Teclistamab confers durable benefit in advanced multiple myeloma
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CHICAGO — Teclistamab continued to demonstrate durable efficacy for patients with relapsed or refractory multiple myeloma, according to results from the phase 1/phase 2 MajesTEC-1 trial.
Updated results from the trial — presented at ASCO Annual Meeting and published simultaneously in The New England Journal of Medicine — showed a median duration of response of more than 18 months among heavily pretreated patients.
Background
Teclistamab (JNJ-64007957, Janssen) — an investigational bispecific antibody that binds B-cell maturation antigen (BCMA) and CD3 — is designed to provide durable treatment benefits while maximizing convenience for patients, according to Ajay K. Nooka, MD, MPH, FACP, associate professor and director of the myeloma program in the department of hematology and medical oncology at Emory University School of Medicine.
“Unfortunately, the options we currently have — including the use of [chimeric antigen receptor T-cell therapies] — involve a lot of processing, which comes at a cost to the patient, as well,” he said.
Antibody-drug conjugates have been approved for these patients and typically result in response times of approximately a year, Nooka added.
“There is room in this space for an off-the-shelf agent that can provide more durable benefits,” he told Healio.
Methodology
The MajesTEC-1 investigators presented data from the phase 1 portion of their study at last year’s ASCO Annual Meeting.
As Healio previously reported, those results showed the investigational treatment induced durable and deepening responses among patients with relapsed or refractory multiple myeloma who received three or more previous lines of therapy.
This year, Nooka and colleagues presented data from all 165 patients (median age, 64 years; range, 33-84; 58.2% males) treated in the combined phase 1 and phase 2 portions of the study.
Study criteria excluded patients who received previous BCMA-directed therapy from the phase 1 portion of the study, but those patients were eligible to participate in the phase 2 portion.
Patients received the recommended phase 2 dose of 1.5 mg/kg subcutaneous teclistamab weekly until disease progression.
Overall response rate served as the primary endpoint. Secondary endpoints included safety and other measurements of treatment efficacy.
Key findings
Median follow-up was 14.1 months (0.26-24.4).
Teclistamab conferred an ORR of 63% (95% CI, 55.2-70.4), with a complete response rate of 39.4%. More than half (58.8%) of patients achieved a very good or better partial response.
Researchers reported minimal residual disease (MRD) negativity rates by next-generation sequencing of 26.7% in the overall study population and 46.2% among those who achieved complete response.
Sixty-seven of 104 patients (64.4%) who responded to therapy had an ongoing response as of the data cutoff date. Investigators reported an 18.4-month (95% CI, 14.9-not estimable) median duration of response to therapy, with a 12-month event-free survival rate of 68.5% (95% CI, 57.7-77.1) that increased to 80.1% (95% CI, 67.6-88.2) among patients who had a complete response or better.
The researchers reported median PFS of 11.3 months (95% CI, 8.8-17.1) and median OS of 18.3 months (95% CI, 15.1-not estimable).
The most common grade 3 or grade 4 treatment-related hematologic adverse events were neutropenia (64.2%) anemia (37%) and lymphopenia (32.7%).
Cytokine release syndrome was the most frequently observed treatment-related adverse event (72.1%), with one patient experiencing grade 3 CRS.
Twenty-four patients (14.5%) experienced neurotoxicity, including five (3%) who developed immune effector cell-associated neurotoxicity syndrome. One case of high-grade neurotoxicity occurred (grade 4 seizure with concomitant bacterial meningitis).
Five treatment-related deaths occurred. Two patients discontinued therapy due to treatment-related adverse events, and one additional patient required a dose reduction during cycle 21.
Clinical implications
Teclistamab “absolutely” provided clinical benefit to patients in the MajesTEC-1 trial, Nooka said.
“These are very encouraging results,” he told Healio.
The PFS rate for teclistamab is similar to that observed with the highest dose of the BCMA-directed CAR-T idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) seen in the KarMMa trial, Nooka added.
PFS of nearly a year is a “very good result” for this group of triple-class refractory patients using an off-the-shelf agent, Nooka said.
“There are limited options available for these patients,” he added. “An off-the-shelf agent like teclistamab would be ideal for patients who cannot wait for CAR T cells to become available.”
Trials are underway to investigate teclistamab alone and in combination with other agents as an earlier line of therapy to determine if earlier treatment can prolong survival, Nooka said. These include the ongoing MajesTEC-3 trial, which is evaluating teclistamab in combination with daratumumab (Darzalex, Janssen) for patients with relapsed or refractory multiple myeloma.
Perspective
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Jack Khouri, MD
BCMA blockade demonstrates yet again remarkable efficacy in the treatment of highly refractory multiple myeloma) as evidenced by the results of the MajesTEC-1 study, which examined the role of teclistamab in a heavily pretreated population. Not surprisingly, the drug was very effective, with a response rate of 64% and more than one-third of patients achieving a complete response. Responses appeared durable but relapse still occurred.
BCMA-directed CAR T-cell therapy has revolutionized the treatment of multiple myeloma but comes with several challenges. The limited access to certified centers and manufacturing slots, as well as prolonged manufacturing time, are significant hurdles for many patients. Thus, having an off-the-shelf, easily accessible BCMA-targeted therapy such as teclistamab is a salient advance in the field. More centers likely will be able to offer teclistamab given its outpatient administration and manageable side effect profile.
Despite the high response rates seen with CAR T-cell therapy, relapse is still common. Teclistamab’s continuous administration may provide a constant driver of T-cell stimulation contributing to response durability and potentially overcoming some of the shortcomings of CAR T cells. Nevertheless, disease relapse with BCMA blockade is a challenge, and our understanding of its mechanisms continues to evolve. The cost implications of continuous therapy associated with bispecific antibodies are yet to be determined.
Choosing between teclistamab and CAR T-cell therapy will be challenging and likely depend on availability and disease burden and tempo, as patients with rapidly progressive disease may be better candidates for bispecific antibodies. Notably, patients with extramedullary disease seem to have lower response rates to teclistamab.
Data pertaining to sequencing BCMA-directed therapies in clinical trials are eagerly awaited and will have tremendous relevance to patient care. Moreover, data on bispecific antibodies and CAR T-cell therapies against different targets are emerging and will represent a substantial addition to our treatment repertoire.
Collapse
Nooka AK, et al. Abstract 8007. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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