B-cell maturation antigen (BCMA) –directed therapies have shown remarkable success in the treatment of multiple myeloma over the past decade.1 We now have three different BCMA-directed therapies approved by the U.S. Food and Drug Administration (FDA) for patients with relapsed or refractory multiple myeloma with four or more prior therapies.2 Belantamab mafodotin, an antibody drug conjugate, was approved in August 2020 based on the results of the phase II DREAMM-2 trial showing an overall response of 31 percent and a median duration of response of 11.0 months.3,4 There were two autologous BCMA-targeted chimeric antigen receptor T cell (CAR-T) FDA approvals — idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) — in March 2021 and February 2022, respectively. Ide-cel was approved based on the results of the KARMMA trial, which showed an overall response of 73 percent and median duration of response of 10.7 months.5 Cilta-cel was evaluated in the CARTITUDE-1 trial where the overall response was 98 percent, and the median duration of response was not reached with a median follow-up of 27 months.6,7 However, the commercial rollout for these two CAR-T therapies has been slow owing to supply chain and manufacturing capacity issues.
These recent FDA approvals notwithstanding, the enthusiasm for BCMA-targeted therapies remains high, and the clinical development of additional novel BCMA-targeted therapies continues at a brisk pace. Bispecific antibodies target CD3 present on the surface of T cells and a tumor-specific antigen, in this case BCMA, present on the tumor cells, leading to anticancer activity.1 There are currently multiple CD3/BCMA–targeted bispecific antibodies in clinical development with promising early results in advanced myeloma.2 The MajesTEC-1 trial as reported by Dr. Philippe Moreau and colleagues is a phase I/II trial of the CD3-BCMA bispecific antibody teclistamab in patients with relapsed or refractory myeloma, and the results from the phase II portion were reported previously.8 Among 165 patients with triple class exposed (i.e., treatment with at least one proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody-based therapy) multiple myeloma treated with weekly subcutaneous injection of teclistamab 1.5 mg/kg, 104 (63%) had an objective response, with a median duration of response of 18.4 months. Sixty-five patients (39.4%) had a complete response, and 44 patients (26.7%) had minimal residual disease negative response (sensitivity, 1 in 105). The treatment was associated with serious toxicities with grade 3/4 adverse events in 156 patients (94.5%). This included cytokine release syndrome and immune effector cell–associated neurologic toxicity in 119 patients (72.1%) and 24 patients (14.5%), respectively; almost all these events were grade 1/2. Notably, 126 patients (76.4%) had an infection, with 74 patients (44.8%) having a grade 3/4 infection. Twelve patients (7.3%) died from COVID-19.8
In Brief
The MajesTEC-1 trial are the first comprehensive safety and efficacy results of a CD-BCMA bispecific antibody for the treatment of myeloma. These results have already led to the European Medicines Agency (EMA) approval of teclistamab for patients with three or more prior therapies.9 Few important observations follow from this trial. First, BCMA targeted T cell engaging therapies (CAR T cells and bispecific antibodies) have remarkable efficacy in myeloma and will be increasingly part of treatment plans for our patients. Second, the prevention and treatment of infectious complications with teclistamab and other bispecific antibodies will be an important challenge and will require careful monitoring and early interventions. Third, choosing between different BCMA-directed treatment options will be challenging, particularly in the absence of randomized data. However, the accessibility of these therapies to the treating physicians would likely dictate choosing one therapy over the other, especially in communities that do not have easy access to a transplant and cellular therapy center. These choices will also be driven by the social support mechanisms in place for a given patient, in addition to the efficacy and safety results of these different products. Finally, the future for drug development in myeloma seems bright with the introduction of these novel immune therapies and the potential to move them to earlier lines and combinations.
Competing Interests
Dr. Mailankody has received research funding from the National Cancer Institute, Juno/Bristol Myers Squibb, Allogene Therapeutics, Janssen Oncology, Takeda Oncology, and Fate Therapeutics; and honoraria from Physician Education Resource and PleXus Communications. Dr. Usmani has received research funding from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; consulting fees from Amgen, BMS, Celgene, EdoPharma, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio; and speaker fees from Amgen, BMS, Janssen, and Sanofi.
