Dr. C. Ola Landgren on Quadruple Therapies and the Future of Multiple Myeloma Treatment

Article Summary
  • Patients with newly diagnosed multiple myeloma are increasingly being treated with a four-part drug combination that includes a new immunotherapy agent.
  • Researchers are continually evaluating how to best combine old and new drugs to achieve durable, long-lasting responses.
  • Sylvester researcher C. Ola Landgren, M.D., Ph.D., will present an overview of new studies and the state of the field at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO).

The treatment landscape for multiple myeloma, the second most common blood cancer, is shifting rapidly.

Over the last decade, options have evolved from double to triple to quadruple combination therapies. What do these new options mean for patients and how will treatment change in the future?

C. Ola Landgren, M.D., Ph.D., will address these questions and more June 3 at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO). He was tapped to discuss new studies on combination therapies and provide his perspective on the field for the audience of scientists and physicians.

“These are great improvements for patients and they deliver deep responses,” said Dr. Landgren, who serves as chief of the Myeloma Division and director of the Myeloma Research Institute at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine.

Sylvester Comprehensive Cancer Center physician-scientist C. Ola Landgren in his white coat.
Dr. C. Ola Landgren

We sat down with Dr. Landgren to discuss the ASCO talk he will deliver at the session: “The More the Better? Quadruple Therapy in Newly Diagnosed Myeloma.”

Below are highlights from our conversation. The interview was lightly edited for brevity and clarity.

Can you speak about the honor of being chosen as a discussant for a key session at ASCO?

First off, it gives me an opportunity to further educate myself, because I have to spend a lot of time reading. I always read to try to stay on top of what’s going on in the field. I talk to colleagues every week around the world and I communicate a lot with other researchers. But being a discussant at ASCO gives me an extra reason to drill deep into to these questions and to put everything into perspective, and that’s something I really enjoy.

What is quadruple therapy in the setting of newly diagnosed multiple myeloma?

Quadruple therapy means that you typically add a monoclonal antibody drug—currently that means a CD38-targeted antibody—to the backbone of small molecule drugs standardly used to treat patients. The backbone typically consists of a proteasome inhibitor, which targets the cell’s protein degradation machinery, an immunomodulatory drug and a steroid. The CD38-targeted monoclonal antibodies are immunotherapies designed to identify myeloma cells by binding to a cell surface protein (i.e., CD38) expressed on them.

Your discussion will highlight three studies being presented at the ASCO session, as well as previous studies. What are they focused on?

The studies are testing the hypothesis that the addition of an antibody will provide deeper responses in more patients and a longer duration of the clinical benefit of progression-free and overall survival. The implications are that patients can live longer without having the disease come back and live longer overall.

How might quadruple therapy change treatment in the long term?

It could have additional implications beyond the clinical outcomes and impact how we use other therapies. People have been thinking, do you need to transplant every patient who is fit and young? Do you need to transplant patients if you have already delivered these four drugs and there is no detectable disease? These are very relevant clinical questions. I think that many patients probably don’t need a transplant. Ongoing studies are looking into that and other related questions.

We are already seeing that immunotherapies can narrow the gap between younger, fit patients and older patients. In the past, only younger, fit patients could benefit from the most effective treatment options because those therapies typically had more severe adverse event profiles. The introduction of immunotherapy has changed that paradigm by being both effective and tolerable. More older patients can now actually tolerate effective therapies.

Going forward, researchers are also already evaluating how to incorporate newer, “bispecific” monoclonal antibody immunotherapies, which target cell surface proteins such as BCMA, GPRC5D and FcRH5.

Tell us more about potentially reducing the need for bone marrow and stem cell transplantation.

There are a lot of clinical trials trying to look into this, and we’re leading one of those trials at the University of Miami, the ADVANCE trial. It’s also possible that in the future, some patients may have CAR T-cell therapy instead of transplants. And we are just about to open a new study using a fixed duration of bispecific monoclonal antibodies instead of transplants. These are questions that are now coming up.

Not all patients who might benefit from the newer drugs are currently being treated. Can you speak more about this?

When looking at variations in treatment strategies within the U.S. and internationally, key factors are access to newer drugs as well as treatment traditions. For instance, not all drugs are available in all countries outside the U.S., and within the U.S., some physicians are early adopters while others are slower to update and change treatment strategies. Myeloma experts who treat large numbers of patients may feel more comfortable implementing newer strategies sooner compared to a more general hematology/oncology physician who primarily sees solid tumors and only treats a handful of new multiple myeloma patients every year.

We are collaborating with many general hematology/oncology physicians, and we are happy to share our experiences and strategies. It is all about teamwork, to better help patients with multiple myeloma.

Please tell us a little bit about the future of precision medicine, quadruple therapy and newer, sensitive measurements to detect small numbers of patient tumor cells.

We can now detect patient tumor cells with sensitive tests for minimal residual disease (MRD). Based on available data, you can achieve MRD negativity quite early on with quadruple therapy. These drugs can deliver deep responses early on. We can use MRD as a measurement to assess patient response and guide the course of treatment. We recently published a study identifying patient genomic and immune signatures that correlate with MRD-negativity and clinical outcomes after quadruple therapy. These kinds of approaches will help us pick the right therapy for each individual patient.

MRD is an area we have studied for over a decade and it will also speed up the development of new therapies. A key FDA committee recently voted to allow MRD as an early regulatory endpoint for accelerated approval in multiple myeloma, based in part on our analysis.

What are some of the key studies opening up the field of quadruple therapy?

Between 2019 and 2021, researchers published key clinical trials, including CASSIOPEIA, GRIFFIN, and MANHATTAN, which I led with my colleagues. In December, researchers published the phase 3 PERSEUS trial. All these studies used a CD38-targeted monoclonal antibody called daratumumab, but the drugs chosen for the backbone varied in the studies. The GMMG-CONCEPT and IsKia trials assessed another CD38-targeted monoclonal antibody, isatuximab. There are other trials as well.

What more will the audience get out of the session you are leading?

They will hear about different types of antibodies for CD38-targeted approaches. Daratumumab was the first approved antibody in this class, and now there is isatuximab—in some ways, it’s almost like the difference between Pepsi and Coca-Cola.

You will also hear updated information on the PERSEUS study, particularly focusing on MRD. That’s a very hot topic. You will hear how this all comes together with the different antibodies added to the backbones and how this translates into MRD-negativity and patient clinical outcomes. This is where the field is right now. The future is looking bright for patients with multiple myeloma.

Tags: ASCO, ASCO 2024, Dr. C. Ola Landgren, multiple myeloma, Sylvester Comprehensive Cancer Center