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Dec 15, 20247 min read

Harnessing the Potential of CAR T-Cell Therapy for Multiple Myeloma

In recent years, chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative approach in the treatment armamentarium for RRMM.

 

By Marcie Morris | Original Article


Multiple myeloma (MM), a blood cancer that develops in plasma cells, can result in low blood counts and weakening of the immune system.


According to the National Cancer Institute, MM accounted for approximately 1.8% of new cancer cases in the United States in 2024.2 The cause of MM is unknown and there is no cure. Approximately 40% of Americans diagnosed with MM die within 5 years.


Despite treatment advancements, MM remains a predominantly incurable disease, with patients experiencing periods of remission and relapse. Each successive line of therapy is associated with poorer outcomes.


Studies show that patients with relapsed or refractory MM (RRMM) who have been treated with the 3 major drug classes (immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) generally have low response rates (20%-30%), a short duration of response (2-4 months), and poor survival, highlighting an unmet need for improved therapeutic options for MM.



In recent years, chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative approach in the treatment armamentarium for RRMM.


Autologous CAR T-cell therapy involves a patient’s own T cells that are collected and genetically modified to have CARs on their surface, giving the T cells the ability to recognize and bind to a specific protein expressed on a tumor cell. This activates the immune system to target and destroy the tumors. Once the new T cells multiply after several weeks, they are reinfused into the patient. The process is detailed in the Figure.


Shortly before the CAR T-cell therapy infusion, a patient receives preparatory chemotherapy to help reduce the amount of cancer cells as well as other immune cells, which improves the body’s acceptance of CAR T cells. The infused cells then circulate throughout the body, attacking the patient’s cancer cells.


Like all treatments, CAR T-cell therapy carries risks. The 2 most common acute adverse events (AEs) are cytokine release syndrome (CRS) and neurologic events (also known as immunologic effector cell–associated neurotoxicity syndrome). Although these AEs are reversible and treatable, they can become severe or life-threatening if not managed early. The onset of CRS symptoms, such as high fevers, shortness of breath, malaise, and a drop in blood pressure and oxygenation, usually occurs within the first week after CAR T-cell infusion. Neurologic events are characterized by confusion, agitation, and delirium, and severe cases may include aphasia, seizures, and cerebral edema.


FDA-Approved CAR T-Cell Therapies for MM


B-cell maturation antigen (BCMA) is a major target for CAR T-cell therapies because it is expressed exclusively on malignant plasma cells and in essentially all patients with MM.


There are currently 2 FDA-approved BCMA-directed autologous CAR T-cell therapies for the treatment of adult patients with RRMM. Idecabtagene vicleucel (Abecma, Bristol Myers Squibb) and ciltacabtagene autoleucel (Carvykti, Legend/Janssen) were first approved in March 2021 and February 2022, respectively, for use in MM patients treated with at least 4 prior lines of therapy.


In April 2024, Abecma and Carvykti both received expanded indications for use in earlier lines of therapy for adult patients with RRMM. Abecma received approval for use as a third-line therapy for RRMM after 2 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Carvykti received approval as a second-line therapy in patients who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide. Both one-time therapies have shown high response rates and improvements in progression-free survival (PFS).


The expanded approval of Abecma for third-line therapy in RRMM was based on data from the pivotal phase 3 KarMMa-3 trial. In the trial, 254 patients were randomized to receive Abecma, and 132 patients were randomized to receive 1 of several standard treatment regimens. In the primary analysis at an estimated median follow-up of 15.9 months, patients treated with Abecma had a median PFS of 13.3 months compared with 4.4 months for those given a standard regimen, representing a 51% reduction in the risk for disease progression or death with Abecma. The overall response rate (ORR) also was significantly improved for patients receiving Abecma, at 71% compared with 42% for those treated with a standard regimen.


Carvykti received expanded approval for second-line therapy in RRMM based on positive results from the phase 3 CARTITUDE-4 study that compared Carvykti and the standard of care. The trial demonstrated that the earlier use of Carvykti reduced the risk for disease progression or death by 59% compared with standard therapies. Carvykti also met key secondary end points, including an ORR of 84.6% versus 67.3% for standard care.12,14

Abecma and Carvykti are restricted under the Risk Evaluation and Mitigation Strategies program due to their high adverse effect profiles. The labeling for Abecma and Carvykti includes a boxed warning about CRS, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, recurrent cytopenia, and secondary hematologic malignancies—all of which can be fatal or life-threatening. Because of these risks, the FDA also requires that hospitals and their associated clinics dispensing CAR T-cell therapies be specially certified and that staff involved in prescribing, dispensing, or administering be trained to recognize and manage CRS, nervous system toxicities, and other associated AEs. In addition, clinicians must inform patients about the potential for serious AEs and of the importance of promptly seeking treatment if AEs develop.


Future Cell Therapies for MM


GPRC5D Target Antigen


GPRC5D is a protein highly expressed on the surface of MM cells. This protein crosses the membrane 7 times and is unlikely to be shed from target cells, potentially allowing therapies targeting this protein to maintain response rates and efficacy in MM patients.


MCARH109 (Juno Therapeutics), BMS-986393 (Bristol Myers Squibb), and OriCAR-017 (OriCell Therapeutics) are new CAR T-cell therapies in phase 1 trials that show promising results in targeting GPRC5D. MCARH109 studies yielded a 71% ORR in a 17-patient trial. Of these patients, 35% had a complete response (CR). BMS-986393 trials in 19 patients yielded a 90% ORR with a 47% CR. Phase 1 trials in 10 patients receiving OriCAR-017 showed a 100% ORR, including 60% with a stringent complete response (sCR).


Dual Antigen Targeting


BCMA/GPRC5D dual-target CAR T-cell therapy is another promising avenue in the treatment of MM. Following BCMA targeting therapy, shedding of BCMA from MM cells may contribute to disease relapse. GPRC5D therapy is not affected by BCMA loss, making these 2 therapies potential partners in MM treatment. Dual-targeted CAR T-cell therapies prevented BCMA escape–mediated relapse in murine models. Additionally, bicistronic structures expressing both BCMA and GPRC5D on the same vector were found to have higher efficacy for MM treatment than a pooled approach that expressed these CARs from different vectors. Combining CARs on the same vector would also reduce the cost, time, and workload for creating 2 autologous CAR T lines in a single patient.


Allogeneic CAR T-Cell Therapy


The current gold standard for CAR T-cell therapies is autologous administration, in which T cells are extracted from a patient, engineered in a lab, and reintroduced back into the patient. This process is invasive, costly, and time-consuming, making these therapies not readily available to patients. Companies such as Allogene Therapeutics are aiming to create allogeneic CAR T-cell therapy using healthy donor T cells. This strategy would remove T-cell extraction procedures from patients and lower the costs associated with bulk manufacturing. The healthy donor T-cell model also can provide an “off-the-shelf” model that enhances speed of treatment from windows of 3 weeks to =6 months down to 2 to 5 days.


Allogene Therapeutics’ product, ALLO-715, is undergoing phase 1 trials. Data from the first 48 patients enrolled yielded patient responses in line with other approved autologous CAR T-cell therapies. Overall, 56% of patients responded to treatment with ALLO-71.


The Role of Specialty Pharmacy


Although CAR T-cell therapy is a medication, specialty pharmacies do not currently dispense this treatment. Due to the specialized nature of manufacturing and administering CAR T-cell therapy, it is available only at certified treatment centers, where CAR T-cell therapy is treated in a similar manner to a stem cell infusion and less like traditional therapy. However, because of its potentially life-threatening risks and monitoring requirements, it is critical for pharmacists to be knowledgeable about the process of CAR T-cell therapy and toxicity management.


Specialty pharmacists are skilled in the clinical management of patients with complex diseases. Additionally, an established, validated clinical management software platform could track the outcomes that may be key to securing value-based contracts to pay for cell therapy products. Specialty pharmacies have the experience needed to effectively communicate with patients living with rare diseases and their healthcare providers, simplifying the collection and reporting of outcomes-focused data.


With next-generation CAR T-cell therapies on the horizon, cell therapies will continue to shift paradigms for manufacturers, patients, healthcare providers, and pharmacies alike.


Dr. Morris reported no relevant financial disclosures.


References

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