Genomic Testing Can Identify the Most Problematic Smoldering Multiple Myeloma Mutations

Genetic testing offers valuable insight into cancer-linked genes and genetic mutations that may be precursors to the development of cancer. However, with increased insight into the genetic mutations associated with cancer, there is an increased need to understand which mutations are problematic and which only warrant careful monitoring for changes. A new genomic test developed by researchers at Dana-Farber Cancer Institute helps doctors to determine whether patients who have smoldering multiple myeloma (an early form of multiple myeloma) are at high risk for subsequently progressing to full-blown multiple myeloma.

Smoldering multiple myeloma (SMM) is a plasma-cell disorder, which is a disease of a specific type of white blood cell (plasma cell) found in bone marrow. This condition is asymptomatic but can progress into multiple myeloma (MM), a cancer of the plasma cells in bone marrow. However, with no treatment for SMM, doctors must monitor SMM to watch for the symptoms of myeloma. Current treatment is commonly known as “watchful waiting.” This new study at Dana-Farber was designed to help doctors determine which mutations in the bone marrow of SMM patients carried the highest risk of disease progression.

Researchers identified three mutations in tissue samples that were associated with an increased rate and speed of disease progression: certain genetic mutations in the MAPK pathway, amplification or translocation of the MYC gene and a mutation or deletion in the TP53 gene. Both in the study and in a validity test, these three variations were all associated with progression to multiple myeloma.

By testing tissue samples in SMM patients for these three mutations, doctors can identify the highest risk patients and schedule regular monitoring for disease progression. This added insight can enable physicians to provide the best possible care after an SMM diagnosis, whether a patient has high-risk mutations or not.

Synthetic IL-18 May Provide a New Immunotherapy Tumor Treatment

The ability of cancerous cells to evade immune response can be instrumental in the growth of cancer within the body. For this reason, researchers examine the ways in which cancer is able to block a normal immune response and aim to develop immunotherapy drugs that target those mechanisms of action. In a new study published in Nature, researchers found that a vital immune protein called interleukin-18 (IL-18) was blocked by tumors, allowing the tumor to evade the human immune system. However, the researchers were able to find a synthetic form of IL-18, known as a decoy receptor, that was unaffected by the tumor’s blocking signals in studies.

Interleukin-18 is a pro-inflammatory protein that is part of the body’s cytokines. IL-18 works to mobilize the T cells and NK cells that attack and kill damaged or infected cells. A tumor that blocks the function of IL-18 can essentially continue to grow unchecked by the NK cells that would typically neutralize or inhibit tumor cells. Many tumors are particularly adept at evading IL-18 by releasing a protein that binds with IL-18 before it can reach the tumor.

Previous research tested IL-18 as an immunotherapeutic treatment for tumors, but this was ineffective because the IL-18 binding protein released by the tumor worked on both the natural IL-18 and the added IL-18 used in immunotherapy. The fact that added pro-inflammatory IL-18 resulted in no effect alerted researchers to the presence of IL-18 binding protein and motivated the search for a form of IL-18 that would be able to resist tumor-released IL-18 binding protein.

This new study by Yale researchers has tested a synthetic form of IL-18 with a specific mutation that prevents the tumor’s IL-18 binding protein from inhibiting the function of the IL-18. Scientists hope that this potential new treatment may work against tumors that have historically been resistant to immunotherapy. Researchers hope that clinical trials for this new form of IL-18 may begin next year.