Classes of Immunotherapy Under Investigation in Multiple Myeloma

Hearn Jay Cho, MD, PhD

In 2017, the FDA halted trials examining checkpoint inhibitors in multiple myeloma due to excess toxicity, which left an unclear role for this class of agents in this disease.

Now, there are 3 classes of immunotherapy under investigation in myeloma: checkpoint inhibitors, antibody-drug conjugates (ADCs), and bispecific T-cell engagers (BiTEs), said Hearn Jay Cho, MD, PhD. He added that the mechanism of action of these drugs and optimal combinations need to be better understood to improve outcomes.

“If we understand the mechanisms of these agents, we could understand how to logically combine them. To make real, rationale combinations of immune therapies, we have to know what they're doing. That's the knowledge deficit that needs to be filled right now,” said Cho.

OncLive: What types of immunotherapy are being investigated?

Trials with checkpoint inhibitors were halted due to safety data. Will they undergo further investigation?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Multiple Myeloma, which was held ahead of the 2018 ASH Annual Meeting, Cho, associate professor of Medicine, Hematology/Oncology, Mount Sinai Hospital, discussed these classes of immunotherapy under investigation in multiple myeloma.Cho: I covered 3 classes of immunotherapies. The first class is checkpoint inhibitors. These have already been approved for patients with solid tumors and classical Hodgkin lymphoma. The second class are ADCs, which are combinations of tumor-targeting antibodies with chemotherapy agents. The third are bispecific engineered agents. These are derivatives of antibodies that bring T cells together with tumor cells, thereby activating the T cells.In the interim analysis of the studies with pembrolizumab (Keytruda), it was noted that there were higher numbers of deaths in the experimental arm than in the control arm. The experimental arm consisted of a combination of pembrolizumab and pomalidomide (Pomalyst) or lenalidomide (Revlimid) and dexamethasone. The control arm was either pomalidomide and dexamethasone or lenalidomide and dexamethasone. The concern was that these deaths were due to immune-related adverse events, which is a known risk of checkpoint inhibitor therapy. The other concern was that there did not appear to be a survival difference between the experimental arm and the control arm.

These trials were only about 50% to two-thirds accrued at the time that these interim analyses were done. After reviewing the data, it was noted that there were some potential imbalances in the patient arms [because the trial had yet to fully accrue]. This was in terms of patient age, comorbidities, or prior lines of therapy. Nevertheless, it was prudent of the FDA to halt these trials for review. I don't necessarily agree with the decision by the sponsors to terminate the trials. [I think that’s] premature. It's fairly clear from the phase I/II trials that there was activity with these agents. It's pretty clear that immunotherapies are effective in multiple myeloma. We should have as many tools available to us as possible as long as they can be safely applied.

What are some potential targets under development?

Ongoing studies are investigating combination therapy. We're combining things like daratumumab (Darzalex) with immune checkpoint inhibitors. Current clinical trials include nivolumab (Opdivo) and atezolizumab (Tecentriq), which are both FDA approved for certain solid tumor [indications]. It's important that we continue this line of work under appropriate safety review in order to find what the role for these powerful immunotherapy agents will be.There are 2 FDA-approved monoclonal antibodies for myeloma; one is targeting CD38, which is daratumumab. The other is targeting SLAMF7, which is elotuzumab (Empliciti). Both of these agents, particularly in combination, show excellent responses and long-term follow-up data. There are a number of antibody-based therapies targeting BCMA, similar to the chimeric antigen receptor (CAR) T-cell therapies. Some of these have shown excellent activity.

Are there any promising combinations you are particularly excited about?

The BCMA ADCs and the BCMA BiTEs have shown very promising responses, especially in early-phase clinical trials. There are a number of other targets that are under investigation. There are different strategies targeting CD38, as well as strategies targeting CD138, which is a common immunophenotypic of multiple myeloma. It's not clear whether there's a "best target" right now. It's pretty apparent that there's a lot of interest in BCMA, so we'll see how those agents pan out.There are trials combining daratumumab with immune checkpoint inhibitors. We're not including immunomodulatory (IMiD) agents or cytotoxic drugs in these combinations. There's a clear response, but these are early-phase trials that are not powered for efficacy. If these combinations turn out to be effective, it's important to understand what their efficacy is relative to other daratumumab combinations. For example, daratumumab combined with pomalidomide and dexamethasone or lenalidomide and dexamethasone shows excellent response rates and long-term follow-up.

However, there are patients who cannot tolerate these agents, particularly older patients, or those who have had a lot of prior therapy. If we had a noncytotoxic-based regimen—such as an all immunotherapy-based regimen—available to these patients, that would be an important addition to our armamentarium. I'm very encouraged about those types of combinations.

Understanding how we can combine immunotherapies with cytotoxic agents is a critical question. The historical trend for combination therapies is if you find an effective agent, you combine it with other effective and approved agents. That sort of “kitchen sink” approach tends to work best with cytotoxic drugs. When you talk about immunotherapy agents, it doesn't necessarily follow that we should be combining these agents. A number of cytotoxic agents are known to suppress T-cell activity. Giving something that's going to activate T cells at the same time you're giving chemotherapy may not be the logical approach.

What is the future of checkpoint inhibitors?

Another important idea that should be entering clinical trials is sequencing. Instead of giving everything all the time, you may want to give one set of drugs to induce immunogenic cell death, then follow that with an immunologic agent to potentiate or expand T cells that recognize tumors. That's going to be an important next step in understanding how to combine immunotherapy.The majority of clinical trials, particularly in combination with IMiDs, have been halted. That doesn't mean there's no room for them. There are a few ongoing clinical trials for checkpoint inhibitors in myeloma. The hope is that those results will justify going to phase II and phase III studies with combinations that don't necessarily contain IMiDs.

What is the biggest challenge in making headway in this space?

The other thing to consider is whether there's going to be an application in patients who don't have other options. In other words, can you take the combination of an immune checkpoint inhibitor and a low-dose IMiD in patients who have failed all other therapies. For example, they've failed proteasome inhibitors, IMiDs, and daratumumab. For those patients whose other choices may be something like a CAR T-cell therapy or another BCMA agent, would it be possible to apply judicious combinations of checkpoint inhibitors and IMiD drugs or other agents to induce remission? That's a viable path to understanding the role of these agents.The biggest thing is understanding mechanism of action. Both elotuzumab and daratumumab were initially thought to be targeting antibodies. As antibodies, they coded the tumor cell, then the fragment crystallizable portion of those antibodies attracted natural killer/T cells and allowed them to kill the tumor cells. It's pretty clear that both of these agents have other activities aside from their ability to code the tumor cell.

The molecules that they target—–CD38 and SLAMF7––have immunologic functions. SLAMF7 is an NK-cell activating molecule. CD38 is part of the adenosine ectoenzyme chain. These have functions that have profound effects on immunity, in particular antitumor immunity. We need to understand the precise mechanism of action to know what the contribution of the targeting antibody function is. What is the contribution of the inhibitory function or activating function of these antibodies when they attach to their targets?

What is coming in the future that you are excited about?

Checkpoint inhibitors are well established in a number of solid tumor indications. Even at that level, a number of investigators have expressed frustration after the initial success of those agents because they haven't been able to move the needle further. They've been combining them with cytotoxic agents or other immune stimulating agents, and they're not seeing increased response rates and overall survival. That tells us that we really don't understand at a very granular level what these agents are doing. That's the most important area of development in this field. A number of investigators are working to understand what these agents are doing at a cellular and molecular level.The bispecific agents are very interesting because we're seeing efficacy data that’s quite comparable to therapies like CAR T cells. Moreover, delivering them is much more straightforward. All of these T-cell directed agents, including engineered CAR T cells, bispecific agents, and engineered T-cell receptor T cells are testing the theory of whether manipulating T cells externally or internally will replicate the result of a naturally produced T cell that goes after an antigen expressed in the cell.

In a very broad sense, antitumor immunity is trying to replicate the antivirus immune response and redirect that towards recognizing and killing tumor cells. The challenge is to understand whether engineering a T cell with an artificial receptor or bringing it together externally with a bispecific agent is going to be equivalent to that type of natural immune response. That's a very important area of research.