From MGUS to Myeloma: Understanding and Interrupting Disease Progression

Multiple myeloma (MM) is an incurable, clonal plasma cell proliferative disorder, accounting for over 35,780 cases in the US in 2024. It is preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which were identified in the 1970s and 1980s, long after the first documentation of MM in 1844.¹

3D visualization of multiple myeloma cells | Image Credit: © AImmersive Imagery - stock.adobe.com

Knowledge of MGUS and SMM has come a long way since then, with a deeper understanding of these precursors' underlying pathologies and more comprehensive risk stratification tools. At the 2025 ASCO Annual Meeting, Omar Nadeem, MD, from the Dana-Farber Cancer Institute, shared key insights into the evolving landscape of risk stratification and growing research into treatment for patients with MGUS and SMM.

MGUS is a premalignant condition defined as the presence of less than 10% of bone marrow plasma cells or less than 3 g of monoclonal protein in the serum. Patients with MGUS have an approximate 1% chance of progressing to active MM per year, and incidence increases with age, particularly among males. MGUS is asymptomatic and does not typically require immediate treatment; however, it does require periodic monitoring to detect potential progression to SMM, according to National Comprehensive Cancer Network (NCCN) guidelines.²

MGUS is commonly seen in about 3% of the population over the age of 50 years, according to findings from iStopMM (NCT03815279), the largest screening study to date for the prevalence of MGUS. The researchers of the study reported SMM in about 0.5% of patients over 40 years of age, and approximately one-third of patients with SMM had an intermediate or high risk of progression to active MM.^2,3

“They screened or offered screening to their entire population of Iceland over the age of 40, and approximately half the population was screened for the presence of MGUS,” explained Nadeem. “And with this, the incidence of MGUS was confirmed. So, it was seen in about 5% of patients over the age of 50. And for the first time, we had a number as to what the absolute incidence is for [SMM].”²

The study was pivotal, providing the first comprehensive population-level data on the prevalence of monoclonal gammopathies—offering critical insights that helped reveal the natural history and progression of MGUS and SMM across a large, diverse population.²

A separate study, PROMISE (NCT03689595), aims to assess 30,000 patients to identify rates of MGUS in Black or African American individuals, as rates of MM tend to be much higher in this population.^2,4

“This study is aiming to do a 30,000-patient effort to identify the rates of monoclonal gammopathies in this population,” said Nadeem. “And again, you can see the incidence goes up with age, and it is strikingly high in patients that have these risk factors over the age of 50. Using some of our more sensitive techniques, about 13% of patients actually have unknown monoclonal protein. And then in African Americans, you can see the incidence as high as 17%.”²

The PROMISE study is still enrolling as of June 2025.²

SMM is a heterogeneous precancer defined as having more than 10% bone marrow plasma cells or an M protein count greater than 3 grams per dL. Approximately 50% of patients progress to MM in the first 5 years, with an Initial progression rate of about 10% per year. After 5 years, the progression rate drops to about 2% per year; however, patients will have a lifetime risk of progression.²

Patients with SMM are stratified into low or high risk. Low-risk patients have a lower probability of progression to active MM at about 2% per year and meet fewer risk criteria, whereas high-risk patients have a progression rate of around 10% per year. To be considered high-risk, patients must present with M protein greater than 2 g/dL, a free light chain ratio greater than 20, greater than 20% bone marrow plasma cells, and high-risk cytogenetic features, according to the 2/20/20 model.²

The 2/20/20 model is an easy-to-use, real-time risk stratification tool that can help guide monitoring frequency, determine potential early intervention, and select high-risk patients for clinical trials.²

"The [International Myeloma Working Group] updated this a few years ago now, where they used the 2/20/20 criteria that I just described but added a few other variables, such as high-risk FISH characteristics [such as t(4:14), t(14:16) del 13q, and gain 1q)]," explained Nadeem. "When you incorporate some of these cytogenetics, you can then identify and even more fine-tune the high-risk patients. A score of more than 12, using this risk score, predicts approximately a 75% risk of progression at 2 years."²

NCCN guidelines recommend close monitoring with potential clinical trial participants for patients with low- and high-risk SMM. In high-risk patients, early intervention with lenalidomide (Revlimid; Bristol-Myers Squibb) or daratumumab (Darzalex; Johnson & Johnson) may be beneficial.²

Treatment of SMM is rather controversial, and data are still in their infancy, leaving some clinicians skeptical about this approach for patients. Among the controversy was the phase 3 AQUILA study (NCT03301220), which evaluated the use of single-agent daratumumab compared with active monitoring in patients with SMM. The therapeutic approach did demonstrate benefit with early intervention, with the potential to delay progression to active MM.^2,5

Although the trial’s primary end point of progression-free survival (PFS) was not met, there was a reported 5-year PFS of approximately 63% for patients treated with daratumumab. The overall survival data were notable, with 93% of patients in the daratumumab arm alive at 5 years compared with 87% in the active monitoring arm. The trial investigators reported multiple deaths in this cohort because of disease progression.²

"[The trial results] led to the [Oncologic Drugs Advisory Committee] (ODAC) meeting with the FDA approximately a week and a half ago, where the ODAC voted in favor of approval of daratumumab in patients with high-risk [SMM],” highlights Nadeem. “Hence, this might be our first agent approved for precursor myeloma. So, we'll stay tuned for updates from the FDA regarding this."²

Other trials are also investigating treatment of SMM with various therapeutic approaches such as combination therapies and even immunotherapies. The GEM-CESAR trial (NCT02415413) was among the first to explore whether early, aggressive treatment could potentially alter the natural course of high-risk SMM. The study evaluated a triplet regimen of carfilzomib (Kyprolis; Onyx Pharmaceuticals), lenalidomide, and dexamethasone, followed by autologous stem cell transplant, consolidation, and maintenance, with the ultimate goal of achieving sustained minimal residual disease (MRD) negativity. Notably, 62% of patients achieved MRD negativity post-transplant—a critical milestone associated with improved long-term outcomes in MM.^2,6

Several ongoing clinical trials are exploring the potential of immunotherapy to alter the disease course in high-risk SMM. For instance, the ITHACA trial (NCT04270409) is evaluating the efficacy of isatuximab combined with lenalidomide and dexamethasone compared to lenalidomide and dexamethasone alone. The ImmunoPRISM trial (NCT05469893) is investigating teclistamab—a bispecific antibody targeting BCMA and CD3—as a novel strategy in this precursor setting. Additionally, early-phase research is underway examining chimeric antigen receptor T-cell therapy with ciltacabtagene autoleucel (cilta-cel, Carvykti; Johnson & Johnson) in high-risk SMM in the CAR-PRISM trial (NCT05767359). Collectively, these studies reflect a growing interest in harnessing immune-based approaches to intercept progression to active MM.^2,7-9

As the understanding of precursor conditions to MM continues to evolve, so too does the potential to intervene earlier and more effectively. Ongoing research will be key to determining which patients benefit most from early intervention, ultimately paving the way toward delaying or even preventing progression to active myeloma.

REFERENCES

1. Gerlach A. Multiple myeloma precursor diseases: Advancing diagnosis and treatment for MGUS and SMM. Pharmacy Times. September 25, 2025. Accessed June 3, 2025. https://www.pharmacytimes.com/view/multiple-myeloma-precursor-diseases-advancing-diagnosis-and-treatment-for-mgus-and-smm

2. Nadeem O, Desai P, Woyach J. Precursors of hematologic malignancies: When to watch and when to treat. 2025 ASCO Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL.

3. A nationwide phase 2 trial of patients with smoldering and active multiple myeloma (mm) (istopmm). ClinicalTrials.gov Identifier: NCT03815279. Updated August 16, 2019. Accessed September 25, 2024. https://clinicaltrials.gov/study/NCT03815279

4. Predicting progression of developing myeloma in a high-risk screened population (PROMISE). Updated April 24, 2025. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT03689595

5. A study of subcutaneous daratumumab versus active monitoring in participants with high-risk smoldering multiple myeloma. Updated September 23, 2024. Accessed September 25, 2024. https://clinicaltrials.gov/study/NCT03301220

6. Carfilzomib in treatment patients under 65 years with high risk smoldering multiple myeloma. Updated September 10, 2022. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT02415413

7. Isatuximab in combination with lenalidomide and dexamethasone in high-risk smoldering multiple myeloma. Updated October 31, 2024. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT04270409

8. Immuno-PRISM (PRecision Intervention Smoldering Myeloma). Updated April 24, 2025. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT05469893

9. CAR- PRISM (PRecision intervention smoldering myeloma). Updated July 18, 2024. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT05767359