(1) Background: Older adults with multiple myeloma (MM) contend with multifaceted physical, psychological, and existential challenges that may compromise quality of life (QoL). This study examined associations between physical symptom burden, functional capacity, depression severity, meaning in life, and QoL in older adults with MM. (2) Methods: Fifty outpatients (mean age = 67.7 ± 8.8 years) completed the EORTC QLQ-C30, PHQ-9, and Meaning in Life Questionnaire (MLQ). QoL was the primary outcome. Secondary outcomes included physical symptom burden (fatigue and pain), functioning domains, depression severity, and meaning in life. Internal consistency of all instruments was satisfactory (Cronbach’s α > 0.70). Analysis and associations among variables were done using Pearson’s and Spearman’s correlation coefficients (p < 0.05). (3) Results: Participants reported high global QoL and preserved functioning. Fatigue and pain were most strongly associated with lower global QoL. Greater depression severeness, although mild, was correlated with higher physical symptom burden and poorer functioning. Higher Presence of Meaning was related to better QoL and lower depression severity, whereas Search for Meaning showed no significant associations. Women reported greater physical symptom burden than men. (4) Conclusions: In older adults with MM, QoL appears to be linked to interrelated physical, psychological, functional, and existential factors. Fatigue, pain, depression severity, and established meaning in life were identified as clinically relevant correlates, highlighting targets for integrated supportive care.