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Bispecific T‑cell engagers or bispecific antibodies target both BCMA on the myeloma cell and CD3 on T-cells, bringing CD3 T‑cells into proximity with the myeloma cell, resulting in a specific cytotoxic response against BCMA-expressing MM cells.
As mentioned, these are “off-the-shelf” therapies, that do not require any cell engineering and various BCMA-targeted therapies have been developed using these modalities and have shown impressive efficacy for patients with even heavily pretreated MM.
Teclistamab is one of these investigational BCMA x CD3 bispecific antibody currently in clinical trials for patients with R/R MM with some of the most mature data for this class of therapy.
MajesTEC-1 is a first-in-human, phase I/II study of teclistamab in patients with R/R MM who had received ≥3 prior lines of therapy and were triple-class exposed, with no prior BCMA therapy.35 The initial phase I results identified the recommended phase II dose as 1.5 mg/kg weekly, given subcutaneously, with step‑up dosing at 0.06 and then 0.3 mg/kg. Updated data from this study have reported outcomes with this dose.36
The primary endpoint in this study is ORR.36 After a median follow-up of 7.8 months (range, 0.5 to 18), the ORR was 62% with teclistamab, and 58% achieved VGPR or better. The MRD negativity rate at the 10-5 level was 37% and 25% at 10-6 level.
Overall, CRS was seen in 72% of patients, but most was grade 1 or 2, apart from 1 transient grade-3 event. Neurotoxicity was seen in 13% of patients, none at grade 3 or higher. Five patients had ICANS events, all at grade 1 or 2. Median follow-up is fairly short at present, but we hope to see more mature data on the true duration of response in future.
Other BCMA‑targeted bispecific therapies are in development, including elranatamab. MagnetisMM‑1 is a phase I study of elranatamab in patients with R/R MM and prior treatment with IMiD, PI, and anti-CD38 monoclonal antibody. Specific to this trial of an anti-BCMA bispecific therapy, previous anti-BCMA therapy was permitted.37 The primary endpoints in this dose-escalation study were safety and establishment of a recommended dose for phase II study.
This trial reported data from various dosing cohorts, including both IV and SC dosing, and the most recent presentation of data focused on the cohort of patients who received SC dosing. In this cohort of patients, the median number of prior lines of therapy was 6, with 22% of participants having received anti-BCMA therapy previously.37 The ORR was 70% at doses ≥215 μg/kg in the dose escalation cohort of this trial and 5 out of 6 patients at elranatamab 1000 µg/kg achieved a response. To attempt to mitigate AEs, particularly CRS, 2 priming cohorts were planned, with patients received a single priming dose of 600 µg/kg elranatamab, followed by a full dose of 1000 µg/kg either weekly or every 2 weeks. ORR was similar with weekly or every 2-week dosing (57% vs 61%, respectively) in these priming cohorts. In addition, 3 of 4 patients with previous use of BCMA‑directed therapy achieved a response, including 1 sCR and 2 VGPRs. Again, these are early observations, but we look forward to seeing longer‑term data with this agent.
CRS was seen in 87% of patients in this trial, similar to that observed in the MajesTEC study of teclistamab above. In addition, 16% of patients experienced ICANS, either at grade 1 or 2 suggesting, again, that this toxicity was manageable.
ABBV-383 (formerly TNB‑383B) is another investigational BCMA‑CD3 bispecific agent that is being evaluated in R/R MM in a first-in-human phase I trial.38 Participants enrolled in this trial had previously received ≥3 prior lines of therapy (including a PI, IMiD, and anti-CD38 monoclonal antibody), were ineligible for standard therapy, and had not previously been exposed to BCMA-targeted treatment. Similar to the previous study, the primary endpoints of this dose-escalation trial were safety and establishment of a recommended phase II dose.
In this study, ABBV-383 was given by IV administration every 3 weeks, which may be attractive for patients who have been on therapy for a year, or even 2 years. Patients had received a median of 5 prior lines of therapy.38
Response rates were reported separately for the dose-escalation and the dose-expansion cohorts in this trial. Among 26 patients in the dose-escalation cohorts who received ABBV-383 at doses of 40 mg or higher, ORR was 81%. This decreased somewhat to 60% when including the 60 patients participating in the expansion and escalation cohorts.
The frequency of CRS was 54% overall, and 69% when including the dose-escalation and dose-expansion cohorts. Again, most cases were grade 1 or 2, although 3% were at grade 3 or higher. All CRS events resolved quickly with tocilizumab or standard supportive care.
Median DoR has not yet been reached in this trial of ABBV-383, but the 12-month DoR rate was 72% in this analysis.38 Similar to the 2 other trials we mentioned, ABBV-383 may prove to be an effective regimen for patients with heavily pretreated R/R MM, and we look forward to seeing more data.
In comparison with CAR T‑cell therapy, which engineers patient-specific BCMA-specific CAR T-cells ex vivo, bispecific therapies enhance the in vivo activity of the patient’s own T-cells and, because they are an “off-the-shelf” therapy, they can be used more quickly and may be more convenient.
If we compare the various bispecific therapies that currently are being evaluated in R/R MM, the reported ORR for each agent is in the range of 60% to 80%.39 The frequency of CRS varies from as low as 38% in a study of REGN-5458 to 87% with elranatamab. The frequency of neurotoxicity is lower, between 2% and 20%, but importantly, these toxicities appear to be manageable. Direct comparisons between studies is not possible since each of these trials has enrolled somewhat different populations, such as allowing patients with prior BCMA therapy use in the case of the elranatamab study. As we noted, some of these therapies are for IV administration, with dosing every 3 weeks, whereas some of these agents use SC dosing. Ultimately, logistics and efficacy will have to be optimized for each agent decide what is the optimal therapy for a particular patient.
Bispecific antibodies have shown promising efficacy, and the use of combination therapy may improve upon it. For example, the TRIMM‑2 study is a phase I trial of teclistamab plus daratumumab for patients with R/R MM who have received ≥3 prior lines of therapy.40
Daratumumab is an anti‑CD38 monoclonal antibody that is approved in multiple combinations for use in MM41 and, in preclinical models, has been shown to lead to T-cell expansions and enhanced cytotoxic T-cell activation. As we have discussed already, teclistamab is an investigational BCMA x CD3 bispecific antibody that brings a patient’s own T-cells in proximity with BCMA myeloma cells. Combining these 2 modalities may result in enhanced myeloma cell killing by the patient’s own immune system. The TRIMM‑2 trial assessed daratumumab given with 3 different dosing regimens of teclistamab.
The combination of daratumumab with teclistamab was well tolerated, with no unexpected or overlapping AEs.40 The frequency of CRS was 65%, and all CRS events were grade 1 or 2. Grade 2 ICANS occurred in 1 patient and was fully resolved in 5 days. Infections (a known AE with daratumumab) were reported in 60% of patients, and these were grade 3 or higher in 30%.
Patients had received a median of 5 prior lines of therapy, with 76% of patients with prior anti-CD38 therapy, and 19% exposed to previous BCMA-targeted therapy.40 The median follow-up at the time of this analysis was 5.1 months. ORR was between 70% and 100% across dosing arms, with higher responses seen with weekly dosing of teclistamab. Among 27 responders, with a median follow-up of 6.5 months, 93% remained on treatment. Overall, these early findings suggest these agents can be combined safely and may pave the way for use of steroid‑free regimens sooner in the course of myeloma management.