Prognosis of hepatitis B virus reactivation in newly diagnosed multiple myeloma in modern era therapy: a retrospective study

Patients

We retrospectively enrolled 412 Chinese patients with NDMM between 2015 and 2020 at the Sun Yat-sen University Cancer Center’s Department of Hematologic Oncology. None of the patients had received anti-tumor treatment previously. Among these 412 patients with NDMM, 57 cases were excluded due to lack of detection data of HBV. Finally, 355 patients were included in our analysis. The MM diagnosis relied on the criteria established by the International Myeloma Working Group (IMWG). The research has received approval from the Sun Yat-sen university cancer prevention and control center for ethics committee (ethical approval referenced number: B2023-471-01). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements. The utilization of electronic health records was employed for the examination of patients’ information.

Patients’ characteristics and initial laboratory parameters were documented upon the commencement of chemotherapy (Table S1). The HBV infection-related data included hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B surface antibody (HBsAb), hepatitis B e-antigen (HBeAg), and hepatitis B e-antibody (HBeAb), and HBV DNA titers. Continuous monitoring of all patients was conducted throughout the study, with the exception of cases where patients could not be traced for follow-up until 31 December 2022 or they had passed away.

Measurements and definitions

HBsAg, HBcAb, HBsAb, HBeAg, and HBeAb were detected by chemiluminescence. Quantitative PCR was utilized to determine the titers of HBV DNA. HBV reactivation was defined as follows: (1) reappearance of HBsAg and loss of HBsAb in patients who were HBsAg-negative and/or HBsAb-positive; (2) increase of HBV DNA level by at least a factor of 10 in HBV DNA levels compared to the initial levels, or an absolute count of HBV DNA reaching 1 × 10⁹ copies/mL In our study, we only analyzed HBV reactivation which occurred before the first progression of NDMM. Overall survival (OS) definition was that time from transplantation to death or date of last follow-up in alive patients. Progression-free survival (PFS) is defined as the time between the NDMM patients received initiation of treatment to disease progression or death from any cause.

Treatment

First-line regimens were as follows (Table 1): cyclophosphamide + thalidomide + dexamethasone (CTD, N = 19); bortezomib + adriamycin + dexamethasone (PAD, N = 140); ixazomib + lenalidomide + dexamethasone (IRD, N = 11); bortezomib + cyclophosphamide + dexamethasone (VCD, N = 16); liposomal doxorubicin + vincristine + dexamethasone (DVD, N = 53); bortezomib + dexamethasone (VD, N = 5); vincristine + doxorubicin + dexamethasone (VAD, N = 24); bortezomib + lenalidomide + dexamethasone (VRD, N = 78) and bortezomib + thalidomide + dexamethasone (VTD, N = 9). A total of 62 patients received autologous stem cell transplantation (ASCT) subsequent to undergoing high-dose chemotherapy. In patients with chronic HBV infection, treatment with entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), or tenofovir amibufenamide (TMF) for a duration of 48 weeks is recommended. If HBV DNA remains detectable after 48 weeks of therapy (HBV DNA > 20 IU/ml), adjustments can be made to the medication treatment plan, excluding errors related to compliance and detection. Patients currently prescribed ETV should consider transitioning to TDF or TAF, while those on TDF or TAF may consider switching to ETV; alternatively, a combination therapy involving both drugs can be considered. In patients with active HBV infection, treatment with ETV, TDF or TAF is recommended and the most appropriate antiviral regimen were selected according to the patient’s specific drug resistance.

Statistical analyses

The results were performed by IBM SPSS Statistics 25.0. The median values, accompanied by their corresponding ranges, were presented to depict the numerical data. The comparison of categorical variables involved the utilization of either Pearson chi-square test or Fisher exact test. The factors influencing HBV reactivation rates were analyzed using a chi-square test in a univariate analysis. Multivariate analysis used Cox regression to further evaluate the hazard elements. The Kaplan-Meier method was performed to analyze OS. Cumulative incidence was applied to calculate the incidence of HBV reactivation and progression of NDMM using competing risk model, and the death was seen as a risk of competition. The utilization of two-sided P-values was employed. The statistical significance was determined when the P-value was less than 0.05. Competitive risk model in R method (R version 4.2.1; R Core Team, 2022) was used to analyze the cumulative incidence.

Patients’ characteristics

In our study, 355 patients (223 males and 132 females) were enrolled. The age distribution of the confirmed cases ranged from 24 to 85 years, with a median age of 58 years. The duration of follow-up ranged from 0 to 104 months, with a median of 44.0 months. The fundamental attributes of the enrolled patients are summarized in Table S1. Among the patients, 152 showed HbsAg-negativity combined with HBcAb-positivity and all of these individuals were administered entecavir (0.5 mg qd) as a prophylactic measure against HBV reactivation. In addition, 35 patients had confirmed HBV infection at diagnosis of MM characterized by HBsAg-positivity, as indicated by the presence of HBsAg, and all these patients received entecavir (0.5 mg qd) for anti-HBV therapy.

Morbidity and hazard elements of HBV reactivation before the first progression of NDMM

Among the 355 patients enrolled in our analysis, 33 (9.3%) developed HBV reactivation before the first progression of NDMM, with a median HBV reactivation time of 3 months (range, 0–31 months). The characteristics of the 33 patients with HBV reactivation including transaminases and HBV DNA copies were shown in Table S2. The 2- and 5-year overall cumulative incidences of HBV reactivation before the first progression of NDMM were 9.1% (95% confidence interval (CI) [5.96–12.24%]) and 9.9% (95% CI [6.76–13.04%]), respectively. Univariable analysis showed that bortezomib-containing regimens (P = 0.006), lenalidomide treatment (P = 0.036), ASCT (P = 0.003), 1q21+ (P = 0.023), HBsAg-positivity (P < 0.0001), HBsAb-positivity (P = 0.014), HBcAb-positivity (P < 0.0001), and HBeAg-positivity (P = 0.012) were hazard elements of HBV reactivation before the first progression of NDMM (Table 1A). Multivariable analysis showed that HBsAg-positivity (P < 0.0001, hazard ratio [HR] 5.584, 95% CI [2.686–11.606]), HBcAb-positivity (P = 0.004, [HR] 4.899, 95% CI [1.646–14.584]), bortezomib-containing regimens (P = 0.018, [HR] 4.222, 95% CI [1.278–13.945]), ASCT (P = 0.006, [HR] 2.751, 95% CI [1.330–5.687]), and 1q21+ (P = 0.012, [HR] 2.572, 95% CI [1.250–6.055]) were identified as independent hazard elements of HBV reactivation (Table 1B).

The occurrence of HBV reactivation during a 2-year period in patients who underwent ASCT (17.7%, 95% CI [8.10–27.30%]) was higher than that in patients who did not undergo ASCT (4.5%, 95% CI [0.21–6.85%]; P = 0.006) (Fig. 1A). The 2-year cumulative incidence of HBV reactivation in patients receiving bortezomib-containing regimens (11.8%, 95% CI [7.88–15.72%]) was higher than that in patients not receiving bortezomib-containing regimens (3.1%, 95% CI [0.43–6.63%]; P = 0.018) (Fig. 1B). Furthermore, the cumulative incidence of HBV reactivation during a 2-year period in patients with 1q21+ (15.9%, 95% CI: 6.30–25.50%) was higher than that of those without 1q21+ (7.7%, 95% CI [4.56–10.84%]; P = 0.009) (Fig. 1C). The 2-year cumulative incidence of HBV reactivation in patients with HBsAg-positivity (42.6%, 95% CI [25.55–59.65%]) was higher than that of those with HBsAg negative (5.5%, 95% CI [2.95–8.05%]; P < 0.0001) (Fig. 1D). Finally, the 2-year cumulative incidence of HBV reactivation in patients with HBcAb-positivity (15.6%, 95% CI [10.31%–20.89%]) was higher than that of those with HBcAb-negativity (1.9%, 95% CI [0.26–4.06%]; P < 0.0001) (Fig. 1E).

Survival analysis

To analyse the relevance of the clinical parameters of patients with NDMM to their OS and PFS, we assessed multiple clinical data of patients with NDMM in Table 2. Of the 33 patients with HBV reactivation before the first progression of NDMM, 19 (58%) survived, and 14 (42%) died at a median follow-up of 40.0 months (range, 5–94 months) after HBV reactivation. Among these 14 patients, five (36%) died of treatment-related complications, including myocardial infarction (one case), septicaemia (two cases), and severe pneumonia (two cases), while nine (64%) died of complications of MM progression. None of the 33 patients with HBV reactivation developed fulminant hepatitis, and none of them experience MM-related treatment withdrawn. The patients with HBV reactivation had poorer 3-year survival than did those without HBV reactivation (63.1 ± 8.5% vs 81.0 ± 2.2%, P = 0.029) (Fig. 2A). Furthermore, univariate analysis revealed that International Staging System (ISS), Revised-International Staging System (RISS), IMWG, ASCT, deletion of P53, progression, and HBV reactivation were significant hazard elements for OS (Table 2; P < 0.05). Multivariable analysis showed that R-ISS stage, IMWG risk stratification, progression of NDMM, and HBV reactivation were identified as independent hazard elements of OS (Table 3A).

Of the 33 patients with HBV reactivation before the first progression of NDMM, 21 (64%) developed NDMM progression at a median follow-up of 31.0 months (range, 0–83 months). The other 12 (36%) patients were free from disease progression, including two patients who died before primary disease progression. Moreover, the patients with HBV reactivation had poorer 3-year PFS than did those without HBV reactivation (38.4 ± 9.4% vs. 67.5 ± 2.8%, P < 0.0001) (Fig. 2B). Univariate analysis showed that DS, R-ISS, IMWG, use of thalidomide or lenalidomide, 1q21+, Immunoglobulin Heavy Chain (IGH) rearrangements, deletion of 13q14, deletion of P53, and HBV reactivation were significant hazard elements for PFS (Table 3; P < 0.05). Multivariable analysis showed that HBV reactivation, use of lenalidomide, deletion of P53 and 1q21+ were identified as independent hazard elements of PFS (Table 3B).

Considering the therapeutic regimen’s impact on survival, patients were categorised into four cohorts: those receiving ASCT, those not receiving ASCT, and those treated with bortezomib-containing regimens, and those without such treatment. Subsequently, we examined the effect of HBV reactivation on OS and PFS. HBV-reactivated patients had a significantly shorter OS (P = 0.012) and PFS (P < 0.0001) than non-HBV-reactivated patients, in the group receiving bortezomib-containing regimens (Figs. 3A, 3C). In contrast, there was no significant difference in either OS or PFS between HBV-reactivated and non-HBV-reactivated patients in the group without bortezomib-containing regimens (Figs. 3B, 3D). HBV-reactivated patients had a significantly shorter OS than did non-HBV-reactivated patients in the group without ASCT (P = 0.040). In comparison, there was no statistical significance in the Kaplan–Meier curves between HBV-reactivated patients and non-HBV-reactivated patients in the group with ASCT despite a trend of shorter OS, which might be because of the insufficient sample size (Figs. 4A, 4C). Finally, HBV-reactivated patients had significantly shorter PFS than non-HBV-reactivated patients in both groups with (P = 0.001) and without ASCT (P = 0.007) (Figs. 4B, 4D).

Clinical practice points

The application of novel treatments of MM, including proteasome inhibitors, immunomodulation intervention, and monoclonal antibodies, has significantly improved the prognosis of MM, but the utilization of the aforementioned medications has been associated with an increasing prevalence of incidents related to HBV reactivation.

Our study provides updated insights into the impact of HBV reactivation on the unfavorable prognosis of NDMM, particularly by significantly diminishing survival rates through its facilitation of disease progression rather than fatal hepatitis, thereby potentially influencing future clinical management and patient care strategies.