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Jagannath Discusses Building on the Biology of Multiple Myeloma

Caroline Seymour
Published: Monday, Dec 17, 2018

Sundar Jagannath, MD
Sundar Jagannath, MD
Understanding the proliferation of malignant myeloma cells can only be discerned by going back to the biology of the disease, explained Sundar Jagannath, MD, and greater understanding of a patient’s cytogenetics may compound the success seen with chemotherapy and novel adoptive cellular therapies, such as chimeric antigen receptor (CAR) T-cell therapy.

“At the moment, the science is not advanced enough to tailor therapy according to the genetic abnormality. That is our next major goal in clinical research,” said Jagannath. “Understanding how to tailor therapy according to the risk status, genetic nature, or the immune composition of the patient’s bone marrow microenvironment could be studied better,” he added.

In an interview with OncLive® during the 2018 State of the Science Summit™ on Multiple Myeloma, Jagannath, director of the Multiple Myeloma program and professor of Medicine at the Tisch Cancer Institute, Mount Sinai Health System, provided insight into the biology of multiple myeloma.

OncLive: How can the biology of myeloma inform the management of newly diagnosed disease?

Jagannath: There are 2 founder clones in myeloma. One is hyper-deployed and another one is nonhyper-deployed; these founder clones multiply over the years. During that time, they undergo additional mutations that gives them growth advantage. By the time a patient is diagnosed with multiple myeloma, they have 1 of these founder clones that has spread and acquired many mutations. Each patient has at least 4 to 6 different clones in the body.

You know 1 or 2 drugs is not going to cure the patient, so you need combination therapy right from the outset. When we look at any cancer, we think that if we give a particular chemotherapy, the patient may develop resistance, but biology says otherwise. The drug-resistant clone is already resident in the patient right from the outset. When you give these combination chemotherapies, you get rid of most of the drug-sensitive clone and are left with this small drug-resistant clone that eventually grows and comes back as a relapse. Myeloma is a highly treatable cancer, but not necessarily curable. [That] doesn't mean that we don't cure myeloma patients. We cure about 10% to 15% of myeloma patients. However, the disease tends to come back in the vast majority of patients.

The next important thing to understand is that any cancer [results from] a genetic change [at the cellular level]. Cancer [is] like a terrorist residing in the community, surrounded by the healthy cells. Just like in real life, we can get rid of the terrorist if the community doesn't want the terrorist to hide among themselves. Likewise, these surrounding cells can get rid of the cancer cells. We want to understand why the cancer cell was able to proliferate and fool the surrounding normal cells. Moreover, [we want to learn] how we can stimulate the immune cells to recognize the cancer cells and eliminate them. Before, we were only using chemotherapy drugs and looking at the genetics to [discern resistance and nonresistance].

Now, immuno-oncology (IO) has come to play a big role in myeloma. What you essentially do with IO is take the surrounding healthy immune cells and turn them against the cancer, so the myeloma can be eradicated. This is quite successful even if the cancer cell has a genetic mutation that shows resistance to chemotherapy. Now, we have chemotherapy and immunotherapy. The treatment for myeloma has made great strides.

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2017 Year in Review™: Clinical Impact of Immunotherapies in the Treatment of CancerMar 30, 20191.75
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