‘Spectacular’ accomplishments in multiple myeloma have led to a shift in patient outcomes
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Key takeaways:
- Quality of life and tolerance of new therapies are significantly better.
- Continued research is needed to identify additional risk factors.
Within the past 2 decades, multiple myeloma has shifted from a highly lethal diagnosis to a condition that will no longer shorten the lifespan for many patients.
“This is a spectacular accomplishment for the field overall and is attributed to the development of all the amazing new treatments we now have,” C. Ola Landgren, MD, PhD, chief of the division of myeloma and director of Sylvester Myeloma institute at Sylvester Comprehensive Cancer Center, told Healio. “The field has shifted from old chemotherapy toward small molecule treatments and immunotherapy. The quality of life and the tolerance of these new therapies is significantly better, and outcomes are significantly better too.”
Despite these treatment advances, there remains a significant unmet need for cure.
“Unfortunately, we cannot promise each and every patient great clinical outcomes; there is a subset of patients — maybe 5 to 10% or so — who have much more aggressive disease biology that we may not be aware of right away,” Landgren said. “For those patients, the myeloma will declare itself by coming back and causing more trouble. Those patients have a different disease trajectory and do not benefit as well from the newer therapies. A lot of work needs to be done here.”
Landgren said precision medicine is the remedy to better understand the diagnostic subtypes of myeloma and to tailor treatment.
“Certain disease cases work in very different ways and it’s not one subtype, but multiple subtypes in this group of patients that lead to treatment failure,” he said.
The shift
Significant advances have also been made in diagnostic tools over the years, according to Landgren.
“Many years ago, we used microscopes to diagnose and characterize myeloma, then we started using flow cytometry machines, followed by fluorescence in situ hybridization [FISH] and cytogenetics,” he said. “What’s happening now in the field is a shift toward modern sequencing and proteomic technologies, and beyond. In the beginning, we used targeted sequencing, then whole-exome sequencing, and we are now doing whole-genome sequencing. We are also integrating mass spectrometry technology to track clonotypic proteins in peripheral blood; we are using the sequencing data to predict which proteins to look for and with minimal amount of peripheral blood we can then determine presence or absence of disease-specific proteins. In addition, we are able to capture circulating disease cells and free-circulating tumor DNA in peripheral blood. We can use all these technologies to characterize the disease and to ensure there is no disease left behind when we have completed our planned therapy. The field of molecular medicine overall has shifted from ‘black and white TV’ toward ‘high-definition color TV.’ There is so much more information available to us, and with that information, we are able to better treat our patients.”
Advances in screening technologies for multiple myeloma have also occurred over the years.
The ongoing Iceland screens, treats, or prevents multiple myeloma (iStopMM) trial is the first population-based screening study for monoclonal gammopathy of undetermined significance (MGUS).
“Together with Dr. Kristinsson and Dr. Stephen Harding from Birmingham, UK, I co-developed the study protocol for iStopMM. I am a co-principal investigator of iStopMM and I work closely with Dr. Kristinsson and his team in Reykjavik, Iceland on several ongoing investigations using the screening study as the vehicle for our work. The Icelandic screening study includes about 80,000 participants,” Landgren said. “We are screening patients for multiple myeloma, and then they are randomized into three different groups. One group is kept for the record on the study, and the other two groups are informed that they have MGUS — a precursor of myeloma — and then they are monitored either with the current technology or with more advanced technologies. When the study reads out, it’s possible that we will show that screening will prolong lifespan for patients. But we will have to wait for the results.”
Risk factors
The established risk factors for multiple myeloma include male sex, older age, African American descent, family history of myeloma or associated plasma cell disorders, such as MGUS.
Environmental risk factors have been introduced, including exposure to pesticides or Agent Orange, and also exposure to the World Trade Center disaster.
In a 2022 study published in Blood Cancer Journal, Landgren and colleagues found that emergency response and recovery workers, law enforcement and construction workers who reported to the World Trade Center site after 9/11 had a twofold higher risk for myeloma precursor disease compared with the general population.
As Healio previously reported, researchers sought to confirm previous findings among a FDNY first-responder cohort (n = 1,482; 96% men; 82.7% white, 8.2% Hispanic, 7.7% Black) with a more heterogeneous cohort of World Trade Center-exposed rescue/recovery workers, dubbed the Stony Brook University-General Responder Cohort (n = 1,181; 96% men; 92% white, 5.3% Hispanic, 1.4% Black).
They screened blood from the responders and compared risk for MGUS among the two cohorts with published general population estimates from Olmsted County, Minnesota. Results showed the Stony Brook University-General Responder Cohort had higher odds of MGUS than the FDNY first-responder cohort (OR = 1.38; 95% CI, 1-1.89).
“The findings provide mounting evidence that environmental exposures — and exposure to the World Trade Center disaster in general — are risk factors for the initiation of multiple myeloma,” Landgren said. “Future laboratory experiments designed to study mechanisms of disease initiation in this setting may help identify mechanisms that can be used as novel drug targets with the aim to prevent progression and development of multiple myeloma.”
There are still other risk factors at play that have yet to be identified, according to Landgren.
“There could be other risk factors in an individual that trigger multiple myeloma that we have yet to discover,” he said. “We cannot be certain, for example, that environmental factors, such as Agent Orange, triggered the myeloma. There is always the possibility that there was another mechanism that triggered it. Is Agent Orange equally harmful to every person or could the genetic system potentially make an individual more susceptible — that’s something that we don’t know yet. It is likely that susceptibility genes control our ability to handle different types of threats, but for myeloma we don’t really know much about how that plays a role in the causation of disease.”
Landgren and colleagues are currently working to identify other risk factors for multiple myeloma that have evolved over the years.
“We have to conduct carefully designed studies where we screen populations to identify risk factors in relation to the endpoint that could be multiple myeloma or the precursor condition, MGUS, for example,” he said. “By nature, it takes some time to identify individuals that we can include in those studies. The design of the cohort we screen has to be done in appropriate scientific ways, and we have to apply the right assays and so forth — the whole conduct of the research is very complicated.”
Going forward
Despite the many advances in the multiple myeloma space, research is still needed to better understand risk factors, according to Landgren.
“There are groups of people who are more prone to develop multiple myeloma, and we need to study the actual mechanism,” he said. “If we can understand the mechanism, then we potentially have identified something that could be used to treat or even prevent the disease. If there are things that happen with an environmental exposure — if an exposure ‘unleashes’ certain things in the body — if we can identify that and can pin that down, then we could technically develop some form of a treatment feature going after that and use that as a way to prevent or treat the disease. But we are not yet there.”
There is a great need to capture the many types of genomic changes that occur in multiple myeloma, Landgren added.
“There are very many types of genomic changes in myeloma, and standard of care does not capture it all. Current methods only captures the basic translocations or the IgH, and you can see that in about 50% of cases. The other 50% of cases have gained some losses or many of the old number of chromosomes,” he said. “Beyond these gross anatomical genomic alterations, the full biological alterations are missed every day around the world because physicians don’t have the tools to look for them. Complex events such as chromothripsis and the impact of genomic signature such as APOBEC activation, they all play an important role. In fact, multivariate analysis shows that they are much more important than any of the results which can be captured by current assays. In the future, it will most likely be used for more individualized treatment. That needs to happen. The technologies are already technically available, but they have not yet been implemented in clinical care. In 5 to 10 years from now, the field will be much more sophisticated for that. It doesn’t yet play a role in screening and diagnosis, but it will be going forward.”
References:
- Rögnvaldsson S, et al. Blood Cancer J. 2021;doi:10.1038/s41408-021-00480-w.
- Zeig-Owens R, et al. Blood Cancer J. 2022;doi:10.1038/s41408-022-00709-2.
For more information:
C. Ola Landgren, MD, PhD, can be reached at col15@miami.edu.
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