Spotlighting New and Emerging Therapies in Myeloma

There is a lot of hype on T-cell engagers and CAR T-cell therapy, but there are other new and exciting immunotherapies in myeloma not talked about that may be approved in the near future, according to an expert.

There are many new emerging therapies and studies for treating myeloma in the pipeline that could accompany current treatments and provide better disease control, according to Dr. Cesar Rodriguez, associate professor of hematology and oncology and director of the myeloma and plasma cell disorder program at Wake Forest Organoid Research Center.

At CURE®’s Educated Patient® Multiple Myeloma Summit, Rodriguez explains in his presentation that there are a lot of drugs available for multiple myeloma that have been approved by the Food and Drug Administration (FDA). And in the past 15 years there has been more drugs developed and approved than ever before. Rodriguez notes that these new drugs are targeting specific parts of the cell which past drugs have not done.

“All of the immunotherapy and these new drugs that are being developed have the uniqueness that they're … focused on a particular pathway or a particular target or a particular protein in the cancer cell, but at the same time, most of them play not just with the cancer cell but it also helps modulate the immune system that can potentially help kill the cancer cell,” Rodriguez explained.

Celmods

Rodriguez explains celmods (or cereblon E3 ligase modulators) as following a recipe in the kitchen. He says, for a pasta sauce, if you add too much of one spice or ingredient, you can always fix it by adding more of another, but when baking cakes or cookies, you need to be following the recipe exactly because it’s not as easy to fix as the pasta sauce.

“Cells, in general, are not very good in following recipes to the dot and being … a baker that has to do the exact dosages of the substance … or ingredients they’re going to use to make the cake,” Rodriguez said. “Cells are more like a cook that’s trying to make a pasta, and they’ll put in the tomatoes and they’ll put in the pepper and the salt, but they are not going to be specifically focused on the doses or the quantities of each of these proteins.”

Cells are constantly making proteins to function and grow, and what protein they will need depends on where it is in its lifespan. Cells can adjust to certain proteins using mechanisms, or as Rodriguez called them “sous chefs”, based on what they need to survive or accomplish. The “sous chef” will also be able to get rid of excess proteins that are not needed in the cell at that time.

“The iberdomide and CC-92480 , which are the newer generations of (celmods) have the same ability to reprogram this system that is in charge of eliminating excess amount of proteins or proteins that are not needed at that time and reprogram it to try to kill and destroy the Ikaros/Aiolos proteins that are helping the myeloma cell survive,” Rodriguez explained.

These new celmods are targeting similar pathways as past ones, but Rodriguez says they will be more efficient, which will be more effective and do the job faster. He also notes they will be effective in those who were resistant to past celmods such as Revlimid (lenalidomide) and Pomalyst (pomalidomide).

In a phase 1b/2a study, of the 51 patients who received iberdomide with dexamethasone, 31% had more than a 50% reduction in their disease. “Having this efficacy with just two drugs is very promising,” Rodriguez said. Ongoing trials are assessing whether iberdomide in combination with other drugs can improve efficacy as well.

The other celmod Rodriguez talks about, CC-92480, resulted in 54% of patients showing a good response in a phase 1 study when combined with Ozurdex. There are ongoing trials of CC-92480 in combination with other drugs.

Checkpoint Inhibitors

Myeloma tends to “hide itself from the immune system because it knows that the immune system is going to want to kill it”, Rodriguez said. So, it will target and bind itself to PD-1, a receptor in the immune system, causing the immune system to “turn off” so it can survive.

“Now, checkpoint inhibitors are drugs that have been used in other types of cancers like lung cancers that have been very effective. We did try using it in myeloma years ago — about four to five years ago — and we didn't have a lot of success, and actually the FDA halted with this combination of drugs because we were having more people die from it than what we expected,” Rodriguez noted. “But now we've learned a little bit more about these checkpoint inhibitors and we're starting to do new studies combining this either as a single agent or in combination with other medications.”

There are several studies in progress researching Keytruda (pembrolizumab), Opdivo (nivolumab), ciforadenant and Tecentriq (atezolizumab).

Monoclonal Antibodies

Monoclonal antibodies, as Rodriguez explained are proteins infused into a patient with the ability to attach to cancer cells and have them destroyed by the immune system.

Rodriguez pointed out that agents including Darzalex (daratumumab), Empliciti (elotuzumab) and Sarclisa (isatuximab) have already been FDA approved and are being used in the clinic. There are trials studying several other forms of monoclonal antibodies, some of which are currently enrolling patients.

Antibody-drug conjugants are similar to monoclonal antibodies, but once these proteins bind to the cancer cell, they release a drug to destroy them. Rodriguez described it as “a very, very personalized delivery service or a mailman service that's going to deliver it to the house that you wanted to take it to — in this case the cancer cells — and then deliver that drug or payload into the cell so it can kill it quickly.”

The only agent approved for myeloma right now is Blenrep (belantamab mafodotin), although several drugs are being investigated and currently enrolling patients.

Vaccines

Rodriguez explained that the first generation of vaccines were not effective and didn’t have a control over the disease, although he mentions that they have learned a lot from that first generation.

“We've learned a lot from the first generation of vaccines, and we have seen that vaccines have not been ideal to target a lot of tumor burden, but they are a good option to try to contain a small amount of disease or to try to prevent small amounts of disease from growing and trying to target it,” Rodriguez said. “So, using them early on like smoldering myeloma or even potential high-risk (monoclonal gammopathy of undetermined significance) is maybe in the future, or using it once somebody gets treated and achieves a good response to try to eliminate it or prevent it from coming back has been the focus of these studies.”

Researchers of a phase 2 study are currently investigating a vaccine, BMT-CTN1401, with Revlimid as post-transplant maintenance to achieve or maintain remission. There are also two other vaccines under study right now in phase 1 and 2 studies.

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