Neurotoxic Effect of Bortezomib Treatment in Patient With Myeloma Multiple

Peripheral neuropathies induced by cancer chemotherapy (CIPN) remain a problem in oncology. These CIPN are induced by certain classes of chemotherapy such as taxanes (paclitaxel and docetaxel), platinum salts (cisplatin and oxaliplatin), alkaloids of the Madagascar periwinkle (vincristine), bortezomib, thalidomide and eribulin. These CIPN is essentially resulting in sensory disturbances such as paresthesia, dysesthesia or numbness. Unfortunately, no treatment can be offered as "gold standard" for preventing or treating the CIPN. Therefore, oncologists reduce or stop doses of chemotherapy because patients suffering from CIPN have a marked deterioration in their quality of life and suffer from comorbidities such as anxiety, depression and sleep disorders.

Among chemotherapy, bortezomib remains relatively understudied in terms of pathophysiology, compared to the platinum salts or taxanes, whereas the neurotoxicity of bortezomib remains a limiting factor for treatment. Currently, bortezomib is indicated for the treatment in 1st line of multiple myeloma in the following protocols:

• Patients <65 years: Protocol VTD: Velcade (bortezomib), thalidomide, dexamethasone + autologous transplant
• Patients> 65: Protocol MPV: Melphalan, Prednisone, Velcade. Or Protocol VD: Velcade, dexamethasone Since 2012, the FDA and the EMA have validated the subcutaneous administration of bortezomib instead of intravenously, in order to limit the adverse effects of bortezomib, including neurotoxicity. Indeed, a large study reported that the subcutaneous bortezomib allowed to keep the same therapeutic efficacy while improving the safety profile and in particular by limiting peripheral neuropathies (CIPN any grade: 38% vs 53%, grade ≥2: 24% vs 41%, grade ≥3 6% vs 16%). However, a recent retrospective study reported that the prevalence of peripheral neuropathies induced by bortezomib after subcutaneous administration remain relatively high: CIPN any grade: 41%, grade ≥2: 18% grade ≥3: 4 %, and especially that this prevalence of CIPN is no different between subcutaneous and intravenous route.

Bortezomib is administered subcutaneously to limit the appearance of neuropathic disorders and no study has evaluated quantitatively and qualitatively (QST) the sensory disorders in patients with peripheral neuropathies induced by bortezomib after subcutaneous administration. On the other hand, a measurement tool like the QLQ-CIPN20 questionnaire (EORTC) evaluating the intensity of sensory, motor and autonomic disorders associated with CIPN has never been tested in this patient population. While the questionnaire is presented as the most appropriate tool in the evaluation of CIPN.

Thus, the exploration of peripheral neuropathies induced by bortezomib after subcutaneous administration through QST (thermal) and QLQ-CIPN20 questionnaire would complement the clinical knowledge of the CIPN. This knowledge will be essential to propose and test new strategies for treatment and prevention of peripheral neuropathies induced by bortezomib.

The objective of this study is twofold: (i) psychophysical evaluation of neuropathic disorders by studying the QST (thermal and vibratory sensory thresholds, thermal nociceptive thresholds) and (ii) quantitative and qualitative assessment of neuropathic disorders by the QLQ -CIPN20 questionnaire (EORTC) and associated comorbidities in patients treated with bortezomib (subcutaneous administration).