Jagannath Shares Insight on Treatment Strategies in Relapsed/Refractory Myeloma

Sundar Jagannath, MBBS

The relapsed/refractory multiple myeloma space has seen the approvals of several novel agents and combination regimens within the past few years, ultimately leading to an increase in survival for a number of patients, explained Sundar Jagannath, MBBS.

But beyond the FDA-approved strategies, additional therapies are moving through the pipeline with hopes to improve outcomes even further.

“On the treatment side, there are exciting new therapies, especially immune-oncology [approaches] that include bispecific antibodies and CAR T-cell therapy,” said Jagannath, a professor of medicine, hematology, and medical oncology at the Tisch Cancer Institute, Mount Sinai School of Medicine.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Multiple Myeloma, Jagannath highlighted the current state of the relapsed/refractory multiple myeloma paradigm and research regarding next steps for advancing treatment.

OncLive: How would you describe the state of relapsed/refractory multiple myeloma treatment?

Jagannath: The way multiple myeloma is viewed and how it is managed is changing. There are dramatic changes that are happening in the understanding of the biology and management of the disease. On the biology side, because of next-generation sequencing, single-cell RNA and DNA sequencing, time-of-flight mass cytometry, and other technologies, we are able to understand the disease much better.

More importantly, [it is useful to see] whether the cancer has been eradicated completely, what the depth of response is, and the assessment of the depth of response. Now, we are able to detect 1 in 1 million cancer cells that are still residing in the patient's bone marrow, or be able to detect the presence of circulating tumor cells, DNA from tumor cells, or even a very small amount of paraprotein made by the tumor cells in circulation.

These technologies have made sure that we eradicate the disease with the treatment available and [inform us] how long to treat the patient. This has improved the overall quality of life (QoL) for patients.

How have addition of proteasome inhibitors shaped treatment decisions?

Carfilzomib (Kyprolis) is a second-generation proteasome inhibitor. It is much more effective than bortezomib (Velcade) or ixazomib (Ninlaro) in improving the depth of response. Therefore, it is a very important addition to the treatment armamentarium. Whenever it is combined with other drugs, such as lenalidomide (Revlimid) or pomalidomide (Pomalyst), it is shown to improve the efficacy even further. This has become an important component in the combination treatment for [patients with] multiple myeloma.

What are your thoughts on the FDA’s decision to lift its partial clinical hold on venetoclax (Venclexta)?

I hope that venetoclax will play an important role for the management of multiple myeloma, especially patients who have t(11;14) and those who have high BCL-2 expression, because this is an oral agent. It is so easily administered with minimal adverse events (AEs) and it is able to get rid of the tumor cells effectively. I hope the [full] hold is lifted and venetoclax becomes available for investigation and treatment of patients with multiple myeloma.

Isatuximab is another agent of excitement in this space. What impact could it have?

Isatuximab is a monoclonal antibody against CD38. There is another anti-CD38 drug that is already commercially available, which is daratumumab (Darzalex), but isatuximab binds to a different part of CD38, so it actually has its own efficacy and clinical benefit. Additionally, its administration and toxicity profiles are slightly different than daratumumab. It is an important drug that needs to come into the treatment armamentarium of multiple myeloma.

You were a lead author on the phase IIb STORM trial. What are your thoughts now that selinexor (Xpovio) has been approved by the FDA?

I'm really excited that the FDA approved selinexor, because this is a first-in-class, new drug. We always want a drug approved, but coming from a completely different class is very important.

We used selinexor in patients who had already failed all other drugs. Not only was it effective in almost 26% of the patients, but a couple of patients went into complete remission and achieved minimal residual disease-negative status. For a small molecule agent to eradicate a tumor so completely, similar to CAR T-cell therapy, is mind boggling and impressive. Moreover, this is an orally administered drug, which makes it very easy for patients to take at home.

Additionally, the safety profile is also impressive. It has no organ, cardiac, liver, or renal toxicities, as well as no neuropathy. We were able to administer the drug very safely for these patients with advanced myeloma, who also have low platelet count and poor kidney function. The major AE that patients with myeloma have not experienced before is nausea, vomiting, and fatigue. Those are the major AEs, which affects QoL. However, oncologists have previously used drugs that cause nausea and vomiting, and there are very good regimens [that can prevent those AEs].

What does the future hold for immunomodulatory (IMiDs) agents?

We have all gotten used to IMiDs, which have almost become backbone drugs. For newly diagnosed patients, it is lenalidomide. For relapsed myeloma patients, it is pomalidomide. These 2 IMiD drugs are used in combination with a proteasome inhibitor and a monoclonal antibody. By nature, IMiD drugs increase T-cell function, but there is a new generation of CELMoDs. These are cereblon-active drugs, and they are much more potent—almost a thousand times more potent than lenalidomide or pomalidomide. These drugs are likely to play a major role.

What other research are you looking forward to seeing the results of this year?

[Following the approval of selinexor], we are looking at 2 classes of drugs that I am very excited about. They are dual[-targeting] antibodies with 2 specificities; one arm of the antibody binds to the cancer cell, and the other arm binds to CD3 or the T cells, bringing them together to wipe out the myeloma. This is a much more effective way of getting rid of the tumor cells. It is well tolerated, especially for older patients.

The other development is the generic modification of the patient's own T cells through gene therapy, in which CAR T-cell therapies are given to patients; these are programmed to wipe out the myeloma cells. [Some of those] patients [are able to go] into complete remission.

This has been shown in patients who have been treated with all of the available, FDA-approved agents and the cancer has progressed. This is still able to get rid of the cancer completely and, for some patients, these remissions have lasted more than 1 year. CAR T cells are very exciting and [they will] play a very important role; in the future, more and more patients with multiple myeloma will be cured.

How is Mount Sinai School of Medicine addressing personalized medicine in multiple myeloma?

We are excited about the personalized medicine that we employ in our hospital, especially patients [with multiple myeloma] who have failed multiple treatment options with their local oncologist. We take patients’ myeloma cells and do RNA sequencing; we do whole-genome sequencing and [look for] mutations by looking at the tumor microenvironment. We are able to come up with a treatment for these patients. Sometimes, we are able to use drugs that are approved for other cancers, but not for myeloma.

Yet, because the patient has that particular mutation or their RNA sequencing tells that a particular pathway is operating and the drug(s) will work, then we are able to procure the drug and get the patient into remission. I'm very excited about the personalized medicine [approach] we are able to employ for patients with relapsed/refractory myeloma at our center.