TO THE EDITOR
Molecular detection of novel molecular targets in multiple myeloma (MM) has given rise to exciting new therapeutic options for MM patients including the use of high-dose dexamethasone, thalidomide, revimid, bortezomib and early single or double autologous stem-cell transplantation.1 Bortezomib is a novel proteasome inhibitor which has recently been approved for the treatment of MM patients who received at least two prior therapies and progressed during the last treatment.2, 3, 4 It targets the 26S proteasome, which functions by eliminating cellular proteins tagged for degradation by polyubiquitin chains. Regulated ubiquitin-dependent proteolysis controls important events such as cell growth and proliferation, development, apoptosis, signal transduction, gene expression and immune response. Proteins entering the proteasome are stripped of their ubiquitin and degraded through catalytic processes within the core of the proteasome. Bortezomib induces apoptosis in various cancer cells, including MM and other lymphoma cells. It also affects nuclear factor-κB (NF-κB), the bone marrow (BM) microenvironment and various cytokine interactions, most importantly IL-6.2, 3, 4 Bortezomib has been shown to induce an impressive overall response rate of 35% in refractory and relapsed MM patients (pivotal phase-II (SUMMIT) trial).2 It was recently tested in an international phase-III (APEX) trial which randomly compared bortezomib and dexamethasone.5 Interim results have demonstrated that patients on bortezomib achieved a highly significant benefit in time to progression, overall survival (OS) and a trend towards a lower incidence of grade ⩾3 infections. Owing to the positive results with bortezomib, the Data Monitoring Committee recommended treatment on the dexamethasone arm to be stopped and patients randomized to dexamethasone were allowed to receive bortezomib. Adverse effects, such as asthenic conditions, nausea, diarrhea, anorexia, constipation, thrombocytopenia, peripheral neuropathy, pyrexia, vomiting and anemia were mostly mild.2, 3, 4
Here, we report on a 62-year old MM patient who received VELCADE at our institution in July 2003, participating in the international phase-III trial. In January 2001, he had been diagnosed with stage IIIA IgA lambda MM, displaying a normal karyotype and multiple osteolytic bone lesions. He initially responded to osteosynthetic operations, radiation and dexamethasone. In October 2001, he developed progressive disease (PD) with growing osteolytic lesions and increased BM infiltration (70%). Therefore, an autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed after conditioning with 200 mg/m2 melphalan (Figure 1). He achieved a substantial decrease in BM infiltration and his IgA levels and other MM-specific markers returned to normal. Nevertheless, PD recurred with bone pain, slowly progressing lytic bone lesions, β2-microglobulin rise and increasing BM infiltration in June 2003. Interestingly, his paraprotein levels remained normal despite PD, suggesting the disease had become nonsecretory following auto-PBSCT. He began treatment on the clinical protocol with 1.3 mg/m2 bortezomib i.v. twice weekly for 2 weeks, followed by 1 week without treatment for up to eight cycles. Side effects comprising of neutropenia and thrombocytopenia (both grade 2) necessitated a dose reduction to 1.0 mg/m2 of bortezomib in cycles three to four. After cycle three, the patient reported a bilateral hearing loss (grade 1), which despite continuing with 1.0 mg/m2 bortezomib slowly but gradually progressed so that bortezomib was discontinued after the forth cycle.
Audiometric tests were performed and revealed a deterioration of auditory thresholds. The patient was treated with daily infusions of hydroxyethylstarch and corticosteroids. Despite this immediate treatment, no significant improvement of his hearing was obtained. Audiometry performed 2 years before the onset of bortezomib had shown a mild right-sided and moderate left-sided high-frequency hearing impairment. Immediately after bortezomib was discontinued, medium and high frequencies were especially affected, with a significant deterioration at 1000–4000 Hz in both ears. After 2 months, the audiogram demonstrated a progressive low-frequency deterioration that persisted over 12 months for all frequencies (Figure 1). The speech audiogram also showed significant bilateral impairment with the hearing aids only attaining minor improvement. The patient now depends on a bilateral hearing aid (grade 3). Since he declined the execution of a brain stem response audiometry, the distinct location of the damage remains uncertain. Nevertheless, a loss of speech discrimination of more than 50% despite his hearing aid strongly suggests a neural component to the hearing impairment.
Ototoxic drugs, such as vinca-alkaloids or platinum, are used in standard- and intensive chemotherapy regimens, the latter also within high-dose chemotherapy schedules and auto-PBSCT. Long-term risks related to the toxicity of the conditioning therapy and the consequently altered immunological status may include bilateral hearing impairment (high tone deficiency). These risks deserve long-term care following intensive regimens. Hearing impairment have most frequently been reported in connection with cis- or carboplatin therapy, but not melphalan. However, even with neurotoxic drugs, such as cis- or carboplatin, significant ototoxicity is generally described as an uncommon complication which is mainly observed in patients with poor general health, with no significant hearing loss at or below 4000 Hz.6 Of interest in our patient was the fact that he had a minor hearing impairment before the start of bortezomib, but showed severe cumulative hear loss after four bortezomib cycles. Peripheral sensory neuropathy (PN) has recently been reported as an important and common toxicity of bortezomib, occurring in 35% of patients.2, 3, 4 In phase-II studies, PN required dose reduction in 12% of patients. In 4–5% of cases, treatment was discontinued due to PN.2, 3 Nerve conduction studies and quantitative sensory testing indicated length-dependent axonal PN with predominantly small fiber involvement.7 The accumulation of undegraded, potentially cytotoxic proteins in normal cells may be postulated as one mechanism by which proteasome inhibition induces neurotoxicity. Increasing evidence supports this concept in neurodegenerative disorders, showing that aberrant or misfolded proteins and dysfunction of the ubiquitin–proteasome system cause neuronal damage.8 This has been determined in Alzheimer's or Parkinson's disease, where toxic, abnormal and aggregation-prone proteins seem to be the molecular bases underlying the disease pathogenesis.8
In summary, we describe a severe bilateral sensorineural hearing loss after four cycles of bortezomib treatment that has to the best of our knowledge never been reported to date. The mechanism leading to the observed hearing loss, especially the role of the proteasome, remains to be fully resolved; however, the accumulation of undegraded, potentially sensorineural and ototoxic proteins may explain its neurotoxicity. Since ototoxicity, as one neurotoxic manifestation of the drug, leads to debilitating conditions, patients receiving bortezomib should be informed about this noteworthy side effect. This side effect might be aggravated by intensive therapies, prior use of ototoxic substances, underlying hearing deficiency, and other conditions which are to be determined.
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We thank the internal reviewer in our institution for critically reading the manuscript and the anonymous external reviewer for thoughtful comments. The study was supported by Millennium Pharmaceuticals. The sponsor Millennium has received, carefully reviewed and fully agreed to this manuscript.
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