Study Shows That Immune Cells May Help Identify Patients With High-Risk Smoldering Myeloma Most Likely to Benefit From Treatment

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For many patients who have smoldering myeloma, early treatment can slow or delay the disease’s progression to multiple myeloma, according to a new study published by Sklavenitis-Pistofidis et al in Cancer Cell. Investigators demonstrated that changes in immune system cells may indicate which cases of high-risk smoldering myeloma are likely to progress and which patients might benefit the most from treatment.

The findings stemmed from a clinical trial showing that a combination of an immunotherapy drug and standard treatment may be safe and effective in this group of patients. The results pointed not only to the combination's ability to stave off progression toward multiple myeloma, but also to a new set of biomarkers that can be used to select patients for treatment and assess how well they're responding to it.

"Our results show that by taking an 'immunological profile' of patients with high-risk smoldering myeloma, we may be able to identify those who stand to be helped by therapy," said first study author Romanos Sklavenitis-Pistofidis, MD, a postdoctoral research fellow and Instructor in Medicine in the Department of Medical Oncology at the Dana-Farber Cancer Institute as well as at the Broad Institute of the Massachusetts Institute of Technology and Harvard. "Our data also show that patients' blood shares many of the same immunological changes that we see in the bone marrow. This raises the possibility of a blood test not only to detect immune dysregulation in patients but to monitor it in response to treatment."

Research Background

A symptomless condition characterized by copious amounts of monoclonal proteins in the blood and high levels of abnormal plasma cells in the bone marrow, smoldering myeloma develops into multiple myeloma within 5 years of diagnosis for about half of patients, yet some never develop the disease at all.

It is standard practice not to treat patients with smoldering myeloma until they develop multiple myeloma symptoms. Patients with high-risk smoldering myeloma, however, can be treated prior to the emergence of symptoms, usually as part of a clinical trial. While treatment advances have extended the period in which many patients can live with the disease, it remains incurable.

In recent years, there have been multiple clinical trials aiming to find treatments that impede or halt smoldering myeloma from progressing into multiple myeloma. Two phase III trials have shown that the immune-modulating drug lenalidomide—taken by itself or in combination with the anti-inflammatory drug dexamethasone, which has great activity against myeloma cells—can significantly extend the period before disease progression occurs in patients with high-risk smoldering myeloma.

Study Methods and Findings

In this phase II study, investigators treated 51 patients who had high-risk smoldering myeloma with a regimen of lenalidomide, dexamethasone, and elotuzumab. As part of the study, the researchers collected 149 blood and bone marrow samples from the patients as well as from individuals without smoldering myeloma and separated out the immune system cells from each sample. The researchers then analyzed the RNA within these cells—which enabled them to detect changes in gene expression and in the T-cell receptor—information they used to identify the types of immune cells present in each sample as well as the relative levels of each subtype.

The investigators discovered that 87% of the patients eligible for the study responded to the three-drug combination, and that the 2-year survival rate was 95.6% after treatment. Although the trial didn't include a control group who received no treatment, the results indicated that the three-drug regimen was safe and effective and revealed that the rate of progression to multiple myeloma was lower than expected for patients with high-risk smoldering myeloma.

When comparing the immune system cells of patients with those of the general population participants, the researchers found that patients whose immune cell composition in the bone marrow was least like the immune cell composition of general population participants had significantly longer progression-free survival. The researchers suggested that this was because the balance of T cells in the bone marrow had shifted toward cells best equipped to attack myeloma. Researchers also uncovered that patients who had a greater abundance of granzyme K+ CD8+ effector memory T cells responded best to the three-drug treatment.

Additionally, the investigators found that many of the immune changes that had occurred in the patients' bloodstream resembled those in the bone marrow. The investigators hope that their research might allow for a simple blood test to detect and monitor immune dysregulation in patients and, potentially, for a test capable of selecting patients with the highest likelihood of benefiting from treatment.

Disclosure: The research in this study was supported by a Stand Up To Cancer Catalyst Research Grant: Bristol Myers Squibb Supported Projects, the National Institutes of Health, the Leukemia and Lymphoma Society, the Multiple Myeloma Research Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, as well as a Multiple Myeloma Research Foundation Research Fellowship Award, the International Waldenstrom’s Macroglobulinemia Foundation’s Robert A. Kyle Award, the Claudia Adams Barr Award for Innovative Basic Cancer Research, and the International Myeloma Society. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.