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Hello, I’m Dr Joshua Richter. I’m an associate professor of medicine at The Tisch Cancer Institute, Icahn School of Medicine, and the director of multiple myeloma at The Blavatnik Family Chelsea Medical Center at Mount Sinai. I will be discussing the current challenges for patients with multiple myeloma and sharing thoughts on treatment approaches for patients with relapsed/refractory disease.
What are some unmet needs for patients with relapsed/refractory multiple myeloma?
Multiple myeloma is considered an incurable disease, and relapse is unfortunately inevitable. With each relapse, the disease can become more resistant, and in turn subsequent treatments can have less deep—and therefore less durable—remissions. Throughout the disease course, most patients receive multiple lines of therapy, with not only the potential for progressive decline in clinical outcomes, but also worsening toxicities and diminishing quality of life. Toxicities can take many forms, from traditional disease and treatment-related adverse events to more global challenges such as financial, emotional, and spiritual burdens. The uncertainty, fear of relapse, and subsequent decrease in treatment options can take a considerable emotional toll. Therefore, there is a need for therapies that prolong treatment remission and maintain quality of life. New treatments, such as BCMA-directed therapies, are emerging in the clinic and have the potential of meaningful clinical responses in relapsed/refractory multiple myeloma.
How do you select a treatment approach for patients with relapsed/refractory multiple myeloma?
In multiple myeloma, the disease is complex, and the patients are diverse. As there are oftentimes multiple potential options for patients, I turn to 3 key factors that guide our treatment decisions: patient-related factors, disease-related factors,and treatment-related factors.
For patient-related factors, I typically take into account whether the patient is fit or frail, has significant comorbidities, or patient preferences. I consider whether the disease is undergoing a biochemical relapse or a clinical one, with new CRAB symptoms, whether the disease is growing fast and if there is extramedullary disease. And for treatment-related factors, I assess what therapies the patient has had before, how they responded, what they are refractory to, and what they have residual toxicities to.
Taking all this into consideration, these 3 key factors shape the current approach in selecting treatment for patients with relapsed/refractory multiple myeloma.
I hope this helps you further understand the challenges and ongoing needs of patients with multiple myeloma. I am excited for the new and emerging approaches in this field, such as BCMA-directed therapies. Thank you for joining us today and for caring for patients with multiple myeloma.
Hello, I’m Dr Ola Landgren. I'm chief of the Myeloma Division and leader of the Experimental Therapeutics Program at the Sylvester Comprehensive Cancer Center at the University of Miami. As a hematologist specializing in multiple myeloma, I'm excited to share recent developments in this therapeutic area.
Recently, there have been many treatment options becoming available in multiple myeloma. Unfortunately, we do not yet have an established curative approach for these patients. For patients who become refractory to existing treatments, new therapies are urgently needed, especially those with the potential to provide deep and durable responses.
B-cell maturation antigen, otherwise known as BCMA, has been identified as an important therapeutic target in multiple myeloma. BCMA is a type III transmembrane glycoprotein within the tumor necrosis factor receptor superfamily. It’s a tumor-associated antigen that is universally present in multiple myeloma and is expressed at higher levels on malignant plasma cells compared with normal plasma cells. Research into BCMA has led to the development of several BCMA-directed treatment modalities, both approved and experimental, including antibody-drug conjugates, or ADCs, chimeric antigen receptor, or CAR T-cells, and bispecific antibodies.
ADCs are composed of a tumor antigen-targeted monoclonal antibody that’s linked to a cytotoxic chemotherapy agent. ADCs targeted to BCMA are internalized by the myeloma cell, leading to release of the toxic payload and induction of selective tumor cell death.
The second type of BCMA-directed modality that I will review is CAR T-cell therapy. CAR T-cell therapies are T-cells collected from a patient, genetically modified to express a chimeric antigen receptor, otherwise known as CAR, which binds to a specific tumor associated antigen, in this case BCMA, on the target cells. Upon binding, T-cell activation occurs, initiating myeloma cell lysis and death.
CAR T-cell therapies currently approved for multiple myeloma are generated from autologous T-cells, which are collected from the patient via leukapheresis, modified to express the CAR, and reinfused back into the same patient. This means that CAR T-cells require patient-specific manufacturing. While CAR T-cells are currently administered as a one-time intravenous dose, patients may receive bridging therapy to help maintain disease control before the CAR T-cells are ready for reinfusion.
The last type of BCMA-directed therapy that I’ll discuss are bispecific antibodies. Bispecific antibodies designed to target BCMA have the potential to function as tumor-recognizing immune enhancers. They can engage BCMA found on myeloma cells and CD3 on T-cells, simultaneously bringing these 2 types of cells into proximity and forming an immune synapse between the T-cell and the myeloma cell.
The formation of this synapse between the T-cell and myeloma cell leads to T-cell activation. This initiates a cascade in which enzymes such as granzyme and perforin are released, inducing cell lysis. This major histocompatibility complex-, or MHC-independent, interaction has been shown to generate a robust T-cell response. This T-cell response activates cytotoxic CD8+ T-cells, as well as regulatory and helper CD4+ T-cells, without the need for costimulatory molecules. This independence from costimulatory molecules can help overcome tumor escape mechanisms.
The design and structure of a bispecific antibody may affect the binding affinity to the target and immunogenicity, which could impact patient outcomes. Bispecific antibodies are being investigated for both subcutaneous and intravenous administration and are intended to be administered until disease progression. They could be used as an off-the-shelf option, without the need for patient-specific manufacturing.
That concludes a brief overview of therapies that target BCMA, but there’s certainly more to come as we look towards the future. I hope you are as excited as I am to continue to explore the potential of BCMA as a therapeutic target for patients with multiple myeloma.
Pfizer host:
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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. |
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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. |
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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. |
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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. |
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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. |
Narrator: BCMA-directed bispecific antibodies in multiple myeloma.
For patients with multiple myeloma, each relapse after a treatment response has a higher risk of treatment resistance, shorter remission, and lesser response to standard treatments than earlier courses of therapy. New treatments are needed for relapsed and refractory multiple myeloma that counter the mechanisms for treatment resistance, including immune evasion. Bidirectional interplay of immunosuppressive factors between multiple myeloma cells and accessory cells in the tumor microenvironment suppress the immune bone marrow milieu leading to immune exhaustion. Ongoing research is investigating the benefit of therapies targeting multiple myeloma cell-surface antigens on multiple myeloma cells.
The cell-surface proteins CD38, CD138, GPRC5D, SLAMF7, TACI, and BCMA are targets for agents approved or currently under investigation for multiple myeloma.
BCMA, or B-cell maturation antigen, is a transmembrane protein found on normal plasma cells and B lymphocytes. In multiple myeloma cells, BCMA is expressed at higher levels compared with nonmalignant cells. BCMA overexpression in multiple myeloma cells can activate pathways that regulate the expression of genes critical for growth, survival, and immunosuppression. Multiple myeloma cells with high levels of BCMA also express IL-10, PD-L1, and other immune regulatory genes that could suppress the immune response in the bone marrow microenvironment. Currently, 3 treatment classes for targeting BCMA are being explored in multiple myeloma: antibody-drug conjugates, CAR T-cells, and bispecific antibodies.
Bispecific antibodies are monoclonal antibodies that bind to 2 different antigens simultaneously to facilitate cell-to-cell interactions, such as for an antitumor immune response. Bispecific antibodies under investigation in multiple myeloma are engineered to bind CD3 on T-cells and a tumor-associated antigen, such as BCMA. The arms' binding affinity to their respective BCMA and CD3 targets impact the activity of a bispecific antibody. Upon binding, a bispecific antibody draws the cells in close proximity through an interaction that is MHC-independent. Signaling from the resulting immunological synapse activates cytolytic cascades and induces proinflammatory cytokines. Simultaneously, bispecific antibodies may inhibit BCMA activity. This immunotherapeutic approach is currently being investigated in clinical studies for the treatment of multiple myeloma.
ADC=antibody-drug conjugate; BCMA=B-cell maturation antigen; BsAbs=bispecific antibodies; CAR=chimeric antigen receptor; CD=cluster of differentiation; CRAB=hypercalcemia, renal insufficiency, anemia, bone lesions; FcRH5=fragment crystallizable receptor-like protein 5; GPRC5D=G-protein coupled receptor family C group 5 member D; IL-10=interleukin 10; MHC=major histocompatibility complex; MM=multiple myeloma; PD-L1=programmed death-ligand 1; SEER=surveillance, epidemiology, and end results; SLAMF7=signaling lymphocytic activation molecule family member 7; TACI=transmembrane activator and calcium modulating ligand interactor.