Novel Antibody-Based Approaches on Horizon in Multiple Myeloma

Hearn Jay Cho, MD, PhD, an associate professor of medicine, hematology and medical oncology at Mount Sinai Hospital

Hearn Jay Cho, MD, PhD

Emerging antibody-based approaches, such as antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and CAR T-cell therapies are inducing promising response rates in patients with multiple myeloma, said Hearn Jay Cho, MD, PhD.

“The concept [of ADCs] is that they act somewhat like a guided missile,” said Cho. “Monoclonal antibodies recognize targets on the surface of multiple myeloma cells and are directly conjugated to chemotherapeutic agents, which are then delivered directly to the myeloma cell by the antibody. The antibody delivers the chemotherapy payload directly to the myeloma cell where it exerts its killing effect.”

Beyond ADCs, BiTEs have also demonstrated potential in patients with multiple myeloma in early-phase trials, despite some toxicity concerns. CAR T-cell therapies have also generated excitement; emerging products such as bb2121 have shown promising antitumor activity and high response rates in myeloma, but further exploration is needed to determine how this approach can best be utilized to provide the most benefit.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Multiple Myeloma, Cho, an associate professor of medicine, hematology and medical oncology at Mount Sinai Hospital, provided background on these novel approaches, while highlighting exciting trials to look for in the future.

OncLive^®: What are some of the latest therapies under investigation in multiple myeloma?

Cho: [In my presentation], I discussed novel, antibody-based therapies for multiple myeloma. I chose to focus on two emerging technologies: antibody-drug conjugates and T-cell redirecting agents, also known as BiTEs.

Similar to ADCs, [BiTEs] have one antigen-recognizing site that sticks to targets on the surface of the myeloma cells. Importantly, they have a second antigen binding site, which is directed against the CD3 molecule. CD3 is part of the T-cell receptor complex expressed on T cells; these are the killing cells of the immune system. With these agents, one end sticks to the myeloma cell through their target—which is typically BCMA—and the other end sticks to the T cell and activates it at the same time. This process physically brings [the myeloma cell and the T cells] together; it activates the T cell and allows it to kill the myeloma cell.

Both classes of agents are currently in clinical trials for multiple myeloma. The ADC data that have been published thus far show that these agents have good, fairly high response rates, but they have unique toxicities that we have to be cognizant of, particularly toxicities of the eye. Similarly, early data with the bispecific agents are also very promising. They induce good response rates and the responses are very deep. However, there are also adverse events associated with these agents, such as cytokine release syndrome, which is typically characterized by an overactivation of the immune system. These are similar toxicities to what is seen with CAR T cells, for example. [These AEs] highlight the fact that we are manipulating the immune system with very powerful agents. These agents can have very profound effects, not only on the tumor cells, but on the patients.

What are some exciting trials exploring BiTEs in myeloma?

There are several different types of BiTEs currently under clinical investigation. The majority of these agents target BCMA, which is expressed in myeloma cells. Several of these drugs are advanced in clinical trials with completed phase I studies, and have very promising response rates and deep responses.

I would like to point out two agents that are currently in investigation. The first is a Janssen molecule that targets a protein called GPRC5D; it is uniquely, highly expressed in myeloma cells and one or two other tissues. This agent has shown very promising activity in early-phase clinical trials. We are expecting a report at the 2019 ASH Annual Meeting. It is an alternative to the BCMA-targeted strategies, which have been largely dominating the field.

The second is an agent produced by Glenmark Pharmaceuticals that targets CD38, which is also the target of daratumumab (Darzalex). Daratumumab is already approved in multiple myeloma. [With this agent], we are actually testing a principle that has not been deeply investigated yet: if a monoclonal antibody such as daratumumab is effective in CD38, will a bispecific agent, which then directs T cells to kill cells that are expressed in CD38, have similar or even greater effectiveness?

That is an important question to answer, because we often think of the target as just something that is decorating the surface of a myeloma cell, distinguishing it from other [proteins]. However, all of those proteins have a function; they do something. Myeloma cells are the malignant counterpart to plasma cells, which are a normal part of the immune system. It is possible that by interfering with the function of that target on myeloma cells, we may either increase or decrease the effectiveness of a therapy. It is important to see how these agents work, not only from their response rates and their depth of response, but also by doing correlative studies to understand how the immune system changes when these agents are used.

How could CAR T-cell therapies be used in myeloma? Specifically, what have we seen with bb2121?

There is a lot of enthusiasm for CAR T-cell therapy right now and it is certainly well-deserved. Many of the trials for these CAR T cells, particularly bluebird bio’s bb2121 and Janssen’s LCAR-B38M product, have demonstrated very high upfront response rates and very deep, fast responses. The experience with the CD19-targeted CAR T-cell products in acute lymphoblastic leukemia and non-Hodgkin lymphoma raises the possibility that these products may be curative. Certainly, in those diseases, there are subsets of patients who are cured by CAR T-cell therapy. It's really an open question as to whether that is going to be the case in multiple myeloma.

That idea highlights a different principle: we often consider CAR T cells as a class of therapy, but in reality, it's pretty clear that the CD19-directed products are very different from the BCMA- directed products. In the next couple of years, we are going to find out whether, for example, CD38-targeted CARs or GPRC5D-targeted CARs in myeloma are going to be different than BCMA-targeted CARs, because these different strategies target different targets on the immune cells. It would be probably more accurate to describe each CAR T cell as a class unto itself. You cannot necessarily extrapolate the results from the CD19-directed CARs to what is going to happen in multiple myeloma with the BCMA-directed CARs, the GPRC5D CARs or the CD38 CARs.

Again, this highlights the importance of doing correlative studies, because we need to understand not only the biology behind the disease, but also how the immune system responds to these very powerful immune-modulating technologies. By doing that, even if a single-agent trial is not successful in resulting in long-term, disease-free remissions, we will better understand the biology of the agent. And, we may then be able to couple it or sequence it with another immune-acting agent to create conditions under which we can induce long-term, disease-free remissions. We are very excited because we now have the technology to do this type of analysis, along with clinical trials, to understand the biology in patients. We can take that information and use it to design the next generation of clinical trials.

Triplet and quadruplet regimens are also emerging. How might these approaches change practice?

This is an important topic because it's going to really test one of the guiding principles of oncology drug development up to this point: more is better. If you consider the history of chemotherapy—in cancer in general and in myeloma in particular—first, we had single-agent, conventional chemotherapy agents, such as melphalan. Then, with the advent of novel agents such as thalidomide (Thalomid) and lenalidomide (Revlimid), we had combinations with dexamethasone, and these were doublet therapies. Then, we had triplets with proteasome inhibitors, such as bortezomib (Velcade) and carfilzomib (Kyprolis). Now, the standard of care is triplet therapies with a proteasome inhibitor, typically with an immunomodulatory drug or possibly cyclophosphamide and dexamethasone.

There is a lot of interest in adding daratumumab to that mix. The early returns sound good. In phase I and phase II studies, there were reports of higher response rates and deeper responses compared with historic controls. In fact, at the 2019 ASCO Annual Meeting, early results were presented and they met their endpoint of higher minimal residual disease-negativity rates after induction chemotherapy. That was an important finding, but the real question is, “Will that translate to longer progression-free survival?” Is that going to result in patients who have durable disease-free remissions? At this point, I don’t necessarily know if that is going to be the case or not. It raises a real dilemma because daratumumab is one of our best agents for relapsed disease.

Several clinical trials have shown that combinations of daratumumab with lenalidomide, bortezomib, and now with pomalidomide (Pomalyst), have very high response rates, and a subset of patients have experienced very long responses. If patients receive daratumumab upfront and then they relapse, are they still going to have those results with daratumumab-based regimens? If the answer is “no,” then that takes away one of our best weapons for relapsed disease.

When you start talking about adding immunologic agents like daratumumab, that becomes a different thing because the “more is better” principle applies to the idea of trying to kill as many myeloma cells as you can with these toxins while minimizing the toxicity to normal tissue. You start adding agents, such as daratumumab or elotuzumab (Empliciti) and then CAR T cells, bispecifics, ADCs and so forth later on.

Now, you’re talking about manipulating the immune system. The immune system is a very delicately balanced system of “checks and balances” that ensure the right cells are killed and the wrong cells are not killed. When you start messing with that system—which we do all the time with approaches like chemotherapy—then putting those together with agents to fine-tune an immune response may not necessarily be the right thing to do.

Do we want to give these drugs all at the same time? One concept that should be tested in clinical investigation is sequencing. Does it make more sense if someone has recurring disease to give them triplet chemotherapy upfront to reduce the disease burden, but then stop that and give an immune-activating agent so the immune system can go in and mop up residual tumor cells? That is more like what happens in terms of immune response when you get a cold or have an infection. There is a sequence of events; it doesn't happen all at the same time.

How does the emergence of these new novel agents affect sequencing?

Everyone wants to get their drug upfront, but again, I don't necessarily believe it’s a foregone conclusion that [the up-front setting] will be the best place to use it. For example, daratumumab is a single agent and does remarkably well in patients with relapsed/refractory disease. There are data to suggest that if it’s moved earlier in treatment as a single agent, then it will have a somewhat higher response rate and depth of response. Although the data haven’t been presented yet, there is suspicion that, for example, if you were to extend that logic to clinical trials with daratumumab as a single agent in smoldering myeloma, then the response rate should be even higher in patients who are not symptomatic yet.

It's not clear to me whether that is going to be the case or not. When those data are presented, it will be very important to look for. The immune system doesn't necessarily want to see something that's like itself; it will ignore things that look too much like normal tissue. It may be that some of these immune-acting agents may be more effective against relapsed disease because that disease is going to be more clonally evolved and look different in comparison with a normal cell. Therefore, [the disease] would be more easily recognized by the immune system. As I said, it's not necessarily a foregone conclusion that this is the best thing to do, because it may not be as effective as it would be if you put it later in treatment.