Winship has enrolled the first patients in two Phase 1 multiple myeloma trials that could advance research and expand future treatment options using novel immune-based and targeted therapies.
Winship Cancer Institute of Emory University is leading the way on two new studies aimed at offering people with multiple myeloma new treatment options and advancing the scientific understanding of the disease.
Winship has enrolled the first consented patient in Trilogy-2, a Phase 1b study evaluating JNJ-79635322, also called JNJ-5322, in combination with other myeloma treatments. Winship also has enrolled the first patient in the PF-07994525 study in adults with relapsed or refractory multiple myeloma who have received at least three previous lines of therapy and have exhausted appropriate established options.
“This was made possible given our Clinical Trials Office operations improvement and reduction in activation timelines, which allowed the studies to open more quickly, bringing these innovative treatments to patients,” says Ticiana Leal, MD, medical director of Winship’s Clinical Trials Office and professor and director of the Thoracic Medical Oncology Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine. “Trilogy-2 was activated in 81 days, well below our target timeframe, and the PF-07994525 study was activated in 126 days.”
Multiple myeloma is a cancer of plasma cells, immune cells that normally produce antibodies. Although treatment has improved dramatically, myeloma remains difficult to cure. The disease can vary considerably from one patient to another, and cancer cells may change over time, allowing them to escape therapies that once controlled them.
The two early-stage clinical trials are approaching this challenge from very different directions. TRILOGY-2 combines an innovative immune-based treatment with established myeloma drugs. C6331001 tests a drug designed to interfere with the internal machinery that helps myeloma cells survive.
TRILOGY-2: Directing the immune system at two targets
TRILOGY-2 includes people with newly diagnosed multiple myeloma as well as those whose disease has returned or stopped responding to treatment. Researchers plan to enroll approximately 240 participants.
JNJ-5322 is a “trispecific” antibody. Antibodies are proteins capable of recognizing particular markers, or targets, on cells. Most antibody drugs bind to one target. Bispecific antibodies bind to two. JNJ-5322 can bind to three: BCMA and GPRC5D, two proteins found on myeloma cells, and CD3, a protein on immune cells called T cells.
By connecting a T cell to two different targets on a myeloma cell, JNJ-5322 is intended to bring the immune system into close contact with the cancer and activate it to attack. Targeting both BCMA and GPRC5D may be especially important because myeloma cells are not identical. Some may have more of one target than the other, and cells can sometimes reduce or lose a target to escape treatment. Recognizing two myeloma markers could make that escape more difficult.
In TRILOGY-2, investigators are combining JNJ-5322 with daratumumab, with or without lenalidomide, or with pomalidomide. These drugs already play important roles in myeloma treatment. The central question is whether adding the trispecific antibody can produce a stronger or more durable response without causing unacceptable side effects.
Sagar Lonial MD, FACP, FASCO
“Combinations of treatments have been a key in cancer therapy since the 1960s when disease such as lymphoma were cured with combination therapy,” says Sagar Lonial MD, FACP, FASCO, Winship’s chief medical officer, chair and professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. “The HIV treatment revolution learned from cancer therapy to evolve towards combinations, and in myeloma, for the past 15 years at Emory we have strongly pushed the idea of combination therapy as it represents the best chance to eliminate or reduce cancer burden and offer dramatically changed outcomes.”
The study builds on encouraging early findings from a first-in-human trial of JNJ-5322 alone in heavily pretreated patients. Those results do not establish that the drug is safe and effective, but they supplied enough evidence to justify testing it in combinations and at additional stages of treatment.
For patients, the long-term promise is an “off-the-shelf” immune therapy that could attack a wider range of myeloma cells. Unlike personalized CAR T-cell therapy, an antibody does not have to be manufactured from an individual patient’s cells. If successful, such treatment might eventually be easier to provide and could potentially be introduced earlier in the course of the disease.
Ajay K. Nooka, MD, MPH, FACP
“As we move immunotherapy trials into the newly diagnosed myeloma space, our expectation is to attain the deepest remission measured as minimal residual disease (MRD) negativity, by leveraging the benefits of targeting multiple agents simultaneously,” says Ajay K. Nooka, MD, MPH, FACP, Winship’s associate director of clinical research and director of the Myeloma Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine. “If sustained MRD negativity is the path to cure in myeloma, these modern immune therapies will likely get us there sooner.”
Scientifically, TRILOGY-2 will help researchers learn whether simultaneously targeting BCMA and GPRC5D reduces treatment resistance, which drug partners work best with a trispecific antibody, and whether responses differ between newly diagnosed and previously treated patients. It will also generate important information about dosing and immune-related side effects, including cytokine-release syndrome and infections.
C6331001: Disrupting the program that sustains myeloma
The Phase 1 C6331001 study takes a different approach. It includes dose-escalation and dose-expansion stages designed to evaluate safety, side effects, drug behavior in the body and preliminary antitumor activity.
PF-07994525 is an oral small-molecule inhibitor of KAT2 lysine acetyltransferases. KAT2 enzymes help regulate transcription—the process cells use to turn genetic instructions on and off. Cancer cells can exploit these regulatory systems to maintain programs that promote abnormal growth and survival.
By inhibiting KAT2, PF-07994525 is intended to disrupt transcriptional programs on which myeloma cells depend. Rather than marking the cell for an immune attack, as JNJ-5322 does, it attempts to interfere with the cancer cell’s underlying biology.
This represents a potentially valuable new treatment class. Many patients eventually develop resistance after receiving proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, bispecific antibodies or CAR T-cell therapy. A medicine working through a substantially different mechanism might remain useful when myeloma no longer responds to those treatments. Its oral form could also prove convenient, although researchers must first establish a safe dose and determine whether the drug produces meaningful responses.
C6331001 could advance research even if its immediate patient benefit proves limited. By examining biological changes before and after treatment, investigators may learn which myelomas depend most heavily on KAT2, identify biomarkers predicting response and clarify how altered gene regulation contributes to drug resistance.
Lonial says,“Phase 1 studies in cancer are dramatically different now from 20 years ago. Not only do we expect responses and even remissions from Phase 1 studies, but we use this information to design the next generation of trials focused on curing more patients of their cancer.”
Both trials are in early development, so their promise should be viewed with appropriate caution. Their chief purpose is to establish safety, dosing and preliminary activity — not to prove that either strategy is better than standard treatment.
Nevertheless, together they illustrate the expanding scope of myeloma research: one mobilizes the immune system against three cancer targets, while the other attacks the molecular program sustaining the cancer. Each could open a new path toward more effective, durable and individualized therapy.