In multiple myeloma (MM), treatment selection and sequencing become increasingly complex with the increasing number of therapeutic options, including antibodies. Choice of treatment is dependent on various factors including patient- and tumor-related features. In addition, treatment-related factors, such as type and response to prior therapy, are also critical in terms of the selection of a new treatment regimen. Furthermore, approval status and reimbursement policies influence treatment choice. At the time of first relapse, patients who received a bortezomib-based regimen can switch to lenalidomide-based treatment, whereas patients who received lenalidomide until progression can switch to a proteasome inhibitor-based therapy. Alternatively, there is increasing evidence that pomalidomide-based triplets are also effective following the development of lenalidomide-refractory disease both in early and later relapse settings. Patients who become refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies have a poor prognosis. These triple-class refractory patients may benefit from novel, recently approved agents such as XPO1 inhibitors or from participation in a clinical trial. Furthermore, retreatment with agents that were received in previous lines of therapy can also be considered in heavily pretreated patients, for example, in combination with classic cytotoxic drugs. Importantly, with the increasing use of CD38 antibodies in newly diagnosed and early relapsed/refractory MM, more information is needed on the potential value of retreatment with CD38 antibodies. With the introduction of new immunotherapies with novel modes of action, we also need a better understanding of sequencing of immunotherapeutic agents by taking into account the effect of prior therapy on immune function.
