Advances in CAR T-Cell Therapy and Bispecifics for Relapsed/Refractory Multiple Myeloma

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The treatment landscape for multiple myeloma (MM) has significantly evolved over recent years with the introduction of chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies. In a presentation at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain, Paula Rodríguez Otero, MD, PhD, a hematologist at Clínica Universidad de Navarra in Pamplona, Spain, provided a comprehensive overview of approved therapies in the US and Europe, highlighting the role of these therapies in treating patients with relapsed or refractory (R/R) MM after exposure to prior treatment regimens.

Traditional Treatments for MM

The treatment paradigm for MM has revolved around 3 main therapeutic classes: proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. These drugs have become integral in both frontline and early-relapse settings, but when treatment after relapse occurs following exposure to all 3 of these drug classes, termed triple-class refractory, treatment becomes a challenge. In these cases, traditional treatment options, often including chemotherapy or further lines of the same classes, have yielded poor outcomes, with an overall response rate (ORR) of approximately 30% and a median progression-free survival (PFS) of less than 5 months, according to Otero.

“So, this was the first unmet medical need population in which CAR T cells and bispecifics were developed,” Otero said during the ESMO session.

CAR T-Cell Therapies for R/R MM

CAR T-cell therapy involves genetically modifying a patient’s T cells to express CARs that recognize specific tumor antigens, allowing the T cells to target and destroy cancer cells. Two CAR T-cell therapies targeting B-cell maturation antigen (BCMA) have gained approval for R/R MM: idecabtagene vicleucel (ide-cel, Abecma; Bristol Myers Squibb) and ciltacabtagene autoleucel (cilta-cel, Carvykti; Janssen Biotech, Inc and Legend Biotech), with ide-cel approved by the FDA on April 4, 2024, and cilta-cel approved on February 28, 2022.

Ide-cel: Early Promise and Real-World Data

Ide-cel gained approval for R/R MM following the results of the phase 2 KarMMa study (NCT03361748). In this trial, 128 patients who were triple-class refractory with MM were treated with 3 doses of ide-cel, showing an impressive ORR of 73%, with 33% of patients achieving complete response (CR). Notably, the median PFS was 1 year, with deeper responders experiencing even longer durations of disease control.

Real-world data have supported the findings of the KarMMa study, according to Otero. In a cohort of 821 patients from the Center for International Blood and Marrow Transplant Research registry, ide-cel maintained both safety and efficacy comparable to the KarMMa study, even among more comorbid patients who would have been ineligible for the KarMMa trial based on their comorbidities.

Cilta-cel: Unprecedented Efficacy

Cilta-cel, a dual BCMA-binding CAR T-cell product, demonstrated strong efficacy in the phase 1b/2 CARTITUDE-1 trial (NCT03548207), with an ORR of 98% and a median PFS approaching 3 years in patients with a median of 6 prior lines of therapy. The depth of response with cilta-cel was striking, with 82.5% of patients achieving stringent CR, according to Otero.

However, cilta-cel is not without challenges in relation to its safety profile. Approximately 5% of patients developed delayed neurotoxicity, including movement and neurocognitive disorders, which were potentially linked to BCMA expression in the basal ganglia, according to Otero.

Emerging CAR T Therapies

Spain has also developed its own CAR T-cell therapy, cesnicabtagene autoleucel (ARI0002h), which has shown a 95% ORR and a median PFS of 20 months in patients with triple-class refractory MM. This therapy is delivered in a fractionated manner, with the option of a second booster dose from day 100 for patients with ongoing response.

Looking ahead, novel therapies such as anito-cel (Kite and Arcellx) and allogeneic products such as P-BCMAALLO1 (Poseida Therapeutics, Inc), a nonviral allogeneic BCMA-directed CAR T, are showing early promise. Rapid manufacturing platforms, such as PHE885 (Novartis), a BCMA-directed CAR T, was in development to reduce the time required for CAR T-cell production, although PHE885 encountered challenges due to severe toxicity and is no longer being developed by the manufacturer.

Bispecific Antibodies: A Paradigm Shift

Bispecific T-cell engagers represent another exciting frontier in MM treatment. These agents redirect T cells to target myeloma cells by binding simultaneously to BCMA and CD3 on T-cells. Three bispecifics have gained attention for their ability to provide durable responses in heavily pretreated patients.

Teclistamab: The First Approved BCMA Bispecific

Teclistamab (Tecvayli; Janssen Biotech, Inc), which was approved by the FDA on October 25, 2022, based on the phase 1/2 MajesTEC-1 study (NCT03145181; NCT04557098), demonstrated an ORR of 63% and a median PFS of 11.4 months in patients with a median of 5 prior lines of therapy. Given as a subcutaneous injection with step-up dosing to mitigate cytokine release syndrome, this drug has shifted the paradigm of care for patients with R/R MM. Interestingly, in patients who achieved CR, the median PFS was not reached with long-term follow-up, underscoring the depth and durability of responses in this heavily treated population.

Elranatamab: A Second BCMA Bispecific

Elranatamab (Elrexfio; Pfizer) offers another BCMA-targeting bispecific option, administered subcutaneously with step-up dosing. The FDA approved elranatamab on August 14, 2023, based on the results of the phase 2 MagnetisMM-3 trial (NCT04649359).

In MagnetisMM-3, elranatamab achieved a 61% ORR with encouraging durability of response, particularly in patients achieving CR. Moreover, its dosing schedule allows for less frequent administration (biweekly after cycle 7), providing more flexibility for patients.

Talquetamab: Targeting GPRC5D for Post-BCMA Treatment

Although BCMA-targeted therapies have shown great success, patients inevitably relapse after BCMA-directed treatments. Talquetamab (Talvey; Janssen Biotech, Inc), a bispecific targeting the novel GPRC5D antigen, has emerged as an important option in such cases, according to Otero. In the phase 1/2 MonumenTAL-1 study (NCT03399799; NCT04634552), talquetamab demonstrated a 71% ORR and a median PFS of 11.2 months, offering a much-needed alternative for patients progressing on BCMA-targeted agents. However, talquetamab is associated with unique toxicities, including skin, nail, and oral issues due to GPRC5D expression.

Sequencing and Combination Strategies: The Path Forward

As CAR T-cell therapies and bispecifics continue to show unprecedented efficacy, the challenge now lies in determining optimal sequencing and combination strategies. Data suggest that the efficacy of BCMA-targeted therapies may diminish if a patient has already been treated with a different BCMA-directed agent. For instance, in patients receiving ide-cel or cilta-cel after prior BCMA treatment, PFS was significantly shorter, according to Otero.

However, Otero noted that changing the target antigen, as seen with talquetamab following BCMA therapy, yields comparable PFS, indicating that non-BCMA targets may provide a viable alternative in relapsed settings. Moreover, combination therapies, such as talquetamab with daratumumab or pomalidomide, are under investigation as strategies to overcome resistance and improve outcomes.

Conclusion

The development of CAR T-cell therapies and bispecific antibodies has revolutionized the management of R/R MM, offering hope to patients with limited treatment options. Both ide-cel and cilta-cel have demonstrated remarkable efficacy, particularly in patients who have been heavily pretreated, whereas bispecific antibodies such as teclistamab and elranatamab have provided durable responses with manageable toxicity profiles.

“All these novel T-cell–redirecting therapies have shown impressive clinical efficacy both in the setting of triple-class exposed and also in early-line relapse,” Otero said. “The safety profile is manageable...but it requires training.”

However, Otero noted that the next challenge is to refine treatment strategies, including optimizing sequencing, improving safety, and expanding access to these therapies.

“There are some things that we need to take a closer look at, such as second primary malignancies, delayed neurological complications, and infections, particularly when speaking about BCMA-targeted bispecifics,” Otero said. “We need to know who are the patients that will benefit most from each of these because apparently the sequencing is not yet optimal. Another significant problem is that the availability of these drugs and the reimbursement for them [are] not yet there in all countries worldwide, so we need to keep working on that.

REFERENCE

Otero PR. CAR T cells and bispecifics. Presented at: European Society for Medical OncologyCongress 2024; September 13-17, 2024; Barcelona, Spain.