The challenge of non-transplant eligible, newly diagnosed multiple myeloma.

Eligibility for autologous transplantation is a key factor for tailoring treatment decisions in patients with newly-diagnosed multiple myeloma. For non-eligible patients, several factors determine the choice of the most appropriate therapeutic regimen. To evaluate optimal first-line strategies, we conducted a meta-analysis of randomized studies with end of search date February 6th, 2025. Modern triplet or quadruplet regimens, significantly reduced the risk of progression or death (HR = 0.63, 95% CI: 0.51-0.77) and approximately tripled MRD negativity odds (OR = 3.15, 95% CI: 2.38-4.16) while generally being well tolerated. These findings support the use of potent combination therapies in this vulnerable population, with quadruplet regimens being the standard for fit patients. Triplets may be considered for intermediate-fit patients, whereas dexamethasone-sparing ones emerged as a valuable option for frail individuals. Frailty assessment should be incorporated in all prospective studies in order to inform tailored treatment approaches.