Purpose <p>Patients undergoing treatment for multiple myeloma (MM), a common hematological malignancy, may experience symptom distress, functional decline, fear of disease progression, and poor quality of life (QOL). This study of MM patients aims to assess patient-reported symptom distress, functional impairment, fear of cancer progression, and QOL and to identify factors associated with QOL.</p> Methods <p>This cross-sectional study used consecutive sampling to recruit subjects from inpatient wards and the outpatient departments of hematology and chemotherapy at a medical center in northern Taiwan. Patients were assessed via self-reported questionnaires for symptom distress, functional impairment, fear of progression (FoP), and QOL. Descriptive analysis, Pearson’s product-moment correlation, multiple regression, independent-samples <i>t-</i>test, and one-way ANOVA were used to analyze the data.</p> Results <p>A total of 100 MM patients were included in this study. The most common symptoms reported to cause distress during treatment were fatigue, immobility, difficulty defecating, pain, numbness, and insomnia. The greatest level of functional impairment was in the ability to get around. A high level of FoP was reported by 32.0% of the patients. Multiple regression analysis showed that MM patients who had higher performance status, lower symptom distress, and lower FoP were more likely to have higher QOL. These 3 factors accounted for 78.1% of the variance in QOL.</p> Conclusion <p>Performance status was the greatest predictor of overall QOL and of five QOL domains. Patient-centered care programs that address symptom management, resistance training, diet control, and supportive care during treatment can reduce symptoms and FoP and improve the performance status and QOL of MM patients during treatment.</p>