Major Victory For CAR T-Cell Therapy in Multiple Myeloma: FDA Advisory Panel Support For Abecma and Carvykti Therapies Earlier in The Disease Course, Despite Safety Concerns

CAR T-cell Therapy Shows Promise In Multiple Myeloma Treatment

• Multiple myeloma treatments that raised concerns among regulators because of an increased rate of “early deaths” during clinical trials managed to get a unanimous vote from the U.S. Food and Drug Administration (FDA) to move forward with development, citing the benefits outweigh the risks in earlier courses of treatment.
• The FDA has already approved Carvykti and Abemca to treat adults diagnosed with relapsed or refractory multiple myeloma who have received four or more prior lines of therapy. However, the ongoing clinical trial could pave the way for the drugs to be approved for multiple myeloma patients earlier in their treatment journey.
• The FDA will review Carvykti and Abecma‘s supplemental Biologics License Applications (sBLA) further, which is a necessary step during the drug approval process. If approved, these treatments can be available to multiple myeloma patients earlier in their treatment journey.
• Safety concerns arose for Bristol Myers Squibb’s Abecma and Johnson & Johnson’s Carvykti – CAR T-cell Therapies – during the clinical trial when several patients using the drugs died several months into the treatment.
• The FDA ultimately felt the risk of early death was worth the greater benefit, which is a “59%” reduction in multiple myeloma disease progression.
• CAR T-cell therapy uses your own modified immune cells to fight cancer, but it can have side effects, including cytokine release syndrome (CRS), which gives patients flu-like symptoms.
• Several FDA-approved CAR-T therapy drugs are on the market to treat blood cancers, including lymphomas, some forms of leukemia, and, most recently, multiple myeloma.

For multiple myeloma patients desperately in need of new, more effective treatments, there is an important new FDA advisory panel recommendation that's likely to clear the path for earlier use of new potent, personalized cell therapies called CAR T-cell therapies. CAR T medications from Bristol Myers Squibb (Abecma) and Janssen (Carvykti) gained support from the U.S. Food and Drug Administration (FDA) advisory panel despite concerns raised about patients in clinical trials who passed away at an increased and potentially earlier rate. "The availability of a cellular therapy like cilta-cel that can be used earlier in the treatment of this progressive disease is critically important, offering patients a chance of deep and durable responses with a one-time infusion," said Dr. Sundar Jagannath, director of the Center of Excellence for Multiple Myeloma at Mount Sinai said. However, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously 11 to 0, noting that the benefits of Carvykti and Abecma outweigh their risks for treating adults with relapsed/refractory multiple myeloma who received at least one prior line of treatment. Dr. Sagar Lonial , chief medical officer at Winship Cancer Institute of Emory University, was a presenter at the ODAC meeting. He tells SurvivorNet, “This is a great step to moving cell therapy for multiple myeloma patients earlier in the disease continuum." Dr. Lonial adds that both Abecma and Carvykti are “highly effective and offer significant benefit to patients.” Dr. Lonial says the next phase in the process for Abecma and Carvykti being approved to treat multiple myeloma patients earlier is for the FDA to make its ruling. Carvykti (which has the molecular name cilta-cel) was approved by the FDA in 2022 to treat adults diagnosed with relapsed or refractory multiple myeloma who already received four or more prior lines of therapy, which includes proteasome inhibitor (blocks the protein complex proteasome to help the body fight cancer), an immunomodulatory agent (stimulates the immune system to fight cancer) and anti-CD38 monoclonal antibody (blocks the CD38 protein on cancer cells to help the immune system fight cancer). Abemca (also called ide-cel) received the same FDA approval for the treatment of adults with relapsed or refractory multiple myeloma who already received 4 or more prior lines of therapy in 2021. The Phase 3 CARTITUDE-4 trial , which used Carvykti and Abemca, was for multiple myeloma patients who had received 1 to 3 prior lines of therapy that included proteasome inhibitors and immunomodulatory drugs and refractory (non-responsive) to lenalidomide. Now that the FDA's ODAC has determined that despite the risk of early deaths Abemca and Carvykti bring amid clinical trials, their greater benefit outweighs those risks with a “59%” reduction in multiple myeloma disease progression. The next steps will be further review by the FDA for Carvykti and Abecma 's supplemental Biologics License Applications (sBLA), which is necessary during the drug approval process. These treatments can be available to multiple myeloma patients earlier in their treatment journey if approved. Again, Abemca and Carvykti are currently approved for patients who have already tried four or more lines of treatment. WATCH: How CAR T-Cell Therapy Works "We are pleased with the advisory committee's support for CARVYKTI in earlier lines of treatment based on the CARTITUDE-4 data," Dr. Jordan Schecter, vice president and disease area leader for multiple myeloma at Johnson & Johnson Innovative Medicine, said in a press release regarding the ODAC’s decision.

The Initial Concerns

FDA briefing documents noted the federal agency had more concerns about Abecma than Carvykti. In reference to Abecma , FDA staffers reportedly said, "The adequacy of exploratory analyses of the KarMMa-3 trial to support the identification of strategies to mitigate this risk warrants further discussion. "Retrospective subgroup analyses, which are not pre-specified at the initiation of the study and not supported by an adequate sample size, cannot adequately characterize a heterogeneous patient population." The FDA also pointed out that its reasons for investigating the deaths varied, but they include the "inability to proceed with the first treatment step," leukapheresis [a procedure to remove white blood cells from your blood], manufacturing failure, disease progression, and adverse events." Other reasons that weren't listed are also said to exist.

Helping Patients Better Understand CAR T-cell Therapy

• CAR T-Cell Therapy Side Effects Can Be Serious, But Many Are Short-Lived
• CAR T-Cell Therapy and BiTE: Two New Approaches to Multiple Myeloma Treatment
• CAR T-Cell Therapy for Non-Hodgkin Lymphoma
• CAR T-Cell Therapy’s Current and Future Success
• CAR T-Cell Therapy: A Promising New Approach to Relapsed Multiple Myeloma
• CAR T-Cell Therapy: A Step-By-Step Guide to Having This Breakthrough Treatment
• CAR T-Cell Therapy: How it Works, and Who Can Get It
• CAR T-Cell Therapy: Making Your Body a More Efficient Cancer Fighter
• CAR T-Cell Therapy: Why Finding the Right Cancer Center Matters
• Can You Afford the High Cost of CAR T-Cell Therapy?

As for Carvykti , an FDA briefing document reportedly said that the Cartitude-4 trial revealed "early detriment" in "overall survival in the treatment arm, and an increased rate of early death is reflected in the Kapan-Meier curves." The document explains, as per BioSpace, that "Crossing hazards pattern favoring the standard therapy arm up to approximately 11 months; heavy censoring limits the estimation of the treatment effect on overall survival after 11 months." It was found that approximately 8% of trial patients died after Carvykti or Abecma CAR T-cell Therapy treatments, which is more than those treated with standard forms of therapy, according to Reuters. Leading up to the meeting, J&J's global oncology and R&D communication leader Brian Kenney said in an emailed statement to BioSpace, "We are confident in the data from the Phase III Cartitude-4 study and look forward to reviewing survival and safety data with the FDA Oncologic Drugs Advisory Committee. "We are committed to working with the FDA in the continued clinical development of Carvykti with a focus on bringing this immunotherapy to patients with multiple myeloma earlier in the course of the disease. We remain confident that the overall benefit-risk profile of Carvykti remains favorable in treating patients with relapsed/refractory multiple myeloma." The news comes months after the FDA announced it was investigating the serious risk of T-cell malignancy "following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies." WATCH: Is CAR T-Cell Therapy right for you? The press release, dated Nov. 28, 2023, explained, "The Food and Drug Administration (FDA) has received reports of T-cell malignancies, including chimeric antigen receptor CAR-positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR T cell immunotherapies. Reports were received from clinical trials and/or postmarketing adverse event (AE) data sources. RELATED: Doctors Urge Calm After FDA Announces ‘Serious Risk’ That Revolutionary CAR T-Cell Therapy for Blood Cancer May Lead to New Cancers "FDA has determined that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T cell immunotherapies. T-cell malignancies have occurred in patients treated with several products in the class." The approved products in this class are listed as:

• Abecma (idecabtagene vicleucel)
• Breyanzi (lisocabtagene maraleucel)
• Carvykti (ciltacabtagene autoleucel)
• Kymriah (tisagenlecleucel)
• Tecartus (brexucabtagene autoleucel)
• Yescarta (axicabtagene ciloleucel)

"Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action," the FDA advised. RELATED: Top Cell Therapy Doctor, Drug Developer & Cancer Survivor Tackles Getting Innovative Cancer Treatment to More Patients The administration added, "As with all gene therapy products with integrating vectors (lentiviral or retroviral vectors), the potential risk of developing secondary malignancies is labeled as a class warning in the U.S. prescribing information (USPIs) for approved BCMA-directed and CD19-directed genetically modified autologous T cell immunotherapies. "The initial approvals of these products included postmarketing requirements (PMRs) under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to conduct 15-year long-term follow-up observational safety studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment." Around the time the FDA raised concerns, Dr. Siddhartha Ganguly, a Carol Cockrell Curran Distinguished Centennial Chief in Hematologic Oncology at Houston Methodist Hospital and Neal Cancer Center, said the FDA investigation should not cause panic but stressed that physicians and patients should remain vigilant. He told SurvivorNet, "This most recent warning by the FDA concerns the anti-cancer gene introduction into the t-cells, which is done in the lab. In some situations, if the genes integrate – in most cases, we have minimal control – into the wrong spot on the T-cell, the T-cell itself can become cancerous. "We are aware that this can happen, which is why we follow patients who receive CAR-T therapy for many years so we can monitor them closely for this type of complication." Dr. Ganguly says he’s been using this form of treatment on patients for years and emphasizes the hope it offers patients battling diseases like advanced lymphoma or myeloma. He adds although safety risks exist, “this particular complication is exceedingly minimal.” Dr. Frederick Lock e, the chair of the Blood and Marrow Transplant and Cellular Immunotherapy Department and co-leader of the Immuno-Oncology Program at Moffitt Cancer Center, also spoke withSurvivorNet, revealing he still sees the value in CAR T-Cell therapy but is awaiting more data. “Thousands of patients have received treatment for cancer with FDA-approved CAR T- cell therapies. To date, I am unaware of any peer-reviewed reports of T cell lymphomas positive for the Chimeric Antigen Receptor with these approved therapies. That said, it is not out of the realm of possibility that one or two out of ten thousand patients could develop T cell lymphoma," Dr. Locke said. Dr. Locke noted rare cases of CAR T-cell therapy contributing to the progression of some blood cancers. However, he also added that immunotherapy has also rarely contributed to lymphoma, a type of blood cancer. "We know that cancer immunotherapy such as checkpoint blockade for solid tumors, which does not rely on gene therapy, can very rarely result in T-cell lymphomas," Dr. Locke added.

What Is Cart T-Cell Therapy?

CAR T-cell therapy is revolutionizing the way doctors treat certain blood cancers. And has been giving patients new hope where they thought none existed. "I've hit on a couple of things in my career that were exciting and hard to believe, and this was one of them," Dr. Stephen Schuster , director of the Abramson Cancer Center's lymphoma program, told SurvivorNet in a previous conversation. "Not only did it work, but with a single treatment, these patients were not relapsing." Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising treatments for blood cancers. It's a type of cancer immunotherapy treatment that uses a patient's own immune cells (T cells) to help fight cancer. Those T cells are genetically modified in a lab, multiplied into the millions, and returned to you. Once inside your body, the newly modified cells can better recognize and eliminate your cancer. WATCH: Why CAR T-Cell Therapy Is So Exciting Currently, CART-T therapy is FDA-approved to treat several types of hematological malignancies, including:

• B-cell acute lymphoblastic leukemia (ALL)
• B-cell non-Hodgkin lymphoma
• Follicular lymphoma
• Mantle cell lymphoma (MCL)
• Multiple myeloma

There are also dozens of trials taking place for solid tumor cancers as well as autoimmune diseases such as Lupus. Receiving CAR T-cell therapy usually takes a few weeks. The steps, according to Penn Medicine, include:

• Collecting the T-cells. Technicians draw blood from a vein in the patient's arm. The blood flows through a tube into a machine called an apheresis, which removes T cells. Once the T cells are removed, the machine returns the rest of the blood into the patient's body through a different tube.
• Re-engineering the T Cells. Scientists in a lab re-engineer the T cells by adding a manufactured CAR. Next, the scientists wait while the CAR T cells multiply and grow.
• Giving the CAR T Cells. When the lab has enough CAR T cells, they are injected back into the patient's arm. Chemotherapy may be recommended for the patient before the infusion to help with the treatment's effectiveness.

The process can occur in an outpatient infusion center or hospital. Patients are closely monitored and followed up with so medical professionals can watch for any adverse side effects or reactions. Although the CAR T-cell therapy process can take several weeks, it is typically administered only once. If you are going to receive CART T-cell treatments, you, your caregiver, and your healthcare team will create a unique plan and make adjustments as needed along the way. While CAR T-cell therapy is a game-changer, it still doesn't always work. Some patients will go into complete remission, while others may still see their disease return.

Side Effects of CAR T-Cell Therapy

CAR T-cell therapy has, however, been found to have significant side effects , Dr. Sven de Vos, a hematologist/oncologist in Santa Monica, California, told SurvivorNet. That's because "The side effects of CAR T-cells are also related to the tumor burden (number of tumors) the CAR T-cells encounter," he explained. In other words, the greater the tumors, the greater CAR T-cell response, and the more potential for side effects. WATCH: CAR T-Cell Therapy Side Effects Common side effects of CAR T-cell therapy include:

• Weakness
• Chills
• Fever
• Fatigue
• Muscle or joint pain
• Nausea, vomiting or diarrhea
• Rapid heartbeat
• Low blood pressure
• Significant loss of appetite

The treatment may also cause nervous system symptoms like confusion, tremors or shaking, trouble speaking, and loss of balance. "We try to keep the tumor burden going into CAR T-cell treatment small," de Vos said. "Enough to activate CAR T-cells and small enough to avoid massive over-activation." "We also learned that it is better to suppress over-reacting CAR T-cells earlier and not later. That way, only a little immunosuppression is needed compared to massive amounts of steroids," De Vos added. However, it's important to note that CAR T-cell therapy can still lead to serious side effects, including the risk of infections, bleeding, and allergic reactions. Dr. Siddhartha Ganguly, director of the Lymphoma/Myeloma Program at the University of Kansas, explained another unintended consequence of CAR T-cell therapy. "I usually give the analogy of the Pac-Man going after the cancer cells. When they are in contact with the cancer cells, they release chemicals to kill those cancer cells," he told SurvivorNet in a previous conversation. WATCH: The Promises and Risks of CAR T-Cell Therapy While those chemicals, called cytokines, are very effective at targeting cancer, they can also cause side effects. When released into the body, cytokines can cause symptoms and reactions in various organs and systems. One serious condition, cytokine release syndrome (CRS), can develop. About one-quarter or more of people who undergo CAR T-cell therapy will have some form of CRS. The good news is that very serious reactions are rare. And few people die from CRS. Doctors are studying methods to prevent CRS and monitoring patients closely. In severe cases, medications can slow the flow of cytokines and relieve symptoms. WATCH: Dr. Ricafort explains how doctors and drug developers can collaborate to increase access to innovative cancer treatments like CAR T-cell therapy. Contributing: SurvivorNet Staff