Data from multiple studies clearly indicate that triplet therapies are better than doublet therapies in patients with multiple myeloma. These agents all work in different ways, and combining them provides multiple different pathways to target the disease, thereby providing a greater potential to mitigate the risks of clonal evolution and resistance and to impact more of the myeloma cells. Trials have shown that patients are more likely to enter remission, stay in remission longer, and live longer with triplet-based IMiD-PI-dexamethasone therapy than with doublets. The most widely utilized upfront regimen in the United States is lenalidomide-bortezomib-dexamethasone–based induction therapy. In the setting of relapsed disease, it has also been shown that a triplet-based approach is superior to a doublet-based approach.. These therapies include the daratumumab-based combinations, 3 of which are currently approved by the US Food and Drug Administration for relapsed/refractory multiple myeloma: daratumumab-lenalidomide-dexamethasone, daratumumab-pomalidomide-dexamethasone, and daratumumab-bortezomib-dexamethasone. Practically speaking, the current practice is to use a triplet approach, at least, in second- and third-line therapy if patients can tolerate the regimen. As you get further along in the disease course, you might not have a triplet that represents new, non–cross-resistant mechanisms of action or patients may not be physically able to tolerate as many agents. With respect to the IMiD portion of the backbone, lenalidomide and pomalidomide are more active and are generally better tolerated than thalidomide, which has not been used in the United States as much in the last decade. Lenalidomide is generally used as early line, maintenance, and second-line therapy, while pomalidomide combinations are used as second-line and subsequent lines of therapy. Trials have not yet been performed with pomalidomide as first-line therapy. Determining when a patient has become refractory to lenalidomide depends on the context of the prior therapy. Take, for example, a patient who progresses after autologous stem cell transplant while on a 10- to 15-mg lenalidomide monotherapy maintenance regimen. Is that patient refractory? Many would say “no” because the full dose of lenalidomide is not being used. On the other hand, if a patient were on an upfront lenalidomide-bortezomib-dexamethasone regimen and experienced an initial response but subsequent progression (ie, per International Myeloma Working Group criteria), there would be agreement between providers that the patient is refractory to lenalidomide. In the latter scenario, the entire regimen should be changed—you would want at least 2 new agents. In my view, multiple factors, rather than a single determinant, come into play when deciding when to move on to second- and third-line therapies.