Impact of Daratumumab on the Development of Engraftment Syndrome after Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma
Authors: Minakata Daisuke , Fujiwara Shin-ichiro , Honda Seina , Tominaga Ryutaro , Yokoyama Daizo , Furuki Shuka , Noguchi Atsuto , Koyama Shunsuke , Murahashi Rui , Nakashima Hirotomo , Hyodo Kazuki , Kawaguchi Shin-ichiro , Toda Yumiko , Umino Kento , Ashizawa Masahiro , Ueda Masuzu , Yamamoto Chihiro , Hatano Kaoru , Sato Kazuya , Ohmine Ken , Kanda Yoshinobu 
Published: December 2024

[Introduction]
Addition of daratumumab to induction, consolidation, and maintenance regimens confers significant benefit in progression-free survival (PFS) of transplantation-eligible patients with newly diagnosed multiple myeloma (MM). However, the relationship between daratumumab administration before autologous peripheral blood stem cell transplantation (ASCT) and ASCT-associated adverse events in patients with MM is not fully understood. In our institution, we add daratumumab-containing regimens before ASCT for patients with insufficient response to initial induction therapy to achieve deeper response. On the other hand, engraftment syndrome (ES), characterized by a continuum of peri-engraftment complications following ASCT, can include fever, diarrhea, rash, pulmonary infiltrates, and liver dysfunction. The present study aimed to determine risk factors for ES after ASCT in patients with MM, focusing daratumumab before ASCT.
[Methods]
This single-center retrospective study aimed to determine the impact of daratumumab before ASCT on disease prognosis and ES development after ASCT in patients with MM.
[Results]
The study cohort included 99 patients with MM who underwent 110 ASCTs, including 11 patients who underwent ASCT twice, with (N=37) or without (N=62) daratumumab administration before ASCT between May 2013 and December 2023. The median age was 61.2 (24.1-70.5) years, and 60.6% of the patients were male. The median follow-up duration was 877 (range, 185-2999) days, PFS at 36 months after diagnosis was 71.0% and 61.7% (P = 0.755), respectively, in patients with and without daratumumab treatment before ASCT. At the time of ASCT, the proportion of patients with very good partial response (VGPR) or better was higher in those with daratumumab treatment than in those without daratumumab treatment (86.5% vs. 71.0%, P = 0.537). The measurable residual disease (MRD) status could be evaluated in 20 of 37 patients treated with daratumumab before ASCT, and 12 patients (60.0%) did not have MRD (at 10−5 level). ES, determined using the Spitzer (3 major or 2 major + 1 minor) and Maiolino (major + 1 minor) criteria, was diagnosed upon fulfillment of at least one of the conditions. Fourteen cases of ES (12.8%) were recorded, with a median onset of 16 (9-23) days following ASCT. By multivariate analysis incorporating potentially confounding variables, age &gt;65 years (odds ratio [OR] 3.820, 95% confidence interval [CI] 1.11-13.2, P = 0.034) and daratumumab treatment before ASCT (OR 6.23, 95% CI 1.55-25.0, P = 0.009) were significant independent risk factors for ES, whereas treatment response before ASCT (&lt;VGPR), MM disease risk (high vs. standard), and infused CD34+ cell dose (≥2.0×106/kg) were not. Tissue biopsies were performed in four of the patients who developed ES. Lower gastrointestinal biopsies were performed in two patients who had diarrhea, and the findings were similar to those of gastrointestinal graft-versus-host disease, showing “lymphocytes and neutrophils invading the crypts, scattered apoptotic bodies, and neutrophils, eosinophils, and lymphocyte/plasma cell infiltration in the interstitium.” Immunostaining did not reveal any cytomegalovirus (CMV)-positive cells in any of the sites.
We further investigated the incidence of CMV infection after ASCT as an ASCT-associated adverse event. In 33 patients who underwent post-ASCT CMV antigenemia testing, 11 patients tested positive for peripheral blood CMV antigenemia. The proportion of CMV antigenemia positivity tended to be higher in patients with daratumumab treatment than in those without daratumumab treatment (40% [10/25] vs. 12.5% [1/8], P = 0.218).
[Summary/Conclusion]
This is the first study reporting the association between pretransplant daratumumab treatment and the risk of ES after ASCT. These findings should be validated in larger cohorts evaluating immunological parameters.