Advances in Myeloma. 2025 Edition Key takeaways from #IMS25 1) Early intervention is here: Given recent EU approval of daratumumab for high risk smoldering myeloma in Europe, and NCCN category 1 recommendation in the US, ~55% of the attendees would offer early intervention for high risk smoldering myeloma. A major shift over the last year. Paradigm change. 2) The choice of frontline therapy is now based more on frailty assessment than transplant eligibility. Outcomes are excellent with quads with or without transplant. 3) Doublet maintenance for high risk is important and seems accepted as standard. Data continue to accumulate supporting doublet maintenance perhaps even for standard risk myeloma especially if MRD+ post initial therapy. 4) I think lenalidomide starting dose in elderly patients should be 15mg, not 25mg. 5) Outcomes for myeloma refractory to Imids, PIs, anti CD38, alkylators, and anti BCMA strategies (Penta-Class Refractory myeloma) is not good. Thus despite all the progress and the 20 drugs in 20 years success story, this unmet need clinical situation in myeloma is common and needs the promising options I list below to come to the clinic quickly for the sake of our patients. 6) New immunotherapy options beyond BCMA CAR-T and bispecifics is gaining ground and we saw promising data: trispecifics, Dual targeting CAR-T, CAR-NK, belantamab alone without the cytotoxic conjugate etc. 7) For t(11;14) myeloma, the response and PFS data with sonrotoclax is promising. 8) Data presented by @FrancescoMaura4 is important and shows that most of smoldering myeloma and almost all of high risk smoldering myeloma is biologically malignancy, not premalignancy, sharing genomic features indistinguishable from active myeloma. The question is why do some not progress despite having biological features of malignancy. What immune or microenvironmental control holds the malignancy in check? When and how is that lost? We need to answer these questions. (Keep in mind with time, almost all high risk smoldering myeloma will progress).