Peripheral neuropathy (PN) and asthenia (fatigue) occur as both disease- and treatment-related complications in patients with multiple myeloma (MM). Risk factors for treatment-related PN, which has an estimated incidence of 37% to 83% among patients with MM, include therapy duration, dose intensity, cumulative dose, and the presence of preexisting neuropathy. Asthenia is the most common adverse effect of treatment, occurring in approximately 76% to 96% of patients receiving therapy. The severity of PN and asthenia can range from mild to potentially debilitating. These conditions can be dose limiting; they may interfere with optimizing duration of therapy and may also substantially affect patient quality of life. Regular screening and monitoring, combined with patient education and effective management strategies, can reduce the risk of these treatment-related complications, as well as their consequences.