Long-Term Data Affirm Enduring Responses With Teclistamab in R/R Multiple Myeloma

Amrita Y. Krishnan, MD, and Binod Dhakal, MD

In a recent Between the Lines program, Amrita Y. Krishnan, MD, and Binod Dhakal, MD, discussed long-term findings from the phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098), which evaluated treatment with teclistamab-cqyv (Tecvayli) for patients with relapsed/refractory multiple myeloma.¹ Krishnan is the executive medical director of hematology, director of the Judy and Bernard Briskin Multiple Myeloma Center, and a professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Orange County Lennar Foundation Cancer Center in Irvine, California. Dhakal is an associate professor of medicine in the Division of Hematology at the Medical College of Wisconsin in Milwaukee.

These experts reviewed how efficacy and safety data from MajesTEC-1, which investigators presented in a poster session at the 2024 American Society of Clinical Oncology Annual Meeting, may build on ongoing therapeutic advancements in the relapsed/refractory multiple myeloma landscape. After a discussion about applying these trial findings to dosing and adverse effect (AE) management practices, Krishnan and Dhakal spoke about potential future directions for further shifting the treatment paradigm.

The Current Relapsed/Refractory Multiple Myeloma Landscape

The experts first contextualized the MajesTEC-1 findings by highlighting the current therapy options for patients with relapsed/refractory disease.

Within the past 5 years, the treatment landscape for patients with late relapses gradually evolved, thanks to newly approved bispecific chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies. The novel B-cell maturation antigen (BCMA)–directed CAR T-cell agents and their respective approval dates included idecabtagene vicleucel (Abecma) in March 2021² and ciltacabtagene autoleucel (Carvykti) in February 2022.³ Furthermore, other bispecific antibody approvals included BCMA-targeting teclistamab in October 2022⁴ and elranatamab-bcmm (Elrexfio) in August 2023⁵; the FDA also approved GPRC5D-directed agent talquetamab-tgvs (Talvey) in August 2023.⁶

When deciding whether to target BCMA or GPRC5D with the currently available bispecific antibodies, Dhakal said that both would be valid options in the frontline setting. Moreover, a patient who experiences a relapse following BCMA-directed therapy, for instance, may be eligible to switch to an agent
targeting GPRC5D.

MajesTEC-1

Krishnan and Dhakal then shifted their focus to the results of the MajesTEC-1 trial. In this study, patients with triple class–exposed relapsed/refractory multiple myeloma received teclistamab at the recommended phase 2 dose of 1.5 mg/kg subcutaneously once weekly. Patients were eligible to switch to dosing every 2 weeks if they achieved a partial response or better after at least 4 cycles in phase 1 or a complete response (CR) or better for 6 months or longer during phase 2. Additionally, patients had the option of transitioning to less frequent dosing if they maintained their response.

The trial’s primary end point was objective response rate (ORR). The median follow-up was 30.4 months, and the data cutoff date was August 22, 2023. Among all evaluable patients (n = 165), teclistamab elicited an ORR of 63.0% (n = 104), which included CRs or better in 46.1% (n = 76). Investigators reported a negative minimal residual disease status in 85.7% (n = 48/56) of evaluable patients.

Other data showed a median duration of response (DOR) of 24.0 months (95% CI, 17.0-not evaluable), a median progression-free survival (PFS) of 11.4 months (95% CI, 8.8-16.4), and a median overall survival of 22.2 months (95% CI, 15.1-29.9). Estimated 30-month rates among patients with a CR or better were 60.8% (95% CI, 48.7%-71.0%) for DOR and 61.0% (95% CI, 48.9%-71.1%) for PFS.

Krishnan highlighted that assessing the risk-benefit ratio of teclistamab, with respect to its toxicity profile, may be a challenge when deciding whether to administer this agent to patients.

In MajesTEC-1, any-grade and grade 3 or higher hematologic treatment-emergent AEs included neutropenia (71.5% and 65.5%), anemia (55.2% and 37.6%), thrombocytopenia (41.8% and 23.0%), lymphopenia (36.4% and 34.5%), and leukopenia (20.0% and 9.1%). Additionally, any-grade and grade 3 or higher infections affected 78.8% and 55.2% of patients, respectively. Of note, 1 patient had an AE leading to a dose reduction, and 8 patients discontinued study treatment due to toxicity, which included 5 with infections.

According to Dhakal, one could partly attribute the incidence of grade 3 infections to the drug’s target or the ongoing COVID-19 pandemic, which was happening at the time investigators were conducting the trial. Additionally, high-grade infections following teclistamab appear to be less frequent in his clinical practice, which he primarily justified based on his decision to decrease dosing frequency after a patient achieves a response. Although some patients in his clinic may experience mild respiratory infections, none of them appear to have high-grade events potentially leading to hospitalization or death, even among those who switch to dosing every other month.

Dosing and AE Prophylaxis Considerations

The conversation transitioned to the practice of adjusting dosing schedules for patients who derive benefit from teclistamab. “This concept of going to monthly dosing [with teclistamab] is a newer one,” Krishnan said. “I’ve also heard some people saying they’ve stopped therapy, which is a real paradigm shift, especially in advanced relapsed myeloma.”

Although no data from the MajesTEC-1 trial support the option of terminating treatment once teclistamab demonstrates efficacy, Dhakal highlighted that a small subset of his patients with long-term responses has continued to experience an enduring benefit after discontinuing therapy. Regardless, he said he opts to complete dosing once every other month based on patient schedules.

According to Krishnan, the growing use of intravenous immunoglobulin (IVIG) prophylaxis has accompanied the rise of bispecific therapies in multiple myeloma. Dhakal said he initially employed IVIG prophylaxis monthly for every patient before cutting down on this practice, depending on individual immunoglobulin G (IgG) levels. Patients with functional IgG after the first few prophylaxis cycles are eligible to undergo a break, but those who are prone to experiencing infections will continue to have monthly evaluations. For those who tend to have infections, Dhakal stated that IVIG prophylaxis may prevent severe events from occurring.

As part of managing infections in patients who receive teclistamab, vaccination for COVID-19 appears to be another challenge in this population. Specifically, compared with those who receive CAR T-cell therapy, patients who are treated with BCMA-directed bispecific agents appear to have approximately no response to the vaccines, according to Dhakal. However, some patients do have responses to COVID-19 booster doses.

Overall, Krishnan recommended COVID-19 vaccination for patients who receive teclistamab, even if the efficacy of such vaccines would be less pronounced for this group compared with that observed in a general population. “For any patient who becomes COVID-19 positive on a bispecific [agent], we are very aggressive about treating it,” Krishnan said.

Long-Term Clinical Implications

The experts concluded the discussion by focusing on the potential long-term implications of the MajesTEC-1 data on treating patients with relapsed/refractory disease. According to Dhakal, findings affirm the efficacy of teclistamab in this population, as patients experienced responses that continued to deepen over time. Additionally, the data indicated no new safety signals for the agent. Altogether, the results appear to support the continued use of teclistamab for patients with relapsed/refractory disease.

Despite these findings, Krishnan stated that the treatment field still holds several unmet needs, especially those regarding the management of extramedullary disease and the prospect of treating patients until disease progression. For example, those with extramedullary disease tend to have worse PFS and response outcomes vs a more general patient population. She suggested that fixed-duration therapy may mitigate some of these challenges while also benefiting patient quality of life.

“Indefinite treatment is something that needs to be explored. That whole concept needs to be changed for future trials,” Dhakal said. “How can we have a finer duration of treatment, and how can we stop the treatment based on response criteria...in addition to those patients who are responding? We’re already seeing—both in trials and clinical practice—that these patients don’t need 2 months of therapy all the time.”

Garfall AL, Nooka AK, van de Donk NWCJ, et al. Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. J Clin Oncol.2024;42(suppl 16):7540. doi:10.1200/JCO.2024.42.16_suppl.7540

References

1. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Accessed August 8, 2024. https://tinyurl.com/bdfz4s9r
2. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Updated March 7, 2022. Accessed August 8, 2024. https://tinyurl.com/4v6nw42f
3. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed August 8, 2024. https://tinyurl.com/2z8pr6wa
4. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed August 8, 2024. https://tinyurl.com/z559yab4
5. U.S. FDA approves Talvey (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. Janssen Pharmaceutical Companies of Johnson & Johnson. August 10, 2023. Accessed August 8, 2024. https://tinyurl.com/46x8ntdd