Risk factors for varicella zoster virus reactivation in newly diagnosed multiple myeloma patients undergoing autologous stem cell transplantation

Abstract

Abstract Multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) have a cumulative risk between 8 and 20% of varicella zoster virus (VZV) reactivation, especially within the first 12 months after ASCT. Currently, there is no global consensus regarding the dosage of antivirals prophylaxis to be administered and the duration of treatment in MM patients after ASCT. Also, the role of the recombinant zoster vaccine, introduced in Italy in 2021, is still to be clarified. The aims of this observational study are to evaluate in real-life cohort of MM patients after ASCT i) the dosage of antivirals used for VZV prophylaxis, ii) the mode of discontinuation of VZV prophylaxis, iii) the rate of VZV reactivation and iv) potential biomarkers for VZV reactivation. A total of 166 sequential patients with MM or plasma cell leukemia undergoing ASCT in our Centre between 2010 and 2023 were included in the present study. Patient characteristics were consistent with MM patients undergoing ASCT. The median age was 60 year, 91 (54%) patients presented ISS 1, 34 (21%) ISS 2 and 33 (20%) ISS 3, whereas for 8 patients (5%) ISS was not available. Patients were equally distributed between male (46%) and female (54%). Among the 91 (55%) patients with available FISH karyotype, 28 (30%) presented at least one high-risk cytogenetic abnormality. MM isotype was IgG kappa in 68 (41%) patients, IgG lambda in 31 (19%), micromolecular kappa in 24 (15%), IgA kappa in 18 (11%), micromolecular lambda in 15 (9%), IgA lambda in 8 (4%) and IgD lambda in 1 patient. All patients underwent ASCT after at least a partial response to induction therapy, which consisted of triplets, quadruplets or combinations of chemoimmunotherapy. Overall, 66 (40%) patients received only one ASCT and maintenance therapy was started in 94 (57%) patients. Maintenance therapy consisted of lenalidomide in 53 (56%) patients, bortezomib for two years in 14 (15%) patients, thalidomide in 4 (4%) patients and other combination for the other 29 patients. Acyclovir prophylaxis was used at the dosage of 400 mg twice daily for all patients, unless adjusted for renal function. In the present cohort, post-transplant prophylaxis discontinuation modalities were the following: 14 (8%) patients stopped acyclovir after achieving CD4+ lymphocyte count > 200/µL, 19 (11%) after about one year after transplant, 24 (15%) after approximately six months after transplant, 36 (22%) after receiving recombinant zoster vaccine, 6 (3%) for cutaneous or hepatic toxicity and 67 (41%) patients continued acyclovir until new relapse. Out of the 166 patients, 20 (12%) experienced VZV reactivation. The 4-year cumulative risk of VZV reactivation was 10.6%, with 15 (75%) patients who reactivated VZV in the first two years, in accordance with previous evidence. Among these 20 patients, 11 (55%) VZV reactivations occurred after stopping acyclovir and 9 (45%) during active prophylaxis. Among the patients who reactivated VZV, none received tthe recombinant vaccine with the correct timing as it was not available, and three of them reactivated VZV few months after vaccination. Regarding VZV reactivation severity, 85% were grade 2, treated with oral aciclovir or valaciclovir, 2 (10%) grade 3 and one patient (5%) grade 4. The patient who experienced grade 4 toxicity (encephalic life-threatening manifestation) discontinued antiviral prophylaxis early after transplantation due to hepatic toxicity. The adverse event resolved with intravenous antiviral therapy. Different biomarkers have been evaluated in this cohort to predict VZV reactivation. A trend towards a shorter time to reactivation of VZV for patients with beta-2 microglobulin (B2M) > 2.3 µg/L (p=0.05) was identified. Patients with B2M > 2.3 µg/L had a 4-year risk of VZV reactivation of 20.6% compared to 2.6% for patients with lower levels of B2M. No difference in the risk of VZV reactivation was seen based on gender, anemia, renal failure, bone lesions documented with imaging, plasma cellular infiltrate >60%, ISS stadium, MM isotype, CD4+ count, lymphocyte count, single or tandem auto transplant or quadruplet versus triplet induction. This study is the first to describe, in a real-world cohort of MM patients undergoing ASCT, the prevalence and potential risk factors for VZV reactivation also in vaccinated patients. The possible role of prognostic biomarkers, namely B2M levels, in predicting VZV reactivation needs to be confirmed in larger datasets.