Hearn Jay Cho, MD, PhD, associate professor of medicine, Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, discusses investigational bispecific T-cell engager (BiTE) therapies in multiple myeloma.

There are several BiTEs under clinical investigation, says Cho. Although the majority of these agents target BCMA, there is a molecule that is being developed by Janssen Pharmaceuticals that targets GPRC5D, which is highly expressed in myeloma cells. The agent has shown very promising activity in early-phase clinical trials, says Cho, and more data are anticipated at the 2019 ASH Annual Meeting.

Another agent is being developed by Glenmark Pharmaceuticals and targets CD38, which is also the target of daratumumab (Darzalex). The theory was that if a monoclonal antibody like daratumumab is effective in targeting CD38, a bispecific agent, that directs T cells to kill cells that are expressed in CD38 could have comparable or superior activity, concludes Cho.

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Hearn Jay Cho, MD, PhD, discusses investigational bispecific T-cell engager therapies in multiple myeloma.

Dr. Cho on Investigational BiTE Therapies in Multiple Myeloma

Hearn Jay Cho, MD, PhD, associate professor of medicine, Hematology/Oncology, Icahn School of Medicine, Mount Sinai Hospital, discusses promising combinations in multiple myeloma.

There are several trials combining daratumumab (Darzalex) with immune checkpoint inhibitors, says Cho. Preliminary analyses have shown promising activity with this approach. However, these are early-phase trials that are not powered for efficacy, he cautions. If these combinations turn out to be effective, it will be important to understand what their efficacy is relative to other daratumumab combinations, as many daratumumab-based combinations show excellent response rates in long-term follow-up. Examples of this include the combination of daratumumab with pomalidomide (Pomalyst) and dexamethasone or lenalidomide (Revlimid) and dexamethasone.

However, some patients cannot tolerate these agents—particularly older patients or those who have received a lot of prior therapy. If a noncytotoxic-based regimen&mdash;such as an all immunotherapy-based regimen&mdash;becomes available to these patients, it will be an important addition to the armamentarium, says Cho.

Dr. Cho on Promising Combinations in Multiple Myeloma

Hearn Jay Cho, MD, PhD, associate professor of medicine, Hematology/Oncology, Icahn School of Medicine, Mount Sinai Hospital, discusses the role of bispecific agents in the treatment of patients with myeloma.

Bispecific agents are interesting because early efficacy data have been comparable to those seen with chimeric antigen receptor (CAR) T-cell therapy; however, Cho says, this class of drugs is more easily administered than CAR T cells. All of these T-cell—directed therapies—bispecific agents, CAR T cells, and engineered T-cell receptors&mdash;are similar in that they are testing the theory of whether a genetically modified T cell can have a similar effect to that seen with a naturally produced T cell directed towards an antigen expressed in the tumor cell.

Broadly speaking, antitumor immunity is trying to hijack natural antivirus immune response and redirect that response towards eliminating tumor cells. The challenge is to understand whether engineering a T cell with an artificial receptor or artificially bringing it together externally with a bispecific agent is going to be equivalent to that natural immune response. This is a very important area of research, Cho says, and understanding the mechanism of action becomes key.

Dr. Cho Discusses Role of Bispecific Agents in Myeloma

Hearn Jay Cho, MD, PhD, associate professor of medicine, Hematology/Oncology, Icahn School of Medicine, Mount Sinai Hospital, discusses current and emerging targets for immunotherapy in the treatment of patients with multiple myeloma.

There are currently 2 FDA approved monoclonal antibodies in this space: daratumumab (Darzalex), which targets CD38, and elotuzumab (Empliciti), which targets SLAMF7, says Cho. Both of these immunotherapy agents, particularly when used in combination with lenalidomide (Lenvima) and pomalidomide (Pomalyst)-based regimens, have shown impressive response rates.

BCMA is another significant target in multiple myeloma with several corresponding antibody-based therapies similar to chimeric antigen receptor T-cell therapies. These agents, specifically BCMA antibody-drug conjugates and bispecific agents, have shown promising response data in early-phase clinical trials.

Additionally, there are several other targets and drugs under clinical investigation, Cho says. In particular, researchers are looking at different strategies for targeting CD38 and CD138. Although it’s unclear whether there’s a superior target in multiple myeloma, Cho notes that there’s a clear interest in BCMA, and that it will be interesting to see how that research pans out.

Hearn Jay Cho, MD, PhD, associate professor of medicine, Hematology/Oncology, Icahn School of Medicine, Mount Sinai Hospital, discusses current and emerging targets for immunotherapy in the treatment of patients with multiple myeloma.


Dr. Cho on Targets for Immunotherapy in Multiple Myeloma

Hearn Jay Cho, MD, PhD, associate professor of medicine, Hematology/Oncology, Icahn School of Medicine, Mount Sinai Hospital, discusses ongoing research with checkpoint inhibitors in multiple myeloma.

In the interim analyses of studies evaluating pembrolizumab (Keytruda) combinations, it was noted that there were higher numbers of deaths in the experimental arms than in the control arms, states Cho. Those in the experimental arms were either treated with a combination of pembrolizumab and pomalidomide (Pomalyst) or lenalidomide (Revlimid) and dexamethasone, while those in the control arm received either pomalidomide and dexamethasone or lenalidomide and dexamethasone. Some expressed concern that these deaths were due to immune-related adverse events. Moreover, there did not appear to be a survival difference between the experimental arm and the control arm.

These trials were only partially accrued at the time that these interim analyses were done, says Cho. Subsequent review of the data revealed that there were some potential imbalances in the patient arms because the trials had yet to fully accrue. Nonetheless, the FDA halted the trials for review, and subsequently, sponsors closed the trials. However, based on the phase I/II trials, there appears to be activity with these agents that warrant further investigation, says Cho.

Dr. Cho on Ongoing Research With Checkpoint Inhibitors in Myeloma

Hearn Jay Cho, MD, PhD, associate professor of medicine, Hematology/Oncology, Icahn School of Medicine, Mount Sinai Hospital, discusses the knowledge deficit in multiple myeloma.

The biggest deficit is in our understanding of a drug’s mechanism of action, explains Cho. For example, elotuzumab (Empliciti) and daratumumab (Darzalex) were initially thought to be targeting antibodies. It is now known that these agents have activities beyond their ability to code the tumor cell.

These agents have a big impact on immunity, particularly antitumor immunity; the molecules that these agents target—CD38 and SLAMF7&mdash;have immunologic functions. However, their precise mechanism of action still needs to be understood in order to know what the contribution of the targeting antibody function is. Understanding the mechanisms of these agents can be used to inform how to logically combine them. That's the knowledge deficit that needs to be filled right now, states Cho.

Hearn Jay Cho, MD, PhD

Articles

Dr. Cho on Investigational BiTE Therapies in Multiple Myeloma

Dr. Cho on Promising Combinations in Multiple Myeloma

Dr. Cho Discusses Role of Bispecific Agents in Myeloma

Dr. Cho on Targets for Immunotherapy in Multiple Myeloma

Dr. Cho on Ongoing Research With Checkpoint Inhibitors in Myeloma

Dr. Cho on the Knowledge Deficit in Multiple Myeloma