Jagannath Discusses Building on the Biology of Multiple Myeloma

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.

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

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.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.

What are the key advances that have been made in the transplant-ineligible population?

Another important component I spoke about was transplant-ineligible patients; these are patients who have renal impairment and comorbidities or elderly and frail patients over the age of 75 or 80. The good news is there has been dramatic progress for these patients. For a long time, we only had chemotherapy. We didn't make substantial progress in the life expectancy of frail patients and renal-impaired patients. With IO and new drugs, we are [now] able to give these kinds of treatments safely to elderly patients. Even those who are over the age of 90 [are able to] get into a meaningful remission, which results in a meaningful improvement in their quality and quantity of life.[We now know that] combination therapy is better [in these patients]. We use 3 drugs, and it could potentially be 4 drugs. As I said, the [greater the number of drugs used], the greater the proportion of myeloma cells will be eliminated. The second important advance is we are able to look for minimal residual disease (MRD), that is 1 in 1 million or 1 in 100,000 myeloma cells that are still in the bone marrow. That is important because we have all these active agents that we’re able to effectively treat patients with. Now, more patients are going into complete remission (CR) or stringent complete remission—–both biochemical remissions––as well as demonstrating morphologically negative bone marrow. Now, we do PET-CT to make sure there is no active disease [in the bone marrow]. [With] flow cytometry or next-generation sequencing, we’re able to look for MRD and see that not even 1 in 100,000 or 1 in 1 million [myeloma cells] are there.

What are the prognostic factors that are being used to direct treatment?

In these patients, the depth of response is so deep that [you can predict if] they’re likely to do well. [If a patient is maintained on maintenance therapy] for 3 years, the prognosis is very good. At 5 years, the patients are probably cured. One of the goals when you start treating a patient with newly diagnosed disease is to keep them in CR and achieve MRD negativity at 5 years.We talk about fluorescence in situ hybridization, cytogenetics, and the revised International Staging System, which has incorporated a patient’s genetics into the system. All of this is important. It helps you identify which patient is likely to run into trouble quickly, so you know to manage them more aggressively and evaluate them more frequently.

Technology has dramatically improved. Before we were doing bulk sequencing of all the tumor cells, as well as DNA and RNA sequencing of all the cells. Now, we can do it in individual cells; we can do single-cell RNA sequencing or DNA sequencing. That is important if you have to identify different clones, especially after a patient achieves remission. [Then, we can understand] what kind of cells are left behind, what kind of abnormalities there are, and how to get rid of them.

Also, we are now able to map the entire surrounding stromal cells and immune cells of the myeloma. Once we know what kind of immune cells are there, whether they are turned off, whether their PD-1 is upregulated, or if their T cells are exhausted, we can use antibodies to stimulate these T cells to become functional, thereby eliminating the myeloma. All of this exciting research is now coming into the myeloma space.