The increased risk of reactivation of the varicella zoster virus (VZV) infection (a type of herpes zoster) observed in previous studies of bortezomib-based therapy was completely abrogated in patients with multiple myeloma who received prophylaxis with acyclovir, in a series of patients treated at Roswell Park Cancer Institute, Buffalo, NY.
“Our data suggest that this side effect of bortezomib therapy can be easily prevented,” said Asher A. Chanan-Khan, MD, senior author of the study (Swaika A, et al. J Support Oncol. Jan 12, 2012. Online before print).
Immunocompromised patients are at increased risk for developing herpes zoster, which can lead to clinically important sequelae, especially postherpetic neuralgia lasting months or years. Previous studies have indicated that treatment with bortezomib is associated with an increased incidence, resulting from reactivation of latent VZV.
In the phase 3 APEX (Assessment of Proteasome Inhibition for Extending Remissions) study of single-agent bortezomib versus high-dose dexamethasone in patients with relapsed multiple myeloma, 13% of patients developed herpes zoster with bortezomib therapy versus 5% with dexamethasone therapy alone (Chanan-Khan A, et al. J Clin Oncol. 2008;26:4784-4790). Similarly, in the phase 3 VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial, 13% of patients receiving the bortezomib-based regimen developed herpes zoster versus 4% receiving the melphalan-based regimen (San Miguel JF, et al. N Engl J Med. 2008;359:906-917). And in a retrospective analysis, the herpes zoster rate increased from 11% at baseline to 22.3% during bortezomib treatment (Kim SJ, et al. Clin Lymphoma Myeloma. 2008;8:237-240).
“We cannot predict which patients will have VZV reactivation, but we know that patients receiving bortezomib, which is essentially all patients with multiple myeloma at some point, have a 13% risk,” Dr Chanan-Khan told Value-Based Care in Myeloma.
“In line with these data, current guidelines for the treatment of multiple myeloma state that herpes zoster prophylaxis should be considered in patients receiving bortezomib, and it has been standard practice to administer concurrent acyclovir in patients treated with bortezomib at Roswell Park for several years,” Dr Chanan-Khan said.
Etiology Poorly Understand
The etiology of VZV reactivation in patients receiving bortezomib is poorly understood, Dr Chanan-Khan and coauthors noted. A potential explanation is that bortezomib directly inhibits the immunoproteasome, which is important in suppressing latent VZV activation. Unlike other closely related herpes viruses, VZV may express transcripts during latency, and proteasome inhibition may impair antigen-presenting activity and increase susceptibility to viral reactivation. In addition, bortezomib is known to affect the dorsal root ganglia, where latent VZV resides.
Study Confirms Complete Benefit of Prophylaxis
Dr Chanan-Khan and colleagues, therefore, retrospectively evaluated 100 consecutive patients with multiple myeloma treated with bortezomib-based therapies at Roswell Park Cancer Institute for the development of herpes zoster. Patients receiving frontline therapy with bortezomib as well as patients with relapsed/refractory myeloma were included, and all patients received bortezomib alone or in combination with agents such as doxorubicin, melphalan, or dexamethasone.
All patients received at least 4 weeks of acyclovir prophylaxis (400 mg twice daily), which was initiated before starting treatment with bortezomib and discontinued 4 weeks after bortezomib therapy.
None of the patients receiving acyclovir prophylaxis developed herpes zoster during treatment with bortezomib, including patients receiving a wide variety of concomitant antimyeloma therapies and regardless of response to bortezomib-based therapy.
“The effect was observed despite the heterogeneous patient population,” Dr Chanan-Khan emphasized. “And the use of bortezomib in a wide variety of combination regimens with different chemotherapeutic agents did not affect the efficacy of acyclovir. Equally, whether patients received bortezomib as frontline therapy or in the relapsed setting, did not affect the risk of VZV reactivation.”
Only 1 patient, who was found to be nonadherent to acyclovir therapy, experienced a VZV reactivation; that patient had received 3 cycles of bortezomib in combination with cyclophosphamide and dexamethasone.
“These results are supported by previous studies suggesting that prophylactic use of antiviral agents in patients receiving bortezomib prevents herpes zoster,” Dr Chanan-Khan said. In patients for whom there are nephrotoxicity concerns, he uses a reduced dose of the drug.
What still remains unclear, he said, is whether patients with multiple myeloma would benefit from the herpes zoster vaccine. “Could we give the vaccine and not worry at all about herpes zoster reactivation? It is always a good thing to avoid giving extra medicines, such as acyclovir, although it has a long, proven track record. However, it’s not clear how safe and effective it would be in cancer patients, since it’s a live vaccine, which could be a concern.”