Multiple Myeloma-Related Peripheral Neuropathy

Multiple Myeloma (MM) is a malignant disease characterized by a large number of abnormal proliferations of monoclonal plasma cells in bone marrow. Clonal plasma cells and their secreted M protein directly infiltrate tissues and organs, leading to various clinical symptoms characterized by anemia, bone pain or osteolytic bone destruction, hypercalcemia, and renal insufficiency. MM is the second most common malignancy in the blood system, mainly occurring in middle-aged and elderly people. Men are significantly more than women. The etiology and pathogenesis of MM are not yet clear. The natural course was 6 to 12 months. In recent years, with the advent of new drugs and the improvement of detection methods, the diagnosis and treatment of MM have been continuously improved and perfected. The survival time of MM patients has been significantly prolonged. At the same time, the incidence rate of severe adverse reactions such as Chemotherapyinduced Peripheral Neuropathy (CiPN) is increasing gradually after treatment, especially for the first-line treatment of MM therapy, the proteasome inhibitor bortezomib, the immunoregulatory drug, thalidomide. It is reported that the incidence of Bortezomib induced Peripheral Neuropathy (BiPN) is 40%~ 60% [1-5], and thalidomide induced peripheral neuropathy (TipN) is 25%~75% [6]. The specific pathophysiological mechanism of MM chemotherapy related PN is still unclear, according to the current studies, and the pathogenesis of PN caused by different therapeutic drugs is also different [7]. Because of the difficulty of diagnosis and the complexity of differentiation of PN and the difference of autonomic sensation, the general discussion focuses on sensory, motor, and sensorimotor neuropathy. This article reviews the characteristics and treatment of PN in MM. The etiology of peripheral neuropathy caused by multiple myeloma is as follows

The specific pathophysiological mechanism of MM chemotherapy related PN is still unclear, according to the current studies, and the pathogenesis of PN caused by different therapeutic drugs is also different [7]. Because of the difficulty of diagnosis and the complexity of differentiation of PN and the difference of autonomic sensation, the general discussion focuses on sensory, motor, and sensorimotor neuropathy. This article reviews the characteristics and treatment of PN in MM. The etiology of peripheral neuropathy caused by multiple myeloma is as follows

Caused by the Disease Itself
There are 1-2%~20% of multiple myeloma can lead to peripheral neuropathy [5]. Although the exact cause of PN caused by MM is unknown, amyloid deposition, immunoglobulin M antibody acting on myelin associated glycoprotein, nerve glycoconjugates participating in the interaction between Schwann cells and axons, and cytokine damage is considered to be the possible mechanism of PN. In addition to the form of nervous system complications, the direct compression of tumor can also lead to PN [8-10]. The etiological mechanism of PN is complex, such as small fiber injury, segmental demyelination, and axonal degeneration. PN is also related to monoclonal gamma globulin imbalance, amyloidosis, and POEMS syndrome [8,11]. The PN pathology of MM is different from other albuminemia, which demonstrates the importance of MM management. Bortezomib can inhibit the transcription of nerve growth factor and genetic factor at the same time [14].

Induced by the Drug
After 12 months of treatment, the incidence of TiPN is 70%, and The down-regulation of tumor necrosis factor α decreased the survival of neural cells d) Genetic factors, such as some gene mutations [15,16].

Other factors of Multiple Myeloma Led to PN
There are few reports on the mechanism of PN induced by other neurotoxic drugs in MM. Clinical data show that vincristine causes distal mutation through local neuroaxonal toxicity [17]. This may be the combination of vincristine and tubulin to interfere with micro polymerization. Platinum induced PN is caused by direct toxic damage to DRG, but it can also involve peripheral and central sensory neuron degeneration [18]. The incidence rate and clinical features of peripheral neuropathy Symptom: The symptoms of PN are usually symmetrical, including paresthesia, numbness and burning sensation; These symptoms are usually mild and mild, but in rare cases they can be paralyzed or even life-threatening. Although there are some differences in the treatment of PN, the acute symptoms are usually symmetrical, starting from the distal end and gradually aggravating.
BiPN is mild and generally tolerable (although it is often reported that more than 15% of patients have severe sensory and motor PN) [19]. Symptoms generally start from the distal end of the nerve, including burning sensation, hypersensitivity, Hypoesthesia, paresthesia, discomfort, neuropathic pain. Thalidomide induced nerve damage may be permanent, and it may be the symptom of peripheral neuropathy after stopping treatment [20]. It is reported that thalidomide can cause neuropathy of sensory and sensorimotor axons, which usually affects the sensory numbness or pain of the distal end of the foot, and sometimes affects the hand [21,22]. The neurotoxicity of vincristine can progress to a distal symmetric sensory neuropathy [23]. Although there is no clear evidence, cisplatin can cause long-term peripheral sensory nerve damage in the treatment of epithelial ovarian cancer [24].  [25][26][27][28][29][30][31][32][33][34][35]. The incidence of BiPN in relapsed and newly diagnosed myeloma patients was basically the same [36][37][38][39]. Importantly, the occurrence of BiPN did not affect the therapeutic effect of bortezomib.
The incidence of TiPN is similar to that of BiPN. After treatment for more than 12 months, over 75% of patients developed peripheral neuropathy [40]. In the naive MM patients, the overall incidence rate, and the incidence of >3 PN were 55% and 10% respectively. Any one or more of the following four aspects of nervous system examination are abnormal: sensory nerve examination; Motor nerve examination; Autonomic nerve examination; One or more items of nerve conduction velocity examination (including sensory nerve and motor nerve conduction velocity measurement) slowed down [43].