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In addition to the widely used bortezomib\u2013lenalidomide\u2013dexamethasone (VRd) combination, an alternative triplet option that can be considered is the combination of the second\u2010generation PI carfilzomib (K) with lenalidomide\u2013dexamethasone (KRd). In patients with transplant\u2010eligible NDMM, US treatment guidelines have included the KRd triplet as a recommended regimen and the quadruplet combinations of either Isa\u2010KRd or D\u2010KRd as additional options. However, currently, KRd does not have regulatory approval for use in the NDMM population. This review describes the current evidence for using KRd as a backbone of therapy in frontline treatment regimens for patients with NDMM. In addition to multiple studies that have examined the KRd triplet in this population, several clinical trials have been investigating anti\u2010CD38\u2010KRd quadruplets. The data reported from these various trials are revealing deep and durable responses with Isa\u2010KRd and D\u2010KRd, including minimal residual disease negativity. Importantly, these benefits have also been demonstrated in high\u2010risk NDMM populations. KRd\u2010based combinations may represent a suitable alternative to VRd for some patients. This article discusses measures that may help to establish KRd\u2010based quadruplets as an additional SOC in this setting, including proper patient selection, steps to mitigate safety concerns, and the establishment of optimal dosing schedules.<\/jats:p>","DOI":"10.1002\/hem3.70178","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T03:41:48Z","timestamp":1752723708000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Current and future role of carfilzomib\u2010based quadruplet combinations as therapy for newly diagnosed multiple myeloma"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-4839","authenticated-orcid":false,"given":"Ola","family":"Landgren","sequence":"first","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, Myeloma Division University of Miami Miami Florida 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