Real-world data shows teclistamab can benefit many multiple myeloma patients who would have been ineligible for pivotal trial

(Press-News.org) Bottom line: Teclistamab-cqyv (Tecvayli) led to clinically meaningful responses in patients with heavily pretreated multiple myeloma who would have been ineligible for the MajesTEC-1 trial, and identified a novel factor independently associated with outcomes.

Journal in Which the Study was Published: Blood Cancer Discovery, a journal of the American Association for Cancer Research (AACR).

Author: Beatrice M. Razzo, MD

Background: Teclistamab-cqyv is a T-cell-engaging bispecific antibody that targets multiple myeloma cells via the B-cell maturation antigen (BCMA) receptor. It received accelerated approval in 2022 for patients treated with four or more lines of prior therapy based on results from the phase I/II MajesTEC-1 clinical trial. However, the potential benefits of the bispecific immunotherapy in populations not represented in the trial, or in the presence of risk factors associated with poorer outcomes, remains an important focus of ongoing clinical investigation.

“Teclistamab is an important treatment option for patients with relapsed/refractory multiple myeloma but there is still a lot to learn about how to modify risk factors and optimize the use of teclistamab in clinical practice,” said Beatrice M. Razzo, MD, an assistant professor at Thomas Jefferson University, former hematology-oncology fellow at the University of Pennsylvania, and the lead author of the real-world study involving patients treated in a consortium of 15 U.S. academic medical centers.

How the Study was Conducted: In the largest study of its kind to date, Razzo and her team retrospectively analyzed data from 509 multiple myeloma patients, half of whom had received at least six prior treatments. Eighty-nine percent (453) of these patients would have been ineligible for MajesTEC-1, with the most common reasons being prior treatment with another BCMA-targeting therapy (236 patients), cytopenias (189 patients), and an ECOG performance status of two or higher (117 patients). Overall, patients in this study represented a higher-risk population, with more frail individuals and a greater prevalence of multidrug refractory disease and cytogenetic abnormalities, according to Razzo.

Results: The bispecific antibody reduced disease burden by at least half in 53% (270) of the 506 evaluable patients, with 45% (228) having at least 90% reduction in disease burden (so-called “very good partial response” in the official response criteria). At a median potential follow-up of 10.1 months, half of patients remained free of progression for at least 5.8 months and an estimated 61% were alive at one year. Even with the high prevalence of patients with high-risk features, there appeared to be no increase in adverse event frequency compared to their prevalence in MajesTEC-1 and other real-world analyses of the bispecific antibody’s use.

Notably, the 56 patients who would have been eligible for MajesTEC-1 had similar overall response rates compared with the registration trial population, 61% and 63%, respectively.

With regard to MajesTEC-1-ineligible patients, the bispecific antibody also benefited many patients previously treated with BCMA-targeting CAR T cells or the antibody-drug conjugate belantamab mafodotin (Blenrep). Forty percent exhibited “very good partial responses,” including 43% of the 58 patients whose disease had been previously treated with the antibody-drug conjugate and 38% of the 104 patients whose disease had previously been treated with CAR T cells.

Further analyses revealed that patients who underwent prior BCMA-targeting therapy within nine months of starting teclistamab-cqyv exhibited lower rates of “very good partial responses” and shorter periods of progression-free survival. However, this therapeutic resistance occurred more often in the group recently treated with CAR T cells than in those recently treated with belantamab mafodotin, who responded at a rate comparable to BCMA therapy-naïve patients.

Author’s Comments: “These findings in patients with prior BCMA CAR T cell exposure suggest that increased spacing may allow for the recovery of T-cell fitness or the reemergence of BCMA-expressing subclones. Alternatively, a longer interval may simply reflect less aggressive disease biology,” explained Razzo.

Extensive pretreatment bone marrow infiltration by myeloma cells (60% fraction or higher) or indirect markers of high disease burden such as anemia, thrombocytopenia, or low absolute lymphocyte count were also significantly associated with lower rates of “very good partial responses” and shorter periods of progression-free survival. The study also found that elevated baseline ferritin was associated with inferior outcomes independently of disease burden.

“Nevertheless, teclistamab-cqyv remains an important treatment option for patients with late-line, relapsed or refractory multiple myeloma, and should be considered even in those with prior BCMA exposure or markers of high disease burden and inflammation.” said Razzo.

“Our results highlight the complex interplay between real-time clinical parameters and baseline disease features in influencing patient outcomes and suggest that the former may be a more reliable indicator of disease biology than the latter in these patients, but there is still a lot to learn,” she added.

To that end, Razzo and her colleagues are focused on their ongoing phase II trial investigating limited-duration drug dosing in patients with advanced multiple myeloma/                 

Study Limitations: Limitations of the study include the nonstandardized nature of the real-world data as well as the lack of a centralized independent review or adjudication process for response and toxicity assessments. Information regarding the dose intensity of teclistamab-cqyv given to patients was also not available for analysis.

Funding & Disclosures: The study was supported by a  National Cancer Institute training grant. Razzo has received advisory board honoraria from Johnson & Johnson.

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