Several tools have been proposed for assessing frailty in multiple myeloma (MM), but most are based on clinical trial data sets. There are also limited data on the association between frailty and patient-reported outcomes and on the prognostic value of social determinants of health. This study evaluates the prognostic impact of frailty, based on the cumulative deficit frailty index (FI), and relationship and socioeconomic status (SES) in patients with newly diagnosed MM. This retrospective study included 515 patients with MM seen at Mayo Clinic (Rochester, MN) at diagnosis between 2005 and 2018. The FI was calculated using patient-reported data on activities of daily living and comorbidity data, with items scored as 0, 0.5, or 1, in which 1 indicated a deficit. The FI was calculated by dividing the total score by the number of nonmissing items. Frailty was defined as FI ≥0.15; 61% were nonfrail, and 39% were frail. Frailty and nonmarried/relationship status were associated with higher disease stage, decreased the likelihood of early transplantation, and independently associated with decreased survival. SES was not independently associated with survival. Frail patients reported worse scores for fatigue, pain, and quality of life. Approximately a quarter of patients had a deterioration in frailty status at 3 to 12 months, and <10% had improvement. In conclusion, a cumulative deficit FI was associated with higher symptom burden and decreased survival in a real-world cohort of patients with newly diagnosed MM. Frailty status is dynamic and should be reassessed during treatment. Social support has prognostic value and should be evaluated in clinical practice.