Incidence of Varicella Zoster Virus (VZV) and Herpes Simplex Virus (HSV) Infections and Use of Prophylaxis in Lenalidomide-Treated Multiple Myeloma (MM) Patients (pts): An Analysis of MM Trials
Authors: Gary Dianna , Weiss Lilia , Yu Zhinuan , Xu Qiang , Minton Neil , Gillen David , Glasmacher Axel , Freeman John 
Published: October 2019

Abstract
Background: The publication of a retrospective analysis of the occurrence of VZV and HSV infections among 93 pts treated with lenalidomide (LEN; König, 2014) reported an increased VZV/HSV rate (10 pts) and recommended mandatory prophylaxis with acyclovir as well as analogous multicenter data reviews. According to the Centers for Disease Control and Prevention (CDC), an estimated 1 in 3 persons in the US will experience shingles during their lifetime. A Swedish study found that MM pts are 12.8 times more likely to have a VZV infection than the general population (Blimark, 2012). For pts with hematologic malignancies, the risk of developing shingles increases from 13% to 55% the year after a stem cell transplant (Harpaz, 2008). An alternative to antiviral prophylaxis, VZV vaccine has only been available since 2006 in US. In 2008, the CDC recommended vaccination for adults without contraindications aged > 60 years, and in Sep 2013, the UK similarly recommended vaccination for adults aged 70 to 79 years.
Aim: To further understand the risk of VZV/HSV and assess the potential benefit of viral prophylaxis in LEN-treated MM pts. An analysis was conducted on data from MM pts, 1727 treated with LEN combination and 1044 with a comparator, who participated in four phase 3 Celgene-sponsored studies (MM-009, MM-010, MM-015, and MM-020). No VZV/HSV prophylaxis was mandated in these studies.
Methods: The incidence rates (IR) and frequencies of VZV/HSV infections were determined by searching the MedDRA high-level terms of herpes viral infections. VZV/HSV or other antiviral prophylaxis data were derived from the concomitant medication report form. Data on VZV vaccination before study entry were not available. Among pts who did not experience a VZV/HSZ infection, antiviral prophylaxis was defined as taking at least 1 antiviral medication during the study, regardless of antiviral duration. Among pts who did have VZV/HSZ infection, prophylaxis was defined as taking at least 1 antiviral medication within the week prior to VZV/HSZ adverse event (AE).
Results : Overall, the cumulative incidence of treatment-emergent VZV/HSV AEs in 1,727 LEN-treated pts was 8.0% and the IR per 100 person-years (PY) was 6.03% (95% CI: 5.11-7.13). The highest IR was for D (16.03%, CI: 11.56-22.23), followed by MP (8.98%, CI: 5.42-14.90), RD (8.73%, CI: 6.35-11.99), Rd (5.49%, CI: 4.40-6.85), MPR (5.12%, CI: 3.37-7.78), and MPT (4.38%, CI: 2.94-6.54) (Table). Of the VZV/HSV AEs, the most commonly reported type in LEN arms was oral herpes (34%) followed by VZV (28%). The majority of LEN VZV/HSV AEs were non-serious, with 11% of AEs being grade 3 or 4. Antiviral prophylaxis was used in 13.9%. Of pts who reported HZV/HSV, 2.2% received antiviral prophylaxis.
Conclusions: The incidence of VZV/HSV infections in MM pts was similar to that reported by König et al. However, there is no indication from these prospective, randomized studies that this rate is specifically associated with LEN, as no increased IRs could be documented. Therefore, there is insufficient evidence to mandate prophylaxis beyond existing guidelines for immunocompromised pts. Clinicians are encouraged to follow their regional recommendations on the prevention of VSV/HSV infections and discuss the benefit-risk of prophylaxis with their MM pts.
Abstract 3451. Table 1: Incidence Rates of Treatment-emergent VSV/HSV Infections in LEN MM Studies MM-009/010 MM-015 MM-020 R-pooled RD D MPR MP Rd MPT N=353 N=350 N=302 N=153 N=1072 N=541 N=1727 Pts with VSZ/HSV Infection n (%) 38 (10.8) 36 (10.3) 22 (7.3) 15 (9.8) 79 (7.4) 24 (4.4) 139 (8.0) Total person-years 435.50 224.55 429.32 166.96 1438.62 547.59 2303.40 IR (/100py) (%) 8.73 16.03 5.12 8.98 5.49 4.38 6.03 95% CI 6.35-11.99 11.56-22.23 3.37-7.78 5.42-14.90 4.40-6.85 2.94-6.54 5.11-7.13
Legend: R=Len, D=high dose dexamethasone, M=melphalan, P=prednisone, d=low dose dexamethasone, T=thalidomide.
Note: CI= Confidence interval; Person-years (PY) were calculated as the time from the first dose to the onset date of first AE for pts with AE, and to the earlier date of last dose + 28 days for pts without AE. IR per 100 PY is calculated as 100* n/T, where n=# of pts with AE (only the first AE is counted per pt) and T = total PY. 95% CI for IR per 100 PY is calculated using the method by RG Miller: IR*exp{±1.96*n^(-1/2)}.
Blimark C, et al. Blood. 2012; 120 (21) 945.
Harpaz R, et al. MMWR Recomm Rep. 2008;57(RR-5):1-30.
König C, et al. Ann Hematol. 2014;93(3):479–84.

Disclosures
Gary: Celgene Corporation: Employment, Equity Ownership. Weiss:Celgene Corporation: Employment. Yu:Celgene Corp: Employment, Equity Ownership. Xu:Celgene Corp.: Employment. Minton:Celgene Corp: Employment, Equity Ownership. Gillen:Celgene Corp: Employment, Equity Ownership. Glasmacher:Celgene Corp: Employment, Equity Ownership. Freeman:Celgene Corp: Employment, Equity Ownership.