Navigating Transitions of Care with a Bispecific Antibody in Relapsed or Refractory Multiple Myeloma

Dr. Ariel Grajales-Cruz from Moffitt Cancer Center

Dr. Ke Ning from Florida Cancer Specialists & Research Institute

In this episode of OncLive On Air, we discuss a bispecific antibody and its role in the treatment of relapsed or refractory multiple myeloma (RRMM) with two leading experts in the field. Doctor Ariel Grajales-Cruz, Moffitt Cancer Center, and Doctor Ke Ning, Florida Cancer Specialists and Research Institute, discuss the efficacy and safety of this bispecific antibody for RRMM. Our guests explore the collaborative efforts required between academic and community centers to start and manage patients on this bispecific antibody, emphasizing the importance of care transitions. Tune in to gain insights into this treatment.

Sponsorship Disclosure: This podcast episode is sponsored by Johnson & Johnson, approved under cp-467742v1. Doctor Grajales-Cruz and Doctor Ning have been compensated by Johnson & Johnson for their time to participate in this podcast.

OncLive® Podcast: Navigating Transitions of Care with a Bispecific Antibody in Relapsed or Refractory Multiple Myeloma

Podcast Intro: Welcome. This podcast from OncLive provides oncology professionals with the resources and information they need to provide the best patient care. Segments cover every angle of oncology practice from new technology to treatment advances to important regulatory decisions.

Ashling Wahner, Host: In today's episode, we have the pleasure of speaking with Ariel Grajales-Cruz, MD and Ke Ning, MD about a treatment option for adults with relapsed or refractory multiple myeloma and transitioning care between academic and community centers.

This podcast episode is sponsored by Johnson and Johnson. Doctor Grajales-Cruz and Doctor Ning have been compensated by Johnson and Johnson for their time to participate in this podcast.

Doctor Ariel Grajales-Cruz is a hematologist at Moffitt Cancer Center and assistant professor at University of South Florida, and he focuses on multiple myeloma and plasma cell tumors. Doctor Ke Ning is a board-certified oncologist at Florida Cancer Specialists and Research Institute, and he has extensive experience in providing patient care within community and academic settings, including in multiple myeloma.

Welcome and thank you both for being here today.

Ke Ning, MD: Thank you for having me. Glad to be here.

Ariel Grajales-Cruz, MD: Very happy to be here. Thank you for the invitation.

Ashling Wahner, Host: Doctor Grajales-Cruz, let's start with you. What is multiple myeloma? And what can you tell us about the patient population?

Ariel Grajales-Cruz, MD: Well, multiple myeloma is a type of plasma cell dyscrasia. It's a very highly variable disease. It remains an incurable cancer and affects mainly a specific type of white blood cell called plasma cells, and these plasma cells are found in the bone marrow. One of the key characteristics of multiple myeloma is that plasma cells are transformed into malignant clones, and then they grow out of control and start crowding normal cells. As a result of the incurability of this disease, multiple myeloma is characterized by the high rates of relapses and disease variability, and it remains a very rare cancer. Altogether, it represents less than 2% of all malignancies with about 35,000 new cases per year diagnosed in the United States, and we estimate that almost 13,000 of these patients will die from the disease. Multiple myeloma affects a somewhat elderly population with a median age of diagnosis of 69 and a five-year relative overall survival rate of 61.1%. We are seeing nowadays that the survival rate is changing.

Ashling Wahner, Host: And then, Doctor Ning, can you share why multiple myeloma is difficult to treat?

Ke Ning, MD: One of the primary difficulties in treating myeloma is in its propensity to relapse. Even after its initial successful treatment, the disease often returns and necessitates multiple rounds of therapies over a patient's lifetime. This repeated recurrence certainly can complicate long-term management strategies. We also have to be mindful of the reduced effectiveness of each subsequent line of therapy. Generally, this occurs due to cumulative resistance as well as drug toxicities. Now, for the treatment resistance, we know that myeloma cells can develop resistance to therapies over time. This typically arises due to genetic mutations and clonal evolutions within the cancer cells, making them less responsive to previously effective treatments. As a result, newer drugs and more aggressive treatments are often required which may or may not be effective for some patients. Now, aside from drug resistance and drug toxicities, we also have to think about the patient. As Doctor Cruz mentioned earlier, the average age of our patients being diagnosed are usually older, mostly frail, and the majority of them come with multiple comorbidities. This will, of course, present additional treatment challenges. These individuals are often less able to tolerate aggressive therapies and may have a higher risk for complications from treatment, therefore leading to less optimal outcomes. As mentioned earlier, we know that myeloma is not curable. The treatment aims are to manage symptoms, control disease progression, and extend survival as much as possible, but unfortunately, they do not eliminate the disease.

Ashling Wahner, Host: Can you share the current treatment landscape for relapsed or refractory multiple myeloma?

Ke Ning, MD: The current treatment landscape for relapsed and refractory myeloma has evolved quite drastically over the recent years. As I mentioned earlier, with disease progression, relapse often becomes more frequent and potentially more aggressive with each line of subsequent therapy. Thankfully, there has been accelerated FDA approval of bispecific therapy that's been making a practice-changing difference in this subset of patients who are very heavily treated.

Bispecific antibodies target and bridge two specific proteins to activate the immune system against myeloma cells; how it works is by dual binding. Essentially, the bispecific therapy has one arm or site to bind a B cell maturation antigen, or BCMA. This is predominantly expressed on a surface of multiple myeloma cells. The other arm or other site will bind to CD3, which is a protein that is found on T-cells. By binding both the BCMA and CD3, bispecific therapy forms a bridge between myeloma cells and T-cells, therefore allowing the T-cells to be brought closer in proximity within the cancer cells and leading to T-cell activation. By allowing activated T-cells to recognize and attack the multiple myeloma cells, this will subsequently cause and lead to destruction of the cancer cells.

Ashling Wahner, Host: And then, Doctor Grajales-Cruz, do you want to talk about TECVAYLI®( teclistamab-cqyv)?

Ariel Grajales-Cruz, MD: When we talk about bispecific antibodies, one of the first names that come to mind is the one that was the first approved, which is TECVAYLI®( teclistamab-cqyv). TECVAYLI® has helped evolve the treatment landscape for relapsed or refractory multiple myeloma. TECVAYLI® was the first FDA-approved bispecific antibody that treated this heavily pretreated population in the relapsed or refractory setting with at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. When TECVAYLI® got its approval, it was based on an accelerated approval for response rate, but this continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trials. It is extremely important to know that in this patient population, there is definitely an unmet need in multiple myeloma given the fact that it's an incurable disease. Every single patient is going to get to this point of a late relapse.

I think one of the most important and relevant things for the patients when considering bispecific antibodies, such as TECVAYLI®, is that it's an off-the-shelf alternative for them. Myeloma, as I mentioned earlier, is a very highly variable disease. Not all patients have time to wait for other therapies and have the opportunity to use a targeted therapy, or BCMA-targeted therapy, that is available and ready to go for the patients. We're extremely excited to see these newer drugs for these advanced stages of the disease. Bispecific antibodies like TECVAYLI® are a promising option for patients with advanced disease because they are off-the-shelf therapies, and after some hospitalization during treatment initiation, they can be dosed on an outpatient basis.

TECVAYLI® has a Boxed Warning and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy, or REMS. TECVAYLI® can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions and can cause serious or life-threatening neurologic toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).

Ashling Wahner, Host: Doctor Grajales-Cruz, what types of results are you seeing with TECVAYLI®?

Ariel Grajales-Cruz, MD: With our patients, we continue to see positive results in patients that are consistent with what the clinical trial showed.

Ashling Wahner, Host: Doctor Grajales-Cruz, let's talk about the MajesTEC-1 study. The study was conducted in patients who had received three lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The primary endpoint was overall response rate, and the median follow up was seven months. Based on that study design, can you talk about the response rates and meaningful efficacy seen in some patients?

Ariel Grajales-Cruz, MD: In the pivotal Phase 1/2 MajesTEC-1 trial, 110 patients were enrolled with relapsed or refractory multiple myeloma. There was a high response rate in this heavily pretreated population, with nearly 62% responding to treatment. Additionally, 28% of those patients actually achieved a complete response or better, and at least half of the patients responded to treatment with a median time of response of 1.2 months.

Ashling Wahner, Host: Doctor Grajales-Cruz, from what I understand, following step-up dosing, patients receive weekly treatment doses until disease progression or unacceptable toxicity and have the option of switching to biweekly dosing if they achieve and maintain a complete response rate or better for a minimum of 6 months until disease progression or unacceptable toxicity. Can you talk about this process?

Ariel Grajales-Cruz, MD: Well, all these adult patients are started on a step-up dosing schedule in the inpatient setting for 48 hours after each administration of all the step-up doses. So step-up one, step-up two, and then the first treatment dose. They are admitted because of the risk of cytokine release syndrome and neurotoxicity, including ICANS. After the step-up dosing is completed, the patient will receive weekly treatment doses, with the option of switching to every other week dosing, if they achieved and maintained a complete response rate or better for a minimum of six months.

Ashling Wahner, Host: Can you explain how you work across the care team to start patients on therapy and then transition their care?

Ariel Grajales-Cruz, MD: As we continue to gain experience with TECVAYLI®, the methods for effectively monitoring these patients during the step-up period will continue to evolve. TECVAYLI® is administered subcutaneously by a healthcare provider only, who has adequate medical personnel and appropriate medical equipment to manage the severe reactions, such as CRS and ICANS, that may occur. As we transition these patients from the hospital following their step-up dosing to treatment centers, we work closely in collaboration to ensure the transition of care is as seamless as possible. That goes from referring patients to treatment centers, preparing them for ongoing treatment, and educating the patients and their caregivers about their treatment plan.

Ashling Wahner, Host: And so then, Doctor Ning, how did you prepare your center to use TECVAYLI®?

Ke Ning, MD: Coordination and communication between providers are of the utmost importance. There needs to be a close collaboration between the community oncologist, their pharmacy team, and the academic center, like Doctor Cruz's team, in managing these patients together. We generally share information on a patient's status during the ramp-up phase, their tolerability during ramp-up, and any type of adverse effects, such as cytokine release syndrome, to ensure a smooth transition.

As a community practice, we also collaborate with our local hospital teams to develop a robust protocol as well as guidelines to manage bispecific therapy overall. This includes CRS monitoring, treatments like prophylaxis for infections, and management of other adverse events. We also enlist other specialists in TECVAYLI® management, such as pulmonary critical care, the neurology team, and the ER teams here locally, mainly to provide education and awareness of such a treatment option. We've also had the opportunity to work with our local hospital’s IT team working with EMR to have a way to identify or flag these patients, should they ever come into the ER for a more expedited consultation to oncology services. Additionally, I do think that establishing protocols and guidelines are also very important.

REMS certification is required for all providers here locally that are involved in any type of management for these bispecific patients, and this, again, is to allow and ensure that we as providers are trained and well-educated to provide this treatment option for our patients in the community.

Ashling Wahner, Host: And so then, overall, what advice do you have for doctors who are transitioning their patients to the community setting?

Ariel Grajales-Cruz, MD: As we discussed, we know that these patients are admitted to start their step-up dosing, and that is in view of the risk of CRS and ICANS. We have to understand the burden of disease that the patient might have. We have to relay and communicate with the providers in the community to share the patient journey during the step-up dosing, not only in terms of efficacy but toleration, most importantly. Because the risk of these toxicities like CRS and ICANS is mainly seen during this period of time, we have to monitor the patients closely. We evaluate them on a daily basis, and this journey is then transmitted to the doctors in the community to know whether or not they develop any type of toxicity, and what kind of management the patient received.

Most importantly, we always have to communicate the schedule very clearly because we want to make sure the patient is then transitioned to an outpatient schedule at an appropriate time. This type of communication is extremely important from the part of the academic center, which is then received by the community providers. This is in an effort to try to obtain not only the best possible outcome but the safest one.

Ke Ning, MD: I agree, Doctor Cruz. I do think that as a community practice oncologist, we generally try to obtain the necessary resources to allow these patients to transition to the maintenance phase closer to home, after this initial ramp-up at the academic hospital. We generally recommend having well-trained staffing to undergo e-learning about bispecific therapy, how to manage adverse effects, and the normal protocol in administering these medications in the office setting. We also lean heavily on support from our academic colleagues, especially when we first initiated a program here locally to gain experience and also have insight about how to manage these down the line. We like to work closely with our partnering local hospitals to provide that support, just in case these patients need additional management or support after a ramp-up and during the maintenance phase. All these things will be essential to having a very successful and robust maintenance program in a community setting.

Ashling Wahner, Host: Thank you both. So, do either of you have any final thoughts on this topic?

Ariel Grajales-Cruz, MD: Given the fact that we have a disease that is extremely challenging to manage, we have been able to change outcomes dramatically compared to 20 years ago. This is just another example of how important research is in a field, which is an unmet need on rare diseases like multiple myeloma. The fact that we can provide this quality of care in the community setting nowadays to facilitate the quality of life for our patients, and especially with an off-the-shelf product, is absolutely meaningful for all of our patients.

Ke Ning, MD: As community oncologists, we are very excited about these modalities of treatment that we're able to provide for our local patients within the community. Overall, during the maintenance phase, we're able to keep these patients closer to home, allowing more time to spend with their family and loved ones.

For more information about managing adult patients with relapsed or refractory multiple myeloma with TECVAYLI® and patient resources, please visit www.TECVAYLIhcp.com.

Ashling Wahner, Host: Thank you both for taking the time to speak with us today. Please stay tuned for the full Important Safety Information, including the Boxed Warning and Indication for TECVAYLI®.

INDICATION AND USAGE

TECVAYLI® (teclistamab-cqyv) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome - TECVAYLI® can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 72% of patients who received TECVAYLI® at the recommended dose, with Grade 1 CRS occurring in 50% of patients, Grade 2 in 21%, and Grade 3 in 0.6%. Recurrent CRS occurred in 33% of patients. Most patients experienced CRS following step-up dose 1 (42%), step-up dose 2 (35%), or the initial treatment dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI®. The median time to onset of CRS was 2 (range: 1 to 6) days after the most recent dose with a median duration of 2 (range: 1 to 9) days. Clinical signs and symptoms of CRS included, but were not limited to, fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation).

Initiate therapy according to TECVAYLI® step-up dosing schedule to reduce risk of CRS. Administer pretreatment medications to reduce risk of CRS and monitor patients following administration of TECVAYLI® accordingly. At the first sign of CRS, immediately evaluate patient for hospitalization. Administer supportive care based on severity and consider further management per current practice guidelines. Withhold or permanently discontinue TECVAYLI® based on severity.

TECVAYLI® is available only through a restricted program under a REMS.

Neurologic Toxicity including ICANS- TECVAYLI® can cause serious or life-threatening neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).

In the clinical trial, neurologic toxicity occurred in 57% of patients who received TECVAYLI® at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients. The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%). With longer follow-up, Grade 4 seizure and fatal Guillain-Barré syndrome (one patient each) occurred in patients who received TECVAYLI®.

In the clinical trial, ICANS was reported in 6% of patients who received TECVAYLI® at the recommended dose. Recurrent ICANS occurred in 1.8% of patients. Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%). Less than 3% of patients developed first occurrence of ICANS following subsequent doses of TECVAYLI®. The median time to onset of ICANS was 4 (range: 2 to 8) days after the most recent dose with a median duration of 3 (range: 1 to 20) days. The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or permanently discontinue TECVAYLI® based on severity per recommendations and consider further management per current practice guidelines.

Due to the potential for neurologic toxicity, patients are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI® step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves.

TECVAYLI® is available only through a restricted program under a REMS.

TECVAYLI® and TALVEY™ REMS - TECVAYLI® is available only through a restricted program under a REMS called the TECVAYLI® and TALVEY™ REMS because of the risks of CRS and neurologic toxicity, including ICANS.

Hepatotoxicity - TECVAYLI® can cause hepatotoxicity, including fatalities. In patients who received TECVAYLI® at the recommended dose in the clinical trial, there was one fatal case of hepatic failure. Elevated aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%. Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

Infections - TECVAYLI® can cause severe, life-threatening, or fatal infections. In patients who received TECVAYLI® at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 30% of patients, with Grade 3 or 4 infections in 35%, and fatal infections in 4.2%. Monitor patients for signs and symptoms of infection prior to and during treatment with TECVAYLI® and treat appropriately. Administer prophylactic antimicrobials according to guidelines. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

Monitor immunoglobulin levels during treatment with TECVAYLI® and treat according to guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Neutropenia - TECVAYLI® can cause neutropenia and febrile neutropenia. In patients who received TECVAYLI® at the recommended dose in the clinical trial, decreased neutrophils occurred in 84% of patients, with Grade 3 or 4 decreased neutrophils in 56%. Febrile neutropenia occurred in 3% of patients.

Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines. Monitor patients with neutropenia for signs of infection. Withhold TECVAYLI® based on severity.

Hypersensitivity and Other Administration Reactions - TECVAYLI® can cause both systemic administration-related and local injection-site reactions. Systemic Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, 1.2% of patients experienced systemic-administration reactions, which included Grade 1 recurrent pyrexia and Grade 1 swollen tongue. Local Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, injection-site reactions occurred in 35% of patients, with Grade 1 injection-site reactions in 30% and Grade 2 in 4.8%. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

Embryo-Fetal Toxicity - Based on its mechanism of action, TECVAYLI® may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECVAYLI® and for 5 months after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.

Please read full Prescribing Information, including Boxed WARNING for TECVAYLI®.

cp-322928v3

For more information about TECVAYLI®, please visit TECVAYLI.com.

Ashling Wahner, Host: That’s all we have for today! Thank you for listening to this podcast episode from OncLive, courtesy of Johnson & Johnson. This podcast was approved under cp-467742v1.