Bispecific Antibody Boosts Survival in Relapsed/Refractory Multiple Myeloma

CHICAGO — Teclistamab (Tecvayli) monotherapy significantly improved survival compared with standard therapies in patients with multiple myeloma who had received up to three previous lines of therapy, the phase III MajesTEC-9 trial showed.

The estimated 18-month progression-free survival (PFS) rate was 69.8% with teclistamab compared with 26.9% with pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or carfilzomib (Kyprolis) and dexamethasone (Kd; HR 0.29, 95% CI 0.23-0.38, P<0.001), reported Cyrille Touzeau, MD, PhD, of the University Hospital of Nantes in France, and colleagues.

The estimated 18-month overall survival rates were 79.2% versus 68.6%, respectively (HR 0.60, 95% CI 0.43-0.83, P=0.002).

The findings were presented at the American Society of Clinical Oncology annual meeting and published in the New England Journal of Medicine.

Along with results from MajesTEC-3, in which treatment with teclistamab and subcutaneous daratumumab-hyaluronidase (Darzalex Faspro) significantly improved PFS in patients who had received up to three previous lines of therapy, these results “support the use of teclistamab-based, glucocorticoid-sparing regimens as second-line and later treatment options for multiple myeloma across a range of practice settings,” Touzeau and colleagues wrote.

In an editorial accompanying the study, Mariá-Victoria Mateos, PhD, of University Hospital of Salamanca in Spain, noted that the study represents a “pivotal step forward.”

Currently, most patients with multiple myeloma receive proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies as frontline therapy.

“Although these advances have prolonged survival, they have also reshaped the biologic features and clinical behavior of early relapse, given that patients at first relapse have disease that is increasingly refractory to both lenalidomide [Revlimid] and anti-CD38 therapy,” she wrote. “By evaluating teclistamab monotherapy in patients who had received one, two, or three lines of therapy previously — that is, all with previous exposure to lenalidomide and anti-CD38 antibodies — this trial addresses a clinically relevant and previously underexplored population.”

MajesTEC-9 included 574 patients who had previously received one to three lines of antimyeloma therapy, including an anti-CD38 monoclonal antibody and lenalidomide, and had documented disease progression or did not have a response to their last regimen. Of these patients, 291 received teclistamab, a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, and 283 received either PVd or Kd.

Median patient age was 70 years (29.2% were 75 or older), 51% were men, 65.4% were white, 19.9% were Asian, and 3.4% were Black. The median number of previous lines of therapy was two, with 21.6% of patients having received only one line of therapy previously.

Overall, 73.6% of patients in the teclistamab group and 74.4% of those in the PVd or Kd group had disease refractory to both anti-CD38 therapy and an immunomodulatory drug.

In other notable findings, the overall response rate was 84.5% in the teclistamab group and 54.2% in the PVd/Kd group (risk ratio 1.56, 95% CI 1.39-1.75). Complete response or better was reported in 65.9% and 16.8% of the two groups, respectively (P<0.001). About 39% of patients in the teclistamab group had a complete response with minimal residual disease-negative status versus 6.7% in the PVd/Kd group (risk ratio 5.76, 95% CI 3.69-9.01).

At 18 months, the percentage of patients without symptom worsening was 73.5% with teclistamab and 55.1% with PVd or Kd.

Adverse events of grade 3 or 4 occurred in 84.9% of patients in the teclistamab group and in 76.3% of patients who received PVd or Kd, with grade 5 adverse events occurring in 6.5% and 3.5%, respectively.

Cytokine release syndrome — mostly grade 1 or 2 — occurred in 66% of teclistamab recipients, and immune effector cell-associated neurotoxicity syndrome occurred in 4.1%.

Infections of any grade occurred in 82.8% of patients receiving teclistamab and in 68.2% of those receiving PVd or Kd, and infections of grade 3 or 4 occurred in 41.6% and 29%, respectively. Fatal infections occurred in 5.5% and 2.8%.

In her editorial, Mateos suggested that safety remains a challenge for BCMA-targeted therapies, particularly with respect to infections, and that questions remain on how teclistamab should be positioned “within an increasingly crowded therapeutic landscape.”

“With BCMA-targeted therapies now established as a cornerstone at first relapse, the focus must shift to optimization,” she concluded. “Teclistamab monotherapy offers a pragmatic and accessible approach, but its broader use will depend on improving safety — particularly, with regard to infections — and refining patient selection and treatment sequencing.”