While significant advances have been made in the treatment of multiple myeloma, the management of the transplant-ineligible (TI) patient population remains challenging. The individuals enrolled in clinical trials for newly diagnosed TI patients, or those with no planned transplant, may not always be reflective of real-world patients, with respect to age, comorbidities, or frailty status. Likewise, results obtained from randomized relapsed/refractory studies also may not be applicable to this generally older and frailer patient population. In this review, we discuss assessment of frailty and focus on treatment options in both the newly diagnosed and relapsed/refractory settings for TI patients. We describe the patient-specific considerations that factor into treatment decisions as well as provide some guidance about management.