Multiple Myeloma Precursor Diseases: Advancing Diagnosis and Treatment for MGUS and SMM

Despite decades of research, there remains little clinical understanding and definition of multiple myeloma (MM), as well as its progression from the precursor diseases monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). At the International Myeloma Society 21st Annual Meeting in Rio de Janeiro, Brazil, experts discuss current knowledge of MGUS, SMM, and MM and the increased study of treating SMM before the disease progresses to MM.¹

MGUS has a risk progression to MM, which, according to clinical study, remains stable at about 1% per year. Image Credit: © LukaszDesign - stock.adobe.com.

MM is the second most common hematological malignancy, accounting for over 35,780 cases in the United States in 2024. It is characterized by the clonal proliferation of malignant plasma cells that drive the overproduction of mature but dysfunctional B lymphocytes. MM has a long history with the first well-documented case reported in 1844 by Samuel Solly; however, it took over a century before the introduction of its precursors diseases MGUS and SMM, which were identified in the 1970s and 1980s. Genomic sequencing has found that presence of MGUS can determine which patients are at high-risk of progressing to SMM and, eventually, MM. Studies have found, through identification of genomic aberrations, that alterations like MYC and MAPK mutations are predictive of progression from MGUS and SMM to overt MM.^2-4

“The genome of [MM] is actually very old. By the time we have overt [MM], it's [been accumulating mutations] for 30 years,” said Irene Ghobrial, MD, professor of medicine at the Harvard Medical School, Dana-Farber Cancer Institute in Boston, Massachusetts. “And by the time we have [SMM] that's progressing, it's exactly the same thing, 30 years of [MM] or [SMM]. By the time it's progressing, it's already very mature and has a lot of genomic aberrations, but MGUS is about 15 years.”

MGUS is a condition where monoclonal proteins, or M proteins, are detected in the blood. Patients with MGUS do not need treatment and typically do not present with any physical symptoms; however some may experience rashes or nerve complications, such as numbness or tingling. The underlying mechanism driving the disease is unknown, but gene changes may play a role. High-risk patients may benefit from regular checkups and watching for symptoms such as bone pain, fatigue, weight loss, anemia, and nerve pain.⁵

The risk of MGUS progression to MM, according to clinical study, remains stable at about 1% per year. This is significantly lower than the 10% annual risk of SMM progression to MM, which is highest in the first 5 years following diagnosis. SMM is a heterogeneous clinical condition that is genomically different from MM and is prevalent in 0.5% of the general population over 40 years old, according to the phase 2 iStopMM study (NCT03815279). The open-label, single-center study in Iceland identified that 3725 out of the 80,000 participants had SMM.⁶

Circulating tumor cells and immune cell function are critical in identifying the prognosis of patients with MGUS, SMM, and MM. The differentiation, early diagnosis, risk stratification, and disease prognosis of MGUS, SMM, and MM is essential for not only optimizing treatment outcomes but can aid in more effective tailoring of treatment to individual patients. Through whole genome sequencing of circulating tumor cells, studies have identified translocations, single nucleotide variants, and structural variants in MGUS and SMM. These findings also led to the creation of a “myeloma-like” genomic model that differentiates high- and low-risk SMM, as well as validates the progression of MGUS to SMM.

“And now you can actually also look at the different transitions from MGUS to smoldering to myeloma,” said Ghobrial. “You can either look at the single cells from 1 patient [sic], and identify transcriptional changes that occur in those patients, as well as the differentiation from normal plasma cells to malignant plasma cells to identify new targets in those patients.”

Through the use of high dimensional functional analyses of immune cells, researchers have assessed the functional profiles of MM bone marrow T-cells and identified differences in cytokine production, alterations in phosphor signaling, and the impact of immune cell aging. Understanding the mechanisms underlying the development of MGUS can aid clinicians in early diagnostic and disease progression predictions efforts.

“We can see what, with active screening, we diagnose their myeloma 1 year earlier. I think this is an important finding when it comes to the concept of early detection and early intervention,” said Sigurdur Kristinsson, MD, PhD, professor of hematology at the University of Iceland.

Research suggests that the immune system plays a role in MM pathogenesis and progression, as explained by Madhav Dhodapkar, MD, director of the Center for Cancer Immunology at Winship Cancer Institute in Emory University in Atlanta, Georgia.

“Patients with [MM] make more cytokines, particularly inflammatory cytokines compared to the MGUS counterparts,” he said. “The 2 broad functional phenotypes that we identified in these studies were 1 set of T-cells that were predominantly making GMCSF [granulocyte-macrophage colony-stimulating factor], a cell type that has been implicated in the context of tissue inflammation and in autoimmunity. And another [phenotype] that's polyfunctional and expresses pretty much all known markers of T-cell exhaustion.”

Phosphor signaling in T-cells and myeloid cells showed alterations across multiple inflammatory pathways, both before and after stimulation, suggesting that underlying immune dysfunction may also contribute to MGUS’s progression to overt MM. Additionally, through analysis of cells from healthy individuals across the first 7 decades of life, including 30% to 40% of Black patients, researchers developed the “immune age calculator.” Accurate measuring of immunological aging may further help with risk stratification and disease progression prognoses.

Understanding these underlying mechanisms is integral to identifying dynamic progression, allowing for the development of methods to improve M-spike values, light chains, and hemoglobin to modify risk of disease progression. Although there is no treatment for MGUS, there are efforts to treat SMM, which is considered controversial amongst practitioners and MM specialists. Additionally, as of 2024, there is no FDA approved agent for treatment of SMM.

However, the PETHEMA study (NCT00480363) led by María-Victoria Mateos, MD, PhD, showed that using lenalidomide (Revlimid; Bristol-Myers Squibb) and dexamethasone (ReDex) compared with observation in high-risk SMM reduced the risk of end organ damage by 82% as well as a 70% decrease in mortality risk. The results of lenalidomide alone were about the same, further highlighting the significant clinical benefit of treating SMM rather than waiting for disease progression to MM.⁷

Researchers recommend clinicians continue observations for patients with intermediate or low risk disease but suggest early intervention in high-risk patients with a regimen, such as lenalidomide or (ReDex), for 1 to 2 years following diagnosis. Multiple speakers suggested use of the 2/20/20 risk stratification model created to identify high-risk patients with a 50% 2-year risk of progression. However, “there’s always room for improvement,” Ghobrial stated while citing the use of cytogenetics to refine risk stratification.

Gaps in approaches to treatment for MM and its precursors remain emphasize the need for further research dedicated to identifying new biomarkers, expanding the definitions of MGUS, SMM, and MM, and the development of treatments for SMM to mitigates its progression to overt MM. Ongoing trials, as of 2024, include the phase 3 Aquila (NCT03301220), Ithaca (NCT04270409), and DETER-SMM (NCT03937635) trials all investigating use of immunotherapies to treat and potentially discover a curative approach for patients with high-risk SMM, aiming to improve progression-free survival, overall survival, and their quality of life.^8-10 With continued research and efforts to address the precursor diseases MGUS and SMM, there are more opportunities for early diagnosis and interventions to mitigate their progression to overt MM.

REFERENCES

1. Ghobrial I, Dhodapkar M, Mateos M, et al. Precursor disease. International Myeloma Society 21 Annual Meeting. September 25, 2024. Rio de Janeiro, Brazil

2. Targeting resistance: navigating the complexity of the tumor microenvironment and car t-cell efficacy. Pharmacy Times. August 16, 2024. Accessed September 25, 2024. https://www.pharmacytimes.com/view/targeting-resistance-navigating-the-complexity-of-the-tumor-microenvironment-and-car-t-cell-efficacy

3. Key statistics about multiple myeloma. American Cancer Society. August 27, 2024. Accessed September 25, 2024. https://www.cancer.org/cancer/types/multiple-myeloma/about/key-statistics.html

4. Landgren O. Advances in MGUS diagnosis, risk stratification, and management: introducing myeloma-defining genomic events. Hematology Am Soc Hematol Educ Program. December 10, 2021. doi:10.1182/hematology.2021000303

5. Monoclonal gammopathy of undetermined significance (MGUS). Mayo Clinic. September 10, 2024. Accessed September 25, 2024. https://www.mayoclinic.org/diseases-conditions/mgus/symptoms-causes/syc-20352362

6. 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

7. QUIREDEX: Revlimid (Lenalidomide) and Dexamethasone (ReDex) Treatment Versus Observation in Patients With Smoldering Multiple Myeloma With High Risk of Progression (QUIREDEX). ClinicalTrials.gov Identifier: NCT00480363. Updated July 31, 2013. Accessed September 25, 2024. https://clinicaltrials.gov/study/NCT00480363

8. A Study of Subcutaneous Daratumumab Versus Active Monitoring in Participants With High-Risk Smoldering Multiple Myeloma. ClinicalTrials.gov Identifier: NCT03301220. Updated September 23, 2024. Accessed September 25, 2024. https://clinicaltrials.gov/study/NCT03301220

9. Ghobrial I, Rodriguez-Ortero P, Koh Y, et al. P-137: ITHACA, a randomized multicenter phase 3 study of isatuximab in combination with lenalidomide and dexamethasone in high-risk smoldering multiple myeloma: safety run-in preliminary results. Clinical Lymphoma Myeloma and Leukemia. November 10, 2021. doi:10.1016/S2152-2650(21)02264-3

10. Lenalidomide, and dexamethasone with or without daratumumab in treating patients with high-risk smoldering myeloma. ClinicalTrials.gov Identifier: NCT03937635. Updated July 9, 2024. Accessed September 25, 2024. https://clinicaltrials.gov/study/NCT03937635