In patients with multiple myeloma exposed or refractory to three standard therapies, treatment with the bispecific antibody teclistamab produced strong and durable responses in the phase I/II MajesTEC-1 study.1 The results of weekly subcutaneous dosing of teclistamab in 165 patients were presented at the 2022 ASCO Annual Meeting.
With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or complete response with no measurable residual disease (MRD). The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively, reported Ajay K. Nooka, MD, MPH, FACP, Associate Professor, Department of Hematology and Medical Oncology, Emory University, Atlanta.
“These data support teclistamab as a promising new, off-the-shelf T-cell–redirecting therapy targeting B-cell maturation antigen.”— Ajay K. Nooka, MD, MPH, FACP
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“Teclistamab yields deep and durable responses in patients with highly refractory multiple myeloma…. These data support teclistamab as a promising new, off-the-shelf T-cell–redirecting therapy targeting BCMA [B-cell maturation antigen],” said Dr. Nooka.
The study was simultaneously published in TheNew England Journal of Medicine.2 The manufacturer, Janssen, has submitted a biologics license application to the U.S. Food and Drug Administration based on the initial results of the MajesTEC-1 trial.
In an interview with The ASCO Post, Dr. Nooka noted the magnitude of this benefit in this difficult-to-treat population: “The data in MajesTEC-1 trial are rivaling what we see in KarMMA-1 with the idecabtagene vicleucel approach in the cohort that received 450 million cells (12.1 months).3 With teclistamab, we have an off-the-shelf bispecific antibody that does not require the whole process of manufacturing CAR T cells, and we are able to see the same benefit,” Dr. Nooka said.
Teclistamab targets both B-cell maturation antigen (BCMA) on the surface of myeloma cells and CD3 on the surface of T cells. It redirects CD3-positive T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells.
Other investigators reported at the ASCO meeting encouraging results by combining teclistamab with daratumumab in the phase Ib TRIMM-2 trial.4
The phase I/II MajesTEC-1 trial enrolled 165 adults who had received at least three previous lines of therapy (median of five); all patients (100%) were triple-class–exposed, 70% were penta-drug–exposed, 78% were triple-class–refractory, and 30% were penta-drug–refractory.
All patients received a weekly subcutaneous injection of 1.5 mg/kg following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.
High Response Rates
With a median follow-up of 14.1 months, the overall response rate was 63.0%, and 39.4% achieved a complete response or better; the median duration of response was 18.4 months. “A response rate of 63% represents a substantial benefit for patients with triple-class–exposed disease,” Dr. Nooka commented.
“The objective response rate was consistent across clinically relevant subgroups, including high–cytogenetic risk and penta-drug–refractory subgroups,” Dr. Nooka noted. The responses were durable and persisted over time, with 64.4% of responders maintaining their response at the time of data cutoff, he added.
A total of 44 patients overall (26.7%) were found to have no MRD at a threshold of 10−5. Almost half the patients (46.2%) with a complete response achieved MRD negativity.
Median progression-free survival was 11.3 months (95% confidence interval [CI] = 8.8–17.1 months). The median duration of overall survival was 18.3 months (95% CI = 15.1 months to not estimable) and was not mature after censoring of data for 97 patients (58.8%).
Teclistamab Plus Daratumumab
In the phase Ib TRIMM-2 study of 65 patients who had received a median of five prior lines of therapy, teclistamab was given in three different dosing cohorts with subcutaneous daratumumab at 1,800 mg. This combination has been shown to upregulate CD38+/CD8+ T cells and proinflammatory cytokines, pointing to synergy, said lead investigator Paula Rodríguez-Otero, MD, PhD, of the University of Navarra, Pamplona, Spain, who presented a poster at the ASCO meeting.4
“The downside of teclistamab—and of the other bispecific antibody being evaluated in myeloma, elranatamab—is the signal for infections is high.”— Paula Rodríguez-Otero, MD, PhD
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Among 51 response-evaluable patients, overall response rates were 76.5%, with very good partial responses or better seen in 70.6%. Among patients with prior exposure to an anti-CD38 antibody, 73.7% responded. Responses were durable and deepened over time, the investigators reported.
“We observed high response rates (74%–100%) in heavily pretreated patients with relapsed/refractory myeloma, the majority of whom (63%) had anti-CD38–refractory disease,” Dr. Rodríguez-Otero reported. There is reason to believe that patients who are still sensitive to daratumumab may have even better responses, a hypothesis that will be tested in MajesTEC-3.
Tolerability: Watching for Infections
In MajesTEC-1, grade 3 or 4 adverse events were reported by 156 patients (94.5%). The most common, cytokine-release syndrome, occurred in 119 patients (72.1%); however, only 1 patient (0.6%) had a grade 3 event, no patient had a grade 4 event, and all fully resolved without treatment discontinuation or dose reduction. Most cases occurred after step-up and cycle 1 doses; six patients experienced this side effect in cycle 2 or later. No patients discontinued teclistamab because of cytokine-release syndrome.
Other grade 3 or 4 adverse events included neutropenia (64.2%), anemia (37.0%), and thrombocytopenia (21.2%). Neurotoxic events, including immune effector cell–associated neurotoxicity, occurred in 24 patients (14.5%), and most were grade 1 or 2. Grade 3 or 4 diarrhea occurred in 3.6% and fatigue, in 2.4%.
Two patients discontinued teclistamab because of toxicities other than cytokine-release syndrome. Five deaths were attributed to teclistamab: two caused by COVID-19, and one each from pneumonia, hepatic failure, and progressive multifocal leukoencephalopathy.
For overall tolerability, the most concern has been focused on the risk for infections, which occurred in 76.4% of patients overall, with a 44.8% incidence of grade 3 or 4. “The downside of teclistamab—and of the other bispecific antibody being evaluated in myeloma, elranatamab—is the signal for infections is high,” Dr. Nooka commented in the interview. “Both have shown infections that you don’t commonly see. For this, we need to develop a strategy. One could be to stop the drug when you achieve the desired response. The other could be to implement aggressive prophylactic strategies that were not routinely given in the clinical trials.”
Acknowledging that administration of teclistamab will not be simple in the community, Dr. Rodríguez-Otero stated: “We need to find out how to deliver it safely in the outpatient setting.”
DISCLOSURE: Dr. Nooka reported financial relationships with Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Pfizer, Secura Bio, and Takeda. Dr. Rodríguez-Otero reported financial relationships with AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen, Kite, Oncopeptides, Pfizer, Sanofi, and Takeda.
1. Nooka AK, Moreau P, Usmani SZ, et al: Teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Updated efficacy and safety results from MajesTEC-1. 2022 ASCO Annual Meeting. Abstract 8007. Presented June 5, 2022.
3. Munshi NC, Anderson Jr LD, Shah N, et al: Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384:705-716, 2021.
4. Rodríguez-Otero P, D’Souza A, Reece D, et al: A novel, immunotherapy-based approach for the treatment of relapsed/refractory multiple myeloma: Updated phase 1b results for daratumumab in combination with teclistamab (a BCMA x CD3 bispecific antibody). 2022 ASCO Annual Meeting. Abstract 8032. Presented June 4, 2022.
Madhav V. Dhodapkar, MBBS
“BCMA-targeting bispecific antibodies work, showing impressive single-agent activity in heavily pretreated multiple myeloma. This class of agents is likely to become an important component of future antimyeloma therapies, but we must learn how to optimally use them,” ...