In many patients with disease that often precedes myeloma, early treatment can slow or delay progression to myeloma. In a new study, researchers at the Dana-Farber Cancer Institute show that changes in immune system cells can indicate which high-risk patients with “smoldering” multiple myeloma are likely to progress to multiple myeloma and who will benefit most from treatment.
The results were published online today in the journal Cancer cell, stems from a clinical trial that showed the combination of an immunotherapy drug and standard therapy to be safe and effective in this patient population. The results point not only to the combination’s ability to prevent progression to multiple myeloma, but also to a new set of “biomarkers” that can be used to select patients for treatment and assess how well they respond.
“Our results show that by taking an ‘immunological profile’ of patients with high-risk smoldering multiple myeloma, we may be able to identify those who should be helped with treatment,” says the study’s first author, Romanos Sklavenitis-Pistofidis, MD. from Dana-Farber and the Broad Institute of MIT and Harvard.
“Our data also show that patients’ blood shares many of the same immune changes we see in bone marrow. This raises the possibility of a blood test not only to detect immune regulation in patients, but to monitor it in response to treatment.”
Smoldering multiple myeloma is an asymptomatic condition in which patients have high levels of an abnormal protein, called monoclonal protein, in their blood and high levels of abnormal plasma cells in their bone marrow. About half of patients with the disease develop multiple myeloma within five years of diagnosis, but some never develop the disease. Patients with smoldering multiple myeloma who are classified as “at risk” are particularly likely to develop multiple myeloma, in which case treatment is necessary.
Myeloma itself is a cancer of white blood cells in the bone marrow called plasma cells, which fight infections and other diseases. Patients with smoldering multiple myeloma are usually not treated until they develop multiple myeloma symptoms. However, patients with high-risk smoldering multiple myeloma can be treated before symptoms develop, usually as part of a clinical trial. Although advances in treatment have extended the length of time many patients can live with the disease, it remains incurable.
In recent years, there have been many clinical trials of treatments aimed at preventing or stopping smoldering multiple myeloma from developing into full-blown multiple myeloma. Two III. Phase I trials have shown that the immunomodulatory drug lenalidomide, alone or in combination with the anti-inflammatory drug dexamethasone, which is highly active against multiple myeloma cells, can significantly extend the time before progression in high-risk patients. multiple myeloma.
In the new, II. In the phase I trial, researchers treated 51 such patients with lenalidomide, dexamethasone, and elotuzumab, an antibody drug that triggers the immune system to attack multiple myeloma cells. As part of the study, researchers collected 149 blood and bone marrow samples from patients and from people without multiple myeloma and isolated the immune system cells from each sample.
They then analyzed the RNA in these cells, which allowed them to detect changes in gene expression and in the T cell receptor—a protein on T cells that recognizes proteins from diseased cells. That recognition triggers an immune attack on the disease and enables the immune system to form a memory against it. They used this information to identify the types of immune cells present in each sample, as well as the relative abundance of each subtype.
The researchers found that 87% of patients eligible for the trial responded to the three-drug combination, and 95.6% were alive two years after treatment. Although the study did not include a control group of untreated patients, the results suggest that the treatment was safe and effective, the study authors say, with the rate of progression to multiple myeloma lower than expected in patients with high-risk smoldering multiple myeloma. . .
When the researchers compared the types of immune system cells in the patients and healthy volunteers, they found that patients with immune cell composition in their bone marrow at least the same as that of healthy individuals had significantly longer progression-free survival — the time before their condition began to worsen.
Presumably, this was because the balance of T cells in the marrow had shifted towards cells that were best equipped to attack the myeloma. The researchers also found that patients with higher levels of T cells known as granzyme K (GZMK)+ CD8+ effector T cells responded best to the three-drug regimen.
Ultimately, the researchers found that many of the immune changes that had occurred in the patients’ bloodstreams resembled those in the bone marrow. This opens up the possibility of a simple blood test to detect and monitor immune dysregulation in patients and perhaps, one day, a test to select patients most likely to benefit from treatment.
Romanos Sklavenitis-Pistofidis et al., Immune markers of response to immunotherapy in patients with high-risk smoldering multiple myeloma, Cancer cell (2022). DOI: 10.1016/j.ccell.2022.10.017
Provided by Dana-Farber Cancer Institute
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