Carfilzomib in Contemporary Multiple Myeloma: Contextualising Efficacy, Toxicity, and Treatment Sequencing

Which patients benefit from carfilzomib in multiple myeloma depends on the regimen, the comparator and the treatment phase. This critical narrative review integrates randomised trials, selected translational and observational studies, guidance, and targeted source verification through 16 October 2026. Frontline substitution trials, including ENDURANCE and CLARION, did not demonstrate progression-free survival superiority over bortezomib-based comparators, whereas FORTE, ATLAS, and IsKia address distinct questions of induction, maintenance, and antibody intensification. In relapse, ASPIRE and ENDEAVOR established benefits against historical active controls, while CANDOR and IKEMA support anti-CD38 intensification with progression-free survival gains and no established overall survival advantage. SUCCESSOR-2 supports a mezigdomide-containing strategy after lenalidomide and anti-CD38 exposure, although differing carfilzomib schedules limit attribution to mezigdomide alone. Cardiovascular, renal, infectious, logistical, and access constraints materially shape treatment value. Current data do not define an optimal sequence, and resensitisation after B-cell maturation antigen (BCMA)-directed therapy remains investigational. At relapse, the evidence for adding daratumumab or isatuximab to carfilzomib and dexamethasone applies most directly to patients naïve to both carfilzomib and anti-CD38 therapy who need a lenalidomide-sparing regimen and have sufficient cardiovascular reserve for repeated infusions.