This article has been updated to note that all high-risk smoldering multiple myeloma patients will develop active disease.
NEW YORK – Researchers at the Multiple Myeloma Research Foundation and Dana Farber Cancer Institute are building a more complete picture of the genomic events that drive some patients with smoldering multiple myeloma to develop active disease, and they will use this knowledge to advance a liquid biopsy test for monitoring patients and identifying those at high-risk of progression.
In December, MMRF began an effort with Dana Farber to identify genomic and immune markers associated with SMM progression into multiple myeloma. That project will analyze the genomic data and medical records from about 500 patients with SMM, a precancerous condition, who are enrolled in Dana Farber's PROMISE and PCROWD studies.
They will receive a 70-gene, cell-free circulating DNA (cfDNA) test developed by MMRF and Dana Farber, called the MM-70 test. Results from that test will be linked to their health records, which may include whole-genome and whole-exome sequencing, circulating tumor cell analysis, and single-cell RNA sequencing. This information will be incorporated into the dataset MMRF has already amassed within its CureCloud research effort, which aims to ease multiple myeloma patients' access to the MM-70 liquid biopsy test and personalize treatments.
The data amassed within this latest project may not only inform the development of a test for the early identification of high-risk SMM patients who will end up with multiple myeloma but also may eventually inform the development of precision treatments that can delay this progression.
Based on current knowledge, the genomic profile of an SMM patient doesn't appear all that different from a patient with full-blown multiple myeloma. According to MMRF CSO Daniel Auclair, an SMM patient has most of the same genomic alterations as an active disease patient, though the foundation's research to date has provided insights worthy of further follow-up.
"There is this thought that the immune system, at least for a while, is able to keep a check on the disease,"Auclair said. "Out of our initial prevention effort, we figured out some very interesting targets and markers that actually could be predictive of disease progression and on top of that may give us some clues about targets to go after from a therapeutic perspective."
In the latest study with Dana Farber, researchers will follow patients from initial diagnosis with SMM until they become active-disease patients. They will conduct regular genomic and immune analysis to identify common markers among patients who progress sooner, within two years of SMM diagnosis, Auclair said.
MMRF is hoping that the MM-70 liquid biopsy test currently being used within CureCloud to identify somatic variants and clonal hematopoiesis of indeterminate potential associated with multiple myeloma can also be used to identify these high-risk SMM patients.
Currently, SMM progression is tracked through bone marrow aspiration tests that measure clinical markers of disease burden, such as the level of the myeloma protein (M Protein), free light chain ratios, and percentage of plasma cells in the marrow. Physicians use the "20/2/20" criteria to measure SMM progression, Auclair explained. If patients have bone marrow plasma cells greater than 20 percent, M protein spike greater than 2 g/dL, and a free light chain ratio greater than 20, physicians may consider initiating early treatment. Doctors may also use fluorescence in situ hybridization (FISH) to measure cytogenetic abnormalities in a SMM patient's blood to monitor their risk.
However, these tests are "barely more predictive than flipping a coin percentage-wise," Auclair said. "which is why many clinicians hesitate to rely on those markers to initiate early treatment and decide to wait until frank disease develops." The uncertainty of standard tests for SMM, combined with the invasive nature of bone marrow aspiration, is why MMRF wants to expand the use of the MM-70 liquid biopsy test for SMM patients. This panel will allow doctors to perform tests more frequently without subjecting patients to invasive procedures.
There is some suggestion that a liquid biopsy-based monitoring test can improve upon bone marrow aspirate. At the 2020 American Society for Hematology annual meeting, Auclair presented findings from a study in which the MM-70 test achieved greater than 90 percent sensitivity for detecting myeloma-linked somatic events. The MM-70 blood test was able to identify the majority of variants in cfDNA that were previously detected by bone marrow aspirate. Importantly, the researchers found the liquid biopsy test detected somatic variants that were not detected by bone marrow aspirate analysis.
With the MM-70 panel, physicians can monitor SMM patients for changes in some commonly altered genes associated with disease progression, including KRAS and NRAS mutations, and alterations in the DNA repair pathway, such as deletion of chromosome 17p, mutations in TP53 and ATM genes, as well as somatic mutations in CHIP genes.
"The hope here is that by combining classical clinical tests [with] the results of modern next-generation molecular assays, such as the MM-70, we will be able to identify smoldering patients with a greater than 80 percent chance of progressing within two years and who might benefit from early treatment," Auclair said.
MMRF began developing its liquid biopsy test for multiple myeloma several years ago with Dana Farber. "We had done some research and found that CHIP alteration can be found in about a quarter of myeloma patients in a very predictable outcome," Auclair said. There was also a desire to create a direct-to-patient service that lifted some of the access barriers to genomic testing. Â
For example, the resulting CureCloud program engages a mobile phlebotomy unit to collect blood samples from patients, saving them from having to travel to see their doctors and endure invasive bone marrow sampling.
Auclair explained that it is not only important to measure the tumor burden, which is currently what is gauged with standard testing, but also track the changing biology of the disease from SMM to multiple myeloma. "We want to be able to monitor [patients'] clonal type and the evolution of the disease as it progresses, and we want to be able to monitor that very frequently," he said.
As MMRF and Dana Farber researchers now work on amassing and analyzing the data that will inform the use of the MM-70 test for gauging SMM progression, Auclair recognized that such a liquid biopsy test may be particularly advantageous from a research standpoint and may make it easier for larger trials to sequence more multiple myeloma and SMM patients.
"There are these large trials that have … hundreds or thousands of patients where you don't have this correlative science because they could not get the bone marrow aspirate for every patient," he explained. "With blood liquid biopsies, it would be much easier to get the genomic and immune data from those patients."
This research on SMM will be added to MMRF's CureCloud initiative, which launched in 2019 with the goal of sequencing 5,000 patients, and building a large repository of genomic, immune, and clinical data to support research on multiple myeloma. To date, the program has sequenced about 160 multiple myeloma and SMM patients. In addition to Dana Farber, MMRF has also partnered with the Broad Institute, My Gene Counsel, Cota Healthcare, Prometheus Research, the consulting firm Prophet, and Prophet's digital services company Springbox.
Eventually, the growing CureCloud dataset may also be useful for drug development purposes. MMRF researchers often work together with pharmaceutical companies to support clinical trials, Auclair said, and once the data from this latest research effort comes in, the foundation may partner with drugmakers to develop a SMM therapy that slows the progression to active disease.
That treatment may be a combination of approaches that includes immunomodulatory drugs to bolster the immune response to myeloma. The MM-70 test could also identify actionable alterations that can be targeted with drugs in development, such as those being studied in MMRF's MyDRUG clinical trial, Auclair said.
"If proven promising, those targeted agents could be deployed to intercept the disease very early in smoldering myeloma patients in combination with immune drugs," he explained. "We affectionately like to call such early precise interception of multiple myeloma 'precision prevention.'"