Parkinsonian Patients Requiring Proteasome Inhibitors for Multiple Myeloma: Exceptional Circumstances Call for Extra Caution

Feedback on the management of patients with both Parkinson’s disease (PD) and multiple myeloma (MM) is not common in the literature, and we would like to report an original possible adverse event (AE) of MM chemotherapy: an increased PD severity induced by ixazomib. The patient, a 68-year-old man with PD (Hoehn and Yahr (HY) stage 3) was effectively and stably treated for 14 years with dopaminergic therapy (levodopa equivalent daily dose (LEDD) 1275 mg). His symptomatic MM was first treated by lenalidomide (25 mg) with dexamethasone (Rd protocol) for 19 months. Then, a second-line therapy combined the proteasome inhibitor (PI) ixazomib (4 mg) with lenalidomide (20 mg) and dexamethasone (IRd protocol, 4-week cycle) due to MM progression.

After one month of IRd the patient described a significant poorer control of his PD with less effective L-dopa therapy, which continued to deteriorate over a 3-month period (progression to HY stage 4): severe nocturnal akinesia, amimia, hypophonia with palilalia, and daily walking time worsened from 45 to 10 min. There was neither distal bradykinesia, nor resting tremor. LEDD increased to 1350 mg with an extended-release levodopa/benserazide and the patient reported a more effective and durable control of PD, though not recovering his basal status. After 11 months of IRd, the patient was hospitalized for bronchitis, altered general condition, repetition of falls and sleepiness, imputed by clinicians to PD progression. IRd was withdrawn and antiparkinsonian treatment was reinforced by adding rasagiline (LEDD 1450 mg). Finally, 6 months after IRd interruption, the patient showed a substantial general and neurologic status improvement with a resumption of walk and a much more satisfactory state of alertness, MM remaining in partial response.

We argue that ixazomib has a role in the increased PD severity, due to its mechanism of action. Cellular proteostasis is notably controlled by the ubiquitin-proteasome system, which ensures the elimination of proteins and the regulation of many essential cellular functions through the proteolysis of identified targets by ubiquitination [1]. Its proteolytic activity is decreased by about 33% to 42% in substantia nigra from postmortem samples of idiopathic parkinsonian patients, leading to the aggregation of misfolded amyloid proteins (including α-synuclein) into typical inclusions [2]. This fundamental discovery was elegantly explored in the early 2000s by McNaught et al. who successfully developed a model of PD involving proteasome inhibition. This inhibition leads to formation of intracytoplasmic inclusion bodies and death of dopaminergic neurons in vitro [3] and in rodent models [4, 5] but failed to show the same effect in non-human primate model, possibly because of a lack of cerebral penetrance [6].

Currently marketed PIs, including ixazomib, have little or no blood-brain barrier (BBB) crossing, which may partly explain their low toxicity on the central nervous system [7–9]. However, the permeability of BBB is increased in the postcommissural putamen of PD patients, suggesting the possibility of a brain diffusion of PIs in this population [10]. More specifically, dopaminergic neurons would be more sensitive to a decreased proteasome activity than other cells, due to physiologically high levels of oxidized proteins and dopamine [11]. In PD patients, these particular conditions may lead to the same observation as seen in various animal models: formation of inclusions, neurodegeneration and finally, progression of PD.

It is commonly challenging to establish the existence of an AE, except in the case of a positive rechallenge. A drug reintroduction is obviously unacceptable for the safety and interest of our patient. We must, therefore, admit the classical biases of this observation and notably the possible imputability of other drugs (especially lenalidomide and clozapine) or the influence of stress associated with the progression of MM. Symptoms improvement may also be due to adjustments in Parkinson medication. However, the increased PD severity following ixazomib initiation and the positive dechallenge evidenced by the remarkable recovery of the patient’s general condition after its withdrawal, reinforce the causality assessment of this AE to the PI. Furthermore, while no such observations were found in the literature, we identified two additional cases of PD progression associated with the use of bortezomib, another PI, in VigiBase^®, the WHO’s global database of individual safety reports.

Finally, we propose the hypothesis that ixazomib, and more generally PIs, may have a role in the evolution of pre-existing PD. This scenario does not compromise the benefit/risk balance of ixazomib in the treatment of MM, which remains an indispensable medication even in parkinsonian patients. However, in this population, the initiation of PI therapy may accentuate a pre-existing clinical imbalance: thus, we are convinced that neurologists will have a prominent role in the follow-up of parkinsonian patients with MM, in close collaboration with hematologists.