Hepatitis B virus reactivation in a myeloma patient with resolved infection who received daratumumab-containing salvage chemotherapy.

A 72-year-old female complaining of back pain was diagnosed with IgG-κ multiple myeloma. After osteosynthesis for fracture of the left femoral shaft due to myeloma, she received bortezomib, melphalan, and prednisolone as an initial regimen for multiple myeloma, but discontinued it after three courses due to progressive disease. The patient subsequently received lenalidomide and dexamethasone as a second-line regimen for 2.5 years, and pomalidomide and dexamethasone as a third-line regimen for only 2 months. An anti-CD38 monoclonal antibody, daratumumab (DARA), and bortezomib and dexamethasone (DVd) as a fourth-line regimen were administered for refractory myeloma. However, hepatitis B virus (HBV) reactivation occurred on day 15 of the third course of DVd. The HBV DNA level in peripheral blood suddenly increased to 2.2 log IU/mL. An anti-HBV nucleotide analog, entecavir, was subsequently administered when the HBV DNA level increased to 2.6 log IU/mL. No HBV-related hepatitis was observed during follow-up. DARA can improve the prognosis of patients with multiple myeloma, but also potentially increase the risk of HBV reactivation. Host and viral risk factors need to be identified in such patients in order to implement a more cost-effective strategy against HBV reactivation.

INTRODUCTION

Daratumumab (DARA), an anti-CD38 monoclonal antibody, has been demonstrated to improve response rates and progression-free survival in patients with relapsed/refractory multiple myeloma in combination with bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone. However, DARA treatment may be associated with an increased risk of viral infection; specifically, cytomegalovirus (CMV) reactivation occurs in patients with multiple myeloma after DARA administration.- Hepatitis B virus (HBV) reactivation is also a potentially fatal complication of DARA treatment., Rituximab, an anti-CD20 monoclonal antibody, plus steroid combination chemotherapy is a risk factor in patients with resolved HBV infection, defined as being seronegative for hepatitis B surface antigen (HBsAg), but seropositive for antibodies against hepatitis B core antigen (anti-HBc) and/or antibodies against HBsAg (anti-HBs). However, data regarding HBV reactivation after DARA administration are markedly limited. We report HBV reactivation in a myeloma patient with resolved HBV infection who received a salvage DVd regimen.

CASE REPORT

A 72-year-old female complained of back pain in September 20XX. She underwent osteosynthesis for fracture of the left femoral shaft. After surgery, she was diagnosed with IgG-κ multiple myeloma as follows: serum monoclonal protein was detected; bone marrow aspiration revealed an increase in the plasma cell ratio to 18.2%. Computed tomography demonstrated multiple osteolytic lesions and compression fractures of the thoracolumbar spine. Blood tests at the time of admission to our hospital revealed the following: white blood cells 3500/µL, hemoglobin 9.4 g/dL, platelets 18.4 × 104/µL, total protein 8.7 g/dL, albumin 3.7 g/dL, lactate dehydrogenase 128 U/L, creatinine 0.86 mg/dL, blood urea nitrogen 18.2 mg/dL, corrected calcium 11.0 mg/dL, IgG 4564 mg/dL, IgA 139 mg/dL, and IgM 26 mg/dL. In addition, screening the blood sample for HBV demonstrated it to be seronegative for HBsAg, but seropositive for anti-HBc (114.8 cutoff index), and seronegative for anti-HBs. Serum HBV DNA was not detectable, suggesting that the HBV infection had resolved. To prevent HBV reactivation-related hepatitis, the patient underwent regular HBV DNA monitoring during and at least one year after myeloma treatment.

The patient received a bortezomib, melphalan, and prednisolone (VMP) combination regimen as the initial treatment for multiple myeloma. However, this was discontinued after three courses of VMP (total doses of bortezomib, melphalan, and prednisolone: 10.4 mg, 87 mg, and 754 mg per body surface area, respectively) due to progressive disease (PD). The patient subsequently received a lenalidomide and dexamethasone (Ld) combination regimen (lenalidomide at 15 mg/day as an initial dose, up to 25 mg/day) as second-line treatment, and continued Ld therapy (total doses of lenalidomide and dexamethasone: 11,641 mg and 2,493 mg per body surface area, respectively) for 2.5 years. A pomalidomide and dexamethasone (Pd) combination regimen (pomalidomide 3 mg/day) was next started as the third-line treatment for relapsed myeloma; however, this was discontinued after only two courses of Pd (total doses of pomalidomide and dexamethasone: 76 mg and 116 mg per body surface area, respectively) due to PD, including bone pain, anemia, and hypercalcemia.

The patient received a DVd regimen as the fourth-line treatment for refractory myeloma, and symptoms gradually improved after one course. However, HBV reactivation occurred on day 15 of the third course of the DVd regimen (total doses of daratumumab, bortezomib and dexamethasone; 144 mg per kg, 10.4 mg and 319 mg per body surface area, respectively; November 20, 20XX + 3 years) because the HBV DNA level in her peripheral blood suddenly increased to 2.2 log IU/mL. Her laboratory data at the HBV reactivation are summarized in Table 1. A course of an anti-HBV nucleotide analog, entecavir, was started when the HBV DNA level increased to 2.6 log IU/mL (Figure 1). Her HBV DNA level decreased thereafter, and remained under the limit of detection during entecavir treatment (January 22, 20XX + 4 years). No HBV reactivation-related hepatitis was observed during follow-up, and DVd therapy was thus continued until PD.

Table 1

Laboratory data at hepatitis B virus reactivation

WBC	3.8	×103/μL		TP	5.4	g/dL
Neutrophils	57	%		Alb	3.4	g/dL
Eosinophils	0	%		T-Bil	0.5	mg/dL
Basophils	0	%		CRP	0.08	mg/dL
Monocytes	7	%		CK	39	U/L
Lymphocytes	36	%		AST	13	U/L
Atyp. Lym.	0	%		ALT	9	U/L
RBC	2.98	×106/μL		LDH	204	U/L
Hb	10.3	g/dL		ALP	493	U/L
Plt	127	×103/μL		γ-GTP	34	U/L
				ChE	269	U/L
PT	11	sec		Cre	0.55	mg/dL
PT-INR	1			Glu	82	mg/dL
APTT	26.5	sec		Na	142	mmol/L
Fibrinogen	295	mg/dL		K	3.9	mmol/L
FDP	4.5	μg/mL		Cl	108	mmol/L
				Ca	8.3	mg/dL
HBV DNA	2.2	Log IU/mL	(+)
HBsAg-HQ	11.6	mIU/mL	(+)

HBsAg-HQ, highly sensitive Lumipulse HBsAg-HQ assay (detection limit, 5 mIU/mL; Fujirebio, Tokyo, Japan).

Fig. 1

Clinical course of hepatitis B virus reactivation during myeloma treatment with regular HBV DNA monitoring

VMP, bortezomib, melphalan, and prednisolone; Ld, lenalidomide and dexamethasone; Pd, pomalidomide and dexamethasone; DVd, daratumumab, bortezomib, and dexamethasone; DARA, daratumumab; WBC, white blood cell; FLC, free light chain; Lym, lymphocyte; HBV, hepatitis B virus; MM, multiple myeloma; Anti-HBc, antibodies against hepatitis B core antigen; Anti-HBs, antibodies against hepatitis B surface antigen; ALT, alanine transaminase; HBsAg-HQ, highly sensitive Lumipulse HBsAg-HQ assay.

On retrospective analysis using serum samples, HBsAg (11.6 mIU/mL) was detected by a highly sensitive Lumipulse HBsAg-HQ assay (detection limit, 5 mIU/mL; Fujirebio, Tokyo, Japan) when HBV DNA appeared in the peripheral blood (HBV DNA 2.2 log IU/mL), as shown in Table 1 and Figure 1. Furthermore, the analysis demonstrated that the virus had no mutations in the precore region or basal core promoter, which may be associated with the rapid increase in HBV DNA level and fulminant hepatitis B; no HBsAg escape mutation was found. This retrospective analysis was approved by the institutional review board of Nagoya City University.

DISCUSSION

To our knowledge, this is the first case report regarding HBV reactivation in a myeloma patient with resolved HBV infection after DARA-containing chemotherapy. Regular HBV DNA monitoring diagnosed HBV reactivation at an early stage when HBV-related hepatitis was not observed.

In this case, several chemotherapy regimens for multiple myeloma were administered over a long period of time, making it difficult to identify the drug related to HBV reactivation. However, the clinical course suggested that DARA-containing chemotherapy is associated with HBV reactivation. HBV reactivation was previously reported in a myeloma patient with resolved HBV infection who received bortezomib and dexamethasone, but in this case, three courses of VMP were administered during the initial treatment and no HBV reactivation was observed. In addition, although Ld was continued for approximately 2.5 years, HBV reactivation was not observed. Of note, a Japanese multicenter retrospective study suggested that lenalidomide can reduce the risk of HBV reactivation during the treatment of multiple myeloma.

DARA can potentially increase the risk of viral infection, but the pathogenesis is unclear. DARA is an IgG1 kappa monoclonal antibody targeting CD38 that that is expressed not only in myeloma cells, but also in non-malignant T cells, natural killer (NK) cells, B cells, and plasma cells., Recently, DARA-containing chemotherapy was reported to be associated with CMV infection,,, suggesting that cellular immunity was suppressed in some patients who received DARA-containing chemotherapy. More recently, a retrospective study assessing circulating lymphocytes revealed that DARA can selectively deplete NK cells, which may lead to viral reactivation. Furthermore, the CD38 antigen is considered to be expressed in blood cells, with the highest expression in plasma cells. Therefore, a decrease in the number of non-malignant plasma cells may lead to the suppression of humoral immunity after DARA administration, which may have increased the risk of HBV reactivation.

Anti-HBs antibody titers at baseline (before lymphoma treatment) have been identified as an important host risk factor for HBV reactivation in lymphoma patients with resolved HBV infection who received anti-CD20 antibody,, which suggested that an antibody against HBV is essential to maintain HBV under immune surveillance and B-cell based humoral immunity may act as a key element for HBV control. Moreover, our patient was seronegative for anti-HBs at baseline, suggesting that HBV reactivation was more likely.

Of note, our retrospective analysis using stored samples revealed that a highly sensitive HBsAg-HQ assay can diagnose HBV reactivation at an early stage. This suggests that monitoring of the HBsAg level is an alternative cost-effective method to prevent HBV-related hepatitis, although limited evidence exists regarding the usefulness of such surveillance.

In conclusion, HBV reactivation occurred in a myeloma patient with resolved HBV infection who received DARA-containing salvage chemotherapy, in whom HBV DNA monitoring-guided preemptive antiviral therapy prevented HBV-related hepatitis. Well-designed clinical studies are warranted to identify host and viral risk factors in such patients to implement a more cost-effective strategy against HBV reactivation.