An Immunotherapeutic Shows Promise for Multiple Myeloma Patients Ineligible for Pivotal Trial

Study found teclistamab-cqyv, an immunotherapy, led to responses in patients with high-risk, heavily pretreated multiple myeloma, including after prior BCMA therapy. 

Teclistamab-cqyv (Tecvayli), a type of immunotherapy, received accelerated approval from the U.S. Food and Drug Administration (FDA) in 2022 for certain patients with relapsed or refractory multiple myeloma, based on results from the phase I/II MajesTEC-1 clinical trial. Researchers now suggest that a patient population ineligible for that trial may benefit from the treatment. This is according to results from a study published in Blood Cancer Discovery, a journal of the American Association for Cancer Research.

“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 the study’s lead author Beatrice M. Razzo, MD, an assistant professor at Thomas Jefferson University and a former hematology-oncology fellow at the University of Pennsylvania.

TARGETING MULTIPLE MYELOMA WITH IMMUNOTHERAPY

Teclistamab-cqyv is a T-cell-engaging bispecific antibody that targets multiple myeloma cells via the B-cell maturation antigen (BCMA) receptor. Researchers tested teclistamab-cqyv in MajesTEC-1, a phase I/II clinical trial for patients treated with three or more lines of prior therapy. However, patient populations, such as those who had previously received other BCMA-targeted therapies, were ineligible to participate in the trial, and the potential benefits of teclistamab-cqyv were unknown.

Dr. Razzo and her team set out to understand how teclistamab-cqyv might benefit higher-risk patient populations characterized by a greater prevalence of refractory disease and cytogenetic abnormalities, among other risk factors. The study retrospectively analyzed data from 509 patients with multiple myeloma, half of whom had received at least six prior treatments. Eighty-nine percent of these patients would have been ineligible for MajesTEC-1, with the most common reasons being:

• prior treatment with another BCMA-targeting therapy;
• cytopenias, a condition in which there is a lower-than-normal number of blood cells; and
• an ECOG performance status of two or higher, which is a scale researchers use to define a patient’s level of functioning before and during the trial.

Extending the Benefits of Teclistamab

The bispecific antibody reduced disease burden by at least half in 53% of the 506 evaluable patients, with 45% having at least 90% reduction in disease burden or better, which was deemed a “very good partial response” in the official response criteria.

With half of the patients having at least 10.1 months of follow-up, 50% 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.

“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,” said Dr. Razzo.

As for the MajesTEC-1-ineligible patients, the bispecific antibody also benefited many patients who had previously been 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.

“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 Dr. Razzo.

Extensive pretreatment bone marrow infiltration by myeloma cells 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 Dr. Razzo.

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