MGUS and Smoldering Myeloma at ASH 2025: What’s New

By Jessie Daw, PhD

The 2025 American Society of Hematology (ASH) meeting moved fast, and attending virtually didn’t slow the pace. As a virtual member of the International Myeloma Foundation’s (IMF) Myeloma Voices team, I was busy, moving between presentations, getting caught up on posters, and posting often in a couple closed Facebook (FB) groups for smoldering multiple myeloma (SMM) as well as on X. Friday’s satellite symposiums set the tone, as I wrote in my first blog, and the rest of the meeting for me became a deep dive into SMM, book-ended by a few sessions in monoclonal gammopathy of undetermined significance (MGUS) and newly diagnosed disease. 

One MGUS presentation (Paiva & colleagues from the Spanish group) offered the first interim look at a large prospective cohort study that has enrolled 1,000 of a planned 5,000 participants. Early analysis of this data show that circulating tumor cells were detectable in 47% of individuals and emerged as one of the strongest independent prognostic markers, with 23 patients progressing to active myeloma over a median two years.

Much of the SMM work this year focused on factors influencing disease development, refining risk, and possible treatment options. Several ASH sessions highlighted emerging tools—CTC dynamics, interferon-related signatures, and single-cell approaches, for example—to understand why some patients remain stable for years while others progress quickly. One group (Mantrala & colleagues from Emory) presented MySCAPE, a single-cell atlas spanning MGUS through post–CAR T therapy, aiming to map immune transitions that may influence risk and treatment response. Another update from the PROMISE study (Allam & colleagues, Dana-Farber Cancer Institute) reinforced that premalignant biology can begin decades before diagnosis. Possible modifiers entered the conversation: one observational analysis (Abidi & colleagues, Virginia Commonwealth) suggested lower progression rates in GLP-1 RA–exposed individuals, although causality and mechanisms remain unclear, while Dr. Shah’s (Memorial Sloan Kettering) Nutrivention work examining plant-based diet and its impact on the microbiome continues. 

I also spent some time in a few newly diagnosed multiple myeloma (NDMM) sessions because some of us with SMM will eventually cross that threshold. The message from these sessions was clear: myeloma at diagnosis is not a single biological entity, and prior treatment in SMM—whether modest or aggressive—will shape first-line therapy. Dr. Caitlin Costello (UCSD) put it bluntly: instead of asking who qualifies for quadruplet therapy, the real question is now who doesn’t. Costello and colleague Dr. Paul Richardson (Harvard; Dana Farber) also emphasized that those in the myeloma disease space should participate in shared decision making with their physician; that there is a broader move away from paternalistic medicine. In addition to the science of treatment efficacy (e.g., biomarkers and trial curves), patient values and risk tolerance have weight in decisions, as well. 

During Monday evening’s IMF’s live Facebook event, that same theme came through in the exchange with Dr. Joe (Dr. Joseph Mikhael, IMF’s Chief Medical Officer) when I asked how patients at different points in their SMM journey should think about the newly approved daratumumab option. His response underscored two points that showed up repeatedly across ASH 2025: every myeloma patient passes through a smoldering phase—sometimes briefly, sometimes for years—and early intervention may spare people from the organ damage of full-blown myeloma. But he also emphasized the other side of the equation: we still don’t know the ideal moment to intervene, and decisions should be individualized, grounded in evolving evidence, and made in close conversation with one’s care team.

The treatment-focused updates reinforced that friction. The latest GEM-CESAR data, presented by the Spanish group (Mateos & colleagues), follow patients receiving an aggressive, multi-modal strategy intended to eradicate disease at the SMM stage. Early results have shown deep responses in many participants, but the durability of those responses—and the long-term tradeoffs—remain unanswered and will require extended follow-up. On the opposite end of the spectrum, the Aquila trial (Voorhees & colleagues, Mayo Clinic) examined a far less intensive approach aimed at slowing progression with daratumumab alone. Together, these studies illustrate the expanding range of options: from “hit hard early” to “delay progression with minimal toxicity.” While these possibilities are exciting, there is still much gray area in the smoldering space. 

While these possibilities are genuinely exciting, there remains substantial gray area in the smoldering myeloma space. Trials such as GEM-CESAR and Aquila continue to yield mixed outcomes—some participants are doing very well, while others still progress to active myeloma—reminding us that the riddle is not yet solved. That said, the pace and breadth of ongoing research give reason for cautious optimism that clearer patterns, better tools, and more actionable guidance will emerge over time.

Taken together, the MGUS analyses, SMM biomarker advances, MySCAPE, PROMISE, GEM-CESAR, Aquila, and others, all point in the same direction: we are improving at identifying risk, catching disease earlier, and exploring interventions before irreversible damage occurs. Yet the evidence remains incomplete, and its implications vary widely from one patient to the next. This is precisely where shared decision making carries real weight—the science is advancing quickly, the menu of choices is expanding, and no two individuals bring the same biology, goals, or risk tolerance to the table.

As someone with SMM, it is impossible to watch this work unfold without deep gratitude. The physicians, scientists, and research teams who devote their careers to understanding MGUS, SMM, and multiple myeloma are not just advancing data—they are shaping futures, extending quality of life, and offering hope where uncertainty once dominated. Your persistence, curiosity, and willingness to ask and try to answer hard questions matter deeply to those of us living with these conditions, and we are profoundly thankful for the care, rigor, and humanity you bring to this work every day.