THE FUTURE OF BsAbs IN MM

Pfizer host:
Dr. Erinn Goldman

Welcome to Pfizer’s first Twitter Spaces event in a series about multiple myeloma.

Before we get started, I want to remind our audience that this Twitter Spaces event is for US healthcare professionals only. Our panelist is not being compensated, and this activity is not certified for continuing medical education.

I’m Dr. Erinn Goldman, a Medical Director in the multiple myeloma group at Pfizer. I’m excited to start our conversation today about unmet needs and emerging innovations in multiple myeloma.

Here with me to explore these topics is Dr. Joseph Mikhael, the Chief Medical Officer of the International Myeloma Foundation and professor at the Translational Genomics Research Institute. Thank you for joining us, Dr. Mikhael.

Dr. Joseph Mikhael

Thanks so much for having me, Dr. Goldman. I’m looking forward to sharing more about my experience treating patients and what I’m most excited about as we look toward the future of treatment of multiple myeloma.

Dr. Goldman

Great—well, let’s get started then. As you know, multiple myeloma is a very aggressive blood cancer and it’s currently incurable. In the US alone, it’s estimated that there will be more than 34,000 new cases in 2022. Could you tell us more about the expected prognosis for these patients, Dr. Mikhael?

Dr. Mikhael

Absolutely, happy to do so. You know, according to the SEER data, the 5-year relative survival rate for patients with multiple myeloma is approximately 58%, although, you know, in my experience, outcomes have been improving with newer treatments and management approaches. Most patients now receive 4 or more different lines of therapy throughout their disease, although survival decreases with each line of therapy. While there are several approved drugs, the unmet need remains substantial. This unmet need is often more pronounced in certain vulnerable populations, such as the African American population, where multiple myeloma is twice as common compared to other groups.

Dr. Goldman

Wow. Well, moving further, can you tell us a little bit about the patients you treat with relapsed refractory multiple myeloma? What types of experiences do they have and what’s their journey like?

Dr. Mikhael

Absolutely. The patients I see face a lot of challenges related to the disease and its treatment, including treatment side effects that can reduce quality of life; the challenges of the disease and symptoms, like organ damage; and the ongoing strain of financial burden, logistics, and care partner support. As the disease becomes more resistant, the uncertainty, the fear of relapse, and the subsequent decrease in treatment options may also impose a huge emotional burden on our patients.

Dr. Goldman

Wow, there are just so many things for patients and loved ones to manage and think about. What criteria do you consider when you’re choosing a treatment pathway for a patient with relapsed refractory multiple myeloma?

Dr. Mikhael

It’s very complex. There are many considerations when selecting treatment, including patient characteristics, such as age and comorbidities and performance status. There’s also the nature of the relapse: I look whether it’s biochemical, indolent, or an aggressive clinical relapse. And then the timing of the relapse. Is it early or late after the prior therapy?

Dr. Goldman

That’s a lot. Is there anything else you consider when evaluating treatment options?

Dr. Mikhael

Absolutely. We also have to review the previous toxicities and responses to the prior treatments. Treatment sequencing, including prior transplant, the patient preferences, and quality of life are all considered.

Dr. Goldman

That sounds like a complicated process and one that I imagine becomes increasingly challenging as patients relapse and have fewer options available.

Dr. Mikhael

Yeah, absolutely. Patients with relapsed refractory multiple myeloma sadly inevitably relapse, and each relapse results in increased risk of treatment resistance, progressively shorter remissions, and diminished responses to those subsequent therapies. And that is why there is a need for therapies that can provide both deep and durable responses and improve quality of life in patients with multiple myeloma.

Dr. Goldman

Speaking of that need, Dr. Mikhael, what are some of the most promising areas of development and innovation in the space?

Dr. Mikhael

You know, I think immunotherapies, in particular CAR T-cell therapies and bispecific antibodies, are an exciting area of development for a whole host of reasons. You know, immune dysfunction is present throughout the course of relapsed multiple myeloma. Myeloma cells, together with their bone marrow microenvironment, express coinhibitory molecules and immunosuppressive cytokines, leading to that immune dysfunction. There are several surface antigens that are now being investigated as potential immunotherapeutic targets, including FcRH5, GPRC5D, as well as B-cell maturation antigen, or BCMA. BCMA is a tumor-associated antigen that is universally present on plasma cells and expressed at higher levels on malignant plasma cells when compared to nonmalignant cells.

Dr. Goldman

BCMA is quickly becoming an important part of the conversation. Can you tell us more about why BCMA is a promising target in multiple myeloma?

Dr. Mikhael

Absolutely. In addition to what I’ve shared, the selective expression of BCMA on mature B-cells and the overexpression on malignant myeloma cells may enable its selective targeting in myeloma therapy. That’s why it’s a target for existing and future treatment options in the development for multiple myeloma. BCMA-directed therapies have reported promising response rates in disease that have been refractory to standard therapies. And now there are 3 different immunotherapeutic approaches targeting BCMA that are either approved or in development: antibody-drug conjugates, known as ADCs; chimeric antigen receptor T-cell therapies, or CAR-Ts; and bispecific antibodies.

Dr. Goldman

This is really interesting. Can you elaborate on these 3 different BCMA-directed treatment approaches, Dr. Mikhael?

Dr. Mikhael

Yeah, absolutely. Let’s start with the ADCs, the antibody-drug conjugates. These are composed of an antibody and a cytotoxic chemotherapy compound. So BCMA-targeting ADCs bind to the BCMA on the surface of the myeloma cells, and upon that binding, the ADCs are internalized, leading to the release of toxic payload and inducing selective cell death. ADCs are readily available therapies. They do not require patient-specific manufacturing. And ADCs are administered intravenously until disease progression.

Dr. Goldman

I see. What about CAR-Ts?

Dr. Mikhael

Well, BCMA-directed CAR-Ts are T-cells that are genetically modified to express a receptor that binds to BCMA on multiple myeloma cells. Upon binding, a T-cell activation occurs, initiating cellular lysis and myeloma cell death. To manufacture these autologous CAR T-cells, T-cells are collected from the patient via leukapheresis; modified to express that CAR, that chimeric antigen receptor; and expanded ex vivo. Patients can receive bridging therapy to help maintain disease control before the CAR-Ts are then ready to be infused back into the patient. CAR T-cells are administered as a one-time intravenous dose.

Dr. Goldman

Interesting. Can we now talk a little more about bispecific antibodies and how that mechanism works?

Dr. Mikhael

Sure, absolutely. So bispecific antibodies are engineered to have a dual antigen specificity to facilitate cell-to-cell interactions between T-cells and the malignant cells that are expressing that tumor-associated antigens, such as BCMA. They can be designed to target BCMA and T-cells simultaneously and have the potential to function as tumor-recognizing immune enhancers. And importantly, they’re designed to bring T-cells into close proximity to the myeloma cell, leading to T-cell activation and the antitumor response.

Dr. Goldman

Dr. Mikhael, can you also explain to our audience how these bispecific antibodies would be administered?

Dr. Mikhael

Yes, so they’re being investigated both as subcutaneous and intravenous administrations and are intended to be administered until disease progression. And they could be an off-the-shelf option that can readily be available to patients without the requirement of patient-specific manufacturing.

Dr. Goldman

That’s great. I think we have time for one more question, and I want to end on a hopeful note. What makes you optimistic about the future for patients with multiple myeloma?

Dr. Mikhael

That’s a great question, Erinn, and I appreciate it. And I’m excited about the multitude of therapies that are becoming available to us that have multiple ways of engaging the immune system and multiple targets for patients—especially as we now consider the potential ability to use those earlier in the disease course.

Dr. Goldman

That’s great. That’s really important. Thank you so much, and thank you all for joining us today. This has been a wonderful conversation, and I hope you’ve all learned something new. I know I have.

A big thank-you to Dr. Joseph Mikhael. I appreciate you sharing your knowledge about multiple myeloma and these promising potential treatment modalities.

Dr. Mikhael

It’s my pleasure, Erinn. It’s always a pleasure to chat with you, and I really appreciate you inviting me to the program today, and I do want to close just quickly reminding our audience that there are many helpful resources for healthcare professionals that can be found at the International Myeloma Foundation website at myeloma.org.

Dr. Goldman

That’s great. Thank you for that, Dr. Mikhael, and as a final reminder, this Twitter Spaces event is for US healthcare professionals only. Our panelist is not being compensated, and this activity is not certified for continuing medical education.