Dear Editor, Daratumumab (Dara)-combination regimens have shown promising outcomes for patients with newly diagnosed multiple myeloma (NDMM) or relapsed and refractory multiple myeloma (RRMM). [1–4] Dara is a monoclonal antibody against CD38, which is expressed on not only myeloma and B cells but also natural killer cells and activated T cells [5–8]. Counts of cells expressing CD38 are decreased during Daracombination regimens, which may lead to the onset or reactivation of infections. [5, 9, 10] Aciclovir prophylaxis against varicella zoster virus is recommended for multiple myeloma patients receiving Dara; however, monitoring or prophylaxis in case of cytomegalovirus (CMV) is not indicated [11]. Recently, several CMV reactivation cases post-Dara treatment were reported in patients with RRMM [12–14]. Between January 2018 and October 2020, we retrospectively reviewed the clinical records of all 15 patients (NDMM, n = 3; RRMM, n = 12) who received Daracombination regimens in our institution. This study was approved by the institutional ethics committee of the National Cancer Center Hospital East, Kashiwa, Japan. These patients (median age = 61 years; range = 46–75) were treated as follows: Dara/bortezomib/dexamethasone (n = 13), Dara / lena l idomide /dexamethasone (n = 1) , and Dara/bortezomib/melphalan/prednisone (n = 1). In our sample, 11 (73.3%) out of 15 patients experienced CMV reactivation after receiving Dara-combination regimens (Table 1). Patients with RRMM received a median chemotherapy of 3.5 (range, 2–5) lines, and 7 patients underwent autologous hematopoietic stem cell transplantation before Dara administration. CMV p65 antigen tests were performed 1–2 times a week in all 15 patients who received Dara-combination regimens. Eleven patients with CMV reactivation showed positive results at a median time of 30 (range, 7–55) days from the start of Dara-combination regimen administration. CMV pp65 antigenemia test demonstrated that median CMV antigenemia levels were 14 (range, 7–19) and 9 (range, 1–104) for patients with NDMM and RRMM, respectively. Of the 15 patients, 12 patients had received intravenous immunoglobulin (IVIG) with the target >500mg/dL during Dara-combination regimen treatment. Among the 11 patients with CMV reactivation, seven (63.6%; NDMM, n = 2; RRMM, n = 5) had immunoglobulin G levels < 500 mg/dL at the time of CMV reactivation. After confirming CMV reactivation in nine (81.8%) of these 11 patients, antiviral drugs (ganciclovir, n = 1; valganciclovir, n = 10) were administered to reduce viremia. In this study, CMV reactivation was observed in both NDMM and RRMM patients who had received Daracombination regimens; therefore, CMV antigenemia monitoring may be required in patients at high risk. Although the mechanism of CMV reactivation after Dara treatment remains unknown, it is hypothesized that reactivation occurs via the effects of Dara or combination agent (e.g., bortezomib and lenalidomide) on immune cells (e.g., regulatory, effector, and helper T cells). [5–8] Further studies comprehensively investigating immunoprofiling in patients administered Dara-combination regimens are required to identify high-risk patient subgroups for CMV reactivation. * Junichiro Yuda [email protected]