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Simple Summary During the course of their disease, almost all multiple myeloma patients experience one or more relapses. Treatment options for relapsed/refractory multiple myeloma (RRMM) have largely increased in the last decades. The choice of when and how to treat in the relapsed/refractory setting can therefore be challenging. Since multiple myeloma (MM) typically affects elderly people, it is of importance to include specific, frailty-related comorbidities in the choice of treatment. The aim of this review was to present an update on treatment options for patients with RRMM, under consideration of today’s available literature, current guidelines and patient-, disease- and treatment-related factors. We focused on geriatric assessments (GA) and frailty scores such as the revised myeloma comorbidity index (R-MCI), international myeloma working group (IMWG-) frailty index and others as these allow obtaining a more accurate picture of the individual patient constitution than the numerical age alone. Abstract Treatment of relapsed/refractory multiple myeloma (RRMM) is more complex today due to the availability of novel therapeutic options, mostly applied as combination regimens. immunotherapy options have especially increased substantially, likewise the understanding that patient-, disease- and treatment-related factors should be considered at all stages of the disease. RRMM is based on definitions of the international myeloma working group (IMWG) and includes biochemical progression, such as paraprotein increase, or symptomatic relapse with CRAB criteria (hypercalcemia, renal impairment, anemia, bone lesions). When choosing RRMM-treatment, the biochemical markers for progression and severity of the disease, dynamic of disease relapse, type and number of prior therapy lines, including toxicity and underlying health status, need to be considered, and shared decision making should be pursued. Objectively characterizing health status via geriatric assessment (GA) at each multiple myeloma (MM) treatment decision point has been shown to be a better estimate than via age and comorbidities alone. The well-established national comprehensive cancer network, IMWG, European myeloma network and other national treatment algorithms consider these issues. Ideally, GA-based clinical trials should be supported in the future to choose wisely and efficaciously from available intervention and treatment options in often-older MM adults in order to further improve morbidity and mortality.