Smoldering Multiple Myeloma: Risk Factors, Who to Treat, How to Treat

It’s been almost 50 years since “monoclonal gammopathy of undetermined significance,” or MGUS, was identified as a precursor to multiple myeloma. Yet the debate over when and how to treat patients who have not developed the organ damage associated with the blood cancer is as lively as ever, according to speakers at a session on precursor disease on the opening day of the International Myeloma Society 21st Annual Meeting & Exposition, taking place in Rio de Janiero, Brazil.

S. Vincent Rajkumar, MD | Image credit: Mayo Clinic

High-risk smoldering multiple myeloma (SMM) has emerged as the condition where treatment yields the greatest benefit, said S. Vincent Rajkumar, MD, professor of medicine at Mayo Clinic. These patients are biologically distinct from those with MGUS, and those with high-risk features should be treated, he explained.

“Initially it was thought that smoldering myeloma is some in-between stage, between MGUS and smoldering multiple myeloma. But that's not what it is,” he said. “We now know that smoldering multiple myeloma is a heterogeneous clinical condition, clinically defined where one-third of the patients have high-risk smoldering myeloma. They actually have myeloma, but they don't have the end organ damage, and two-thirds have MGUS.”

Citing recommendations published in 2022, he said that patients with SMM should undergo risk stratification; those with high-risk SMM should receive either lenalidomide or lenalidomide with dexamethasone for 2 years, or they should enroll in a clinical trial. High-risk patients are those that have a time to progression of 2 years or less, as defined by an algorithm he outlined. Others should be observed every 3 to 4 months.¹

For those who say it’s better to wait for more trial data that compares early data to observation, Rajkumar said there’s not much more data on the way. He is an investigator in the AQUILA trial (NCT03301220), which is studying the use of subcutaneous daratumumab in patients high-risk smoldering multiple myeloma. “We will know the results soon. But after that, there are no more randomized trials with observation along ongoing,” he said.

For those who believe it’s possible to observe patients and catch progression before it happens, Rajkumar said, “At Mayo, we have found out this is easier said than done.” He reviewed results that showed the even at a top institution, “we miss the end organ damage 50% of the time….We want to prevent organ damage.”

Approaches to Risk Stratification. Irene Ghobrial, MD, who is senior vice president for Experimental Medicine, director of the Center for Early Detection and Interception of Blood Cancers, and co-leader of the Lymphoma/Myeloma Cancer Center Program at Dana-Farber Cancer Institute, discussed risk stratification in high-risk patients; in SMM, she said, progression of SMM is about 10% a year.

Irene Ghobrial, MD | Image credit: Dana-Farber Cancer Institute

The question, she said, is how to differentiate between those who will progress—and need early treatment—from those who are “more MGUS-like.” She offered highlights from different models that have been developed to evaluate patient characteristics, and then discussed the elements to be evaluated, which include:

• Dynamic progression of monoclonal protein levels
• Circulating tumor cells
• Genomics and transcriptomics
• Immune and non-immune microenvironment
• Genetics and ancestry

Genomic aberrations can help define precursor conditions, and Ghobrial detailed studies that have used whole genome sequencing, circulating tumor cells, and other strategies to create models that can predict progression. One of the discoveries, she explained, is that the genome for multiple myeloma is present long before a patient presents with full-blown disease.

“By the time we have overt myeloma, it's been there for 30 years,” she said. For smoldering myeloma, “by the time it's progressing, it's already very mature and has a lot of genomic aberrations. For MGUS [it’s] about 15 years.”

Ghobrial then discussed the immune microenvironment. “You cannot look only at the cancer cells without looking at the immune cells. “A few years ago, we asked the question whether, by single cell sequencing, [if] the immune system is altered. And we indeed found that even as early as MGUS, you find that those patients have compositional changes.”

On this topic, she noted that Friday’s plenary session will feature a presentation by her Dana-Farber colleague, Romanos Sklavenitis-Pistofidis, MD, PhD, titled, “Single-Cell RNA Sequencing of 6 Million Tumor and Immune Cells in Patients With Plasma Cell Premalignancy Unveils Coregulation of Disease Progression by Tumor Biology and Immune Dysregulation.”

Key findings will show that as we age, so does our immune system; in patients with MGUS and smoldering myeloma, Ghobrial said, “there is an accelerated immune aging that occurs despite the regular chronological age. And this is critical, because now you can identify specific signatures and specific cells that are changing even as early as MGUS in those patients, independent of age.”

T-cell receptors shrink as disease progresses, and B cells age as well, she said.

How Common Is SMM? Sigurdur Kristinsson, MD, PhD, of the University of Iceland, offered an update and lessons learned from one of the most ambitious projects ever in research: what if you made screening for MGUS available to a population?

After its debut in 2021, the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, has some important lessons about MGUS and SMM. First, both are more prevalent than they believed, at least among the people of Iceland—MGUS was found among .5% of the population over age 40. And second, SMM is also more common than was known before iStopMM.

“In particular, high risk smoldering myeloma that a lot of the individuals have it, so we really need to figure out who to treat and who definitely not to treat,” Kristinsson said. On the positive side, those whose MGUS or SMM was caught early were managed differently than those who did not screen positive, but who later developed multiple myeloma and presented with acute symptoms in the emergency department. On average, he said, myeloma was detected a year earlier, with fewer acute features.

Finally, Kristinsson said, a population wide screening approach had to take into account the mental health effects of learning one had MGUS. Patients filled out a questionnaire after agreeing to take part in the study. How patients might deal with living with a finding of MGUS is a consideration for health systems.

Different Immune Responses by Population. Madhav Dhodapkar, MBBS, director, Center for Cancer Immunology at Winship Cancer Institute, Emory University, examined some key issues in the myeloma field: what drives the disease, and why does myeloma affect the Black population differently?

Madhav Dhodapkar, MBBS | Image credit: Winship Cancer Institute

Dhodapkar said he would share stories “that relate to understanding mechanisms by which immune function is altered In early days of myelomogenesis,” and offer an explanation of how “spatial aspects of [the] immune system actually evolve in the context of antigen specific immunity.”

Understanding an immune-based theory of myeloma is not only critical for disease prevention, but preclinical models now show that immune-based therapies are “the mainstay of treating myeloma,” he said.

First, Dhodapkar outlined the work his team is doing. The literature is full of interpretations based assumptions that T cells were exhausted; however, his work has shown that, in fact, in response to T-cell receptor engagement, T cells have “a fair bit of capacity for proliferation.”²

“Interestingly, what these T cells are also able to do is actually produce cytokines. And in fact, patients with myeloma, T cells with myeloma make more cytokines, particularly those when you look at inflammatory cytokines and compared to the MGUS counterparts,” he said.

He described 2 broad phenotypes of T cells that were delineated in studies; he said 1 type has been “implicated in the context of tissue inflammation,” while the other expresses “known markers of T cell exhaustion in the context of inhibitory checkpoints.”

What this means, he explained, is that in myeloma causes alterations that affect multiple inflammatory pathways, including for CD4 and CD8 T cells, “the 2 cell types that we are most interested in…as the immune system evolves over time.”

This raised other questions, including whether there was increased DNA damage in myeloma and earlier on in MGUS, and whether this damage affected all populations equally.

“So that led us to hypothesize that perhaps what we were seeing was altered dysfunction in the context of what has been called immunologic aging,” Dhodapkar said. The term has been used to refer to at age-related changes in immune cells, he said but many studies have had very few patients with African American ancestry, “as well as people in the first decade of life, where the great majority of ages will see that changes actually occur.”

Of note, in the United States, 20% of all multiple myeloma diagnoses occur among Black patients, although they account for 14% of the overall population.³

Dhodapkar continued: “So we first went back and analyzed a cohort, a cohort of individuals, healthy individuals, between the first to seventh decade of life, including about 30% to 40% of Black patients in that cohort to create what we call an immuno-age calculator, then reapply that data into the data from similar assays into MGUS and myeloma patients.”

“That led to the finding that patients with myeloma are approximately a couple of decades older immunologically compared to their MGUS counterparts,” he said. “Interestingly, the biggest difference in the context of determinants of immunologic aging appears to be race-related, so the group that's at the highest risk for immunologic aging appears to be [those] with Black ancestry, wherein we see a greater aging, again, as early as MGUS, compared to their White counterparts. And it does correlate with immunologic function.”

Dhodapkar even said this could explain why Black patients with myeloma as group have less robust responses to vaccines, including the COVID-19 vaccine. In taking another look at older data sets for the SARS-COV-2 vaccine, immunologic aging, not chronologic aging, was the better predictor of response the vaccine.

“What I think this data is beginning to point out is that there is, in fact, a significant amount of what we call maladaptive immune aging in myeloma that appears to be greater in myeloma compared to MGUS, that appears to be greater in Black patients,” he said. “And [it] correlates with outcomes in these individuals.”

References

1. Rakjumar SV, Kumar S, Lonial S, Mateos MV. Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022;12(9):129. doi:10.1038/s41408-022-00719-0.

2. Dhodapkar MV, Immune-pathogenesis of myeloma. Hematol Oncol Clin North Am. 2024;38(2):281-291. doi: 10.1016/j.hoc.2023.12.011.

3. Disparities in African Americans. International Myeloma Foundation. Accessed September 25, 2024. https://www.myeloma.org/IMF-Diversity-Equity-Inclusion-Policy/disparities-african-americans