Ajay K. Nooka, MD, MPH, FACP, Associate Professor in the Department of Hematology and Medical Oncology at Winship Cancer Institute, Emory University, Atlanta, commented on the promising emergence of bispecific T-cell engaging (bispecific) antibodies, as represented by studies presented at the 2021 ASH Annual Meeting & Exposition.1-7 These studies, which all included triple-class–exposed, heavily pretreated patients, featured four drugs that target BCMA and two that target novel antigens (FcRH5, GPRC5D); a seventh study evaluated a bispecific antibody in combination with the anti-CD38 antibody daratumumab, thus demonstrating the safety of using these drugs in combinations, he said.
As Dr. Nooka noted, the first antibody-drug conjugate targeting BCMA, belantamab, was approved by the U.S. Food and Drug Administration in August 2020 and the first chimeric antigen receptor T-cell therapy, also targeting BCMA, was approved in March 2021 for patients with relapsed or refractory multiple myeloma previously treated with four or more lines of therapy.
“Despite the availability of these antimyeloma therapies, patients continue to relapse, further fueling the need for effective antimyeloma strategies aimed at longer disease control. In this context, early data presented at the 2021 ASH Annual Meeting & Exposition show much promise for bispecific T-cell–engaging antibodies in the treatment of relapsed or refractory myeloma,” he said.
Ajay K. Nooka, MD, MPH, FACP
“The availability of the bispecific T-cell engagers has revolutionized the playing field for patients with BCMA-sensitive and BCMA-resistant disease. As readily available, off-the-shelf agents with a predictable onset of cytokine-release syndrome (within 1–2 days of administration) and resolution (within 1–3 days) and confined to the priming doses and cycle 1, bispecific antibodies seem attractive and manageable,” Dr. Nooka commented, adding that neurotoxicity was also rare and self-limited.
“With safety established, the efficacy seems promising and in parallel with other BCMA-targeted therapies, with response rates of 60% to 70% in heavily pretreated patients and a median time to response of about 1 month. Of note, these responses are deep (mostly very good partial responses or better) and durable,” Dr. Nooka said.
In addition, efficacy extended to the BCMA-refractory cohorts in the studies. Cevostamab5 and talquetamab6 may become “viable options” for patients experiencing disease progression on BCMA-targeted therapies, he added.
Higher doses administered at increased intervals (elranatamab at 1,000 μg/kg subcutaneously every 2 weeks, talquetamab at 800 μg/kg subcutaneously every 2 weeks, and ABBV-382 at 60 mg intravenously every 3 weeks)3,6,4 appear to have comparable efficacy and safety to weekly dosing (and is supported by their pharmacokinetic profiles), and this allows for a reduced frequency of dosing in the future. REGN54582 did not reach its maximum-tolerated dose but delivered a high response rate (75%), “proving the safety of bispecific antibodies as monotherapy,” he said.
The future may also include combinations. Talquetamab-mediated induction of cytotoxic T cells in the presence of daratumumab7 and the increased response rate compared with talquetamab monotherapy provide a rationale for further exploration of this combination, according to Dr. Nooka. “More bispecific combination approaches to leverage synergy are underway,” he added.
BCMA-Targeted Bispecific Antibodies
In the MajesTEC-1 trial,1 an overall response rate of 62% and a very good partial response or better rate of 58% were observed. The time to first response was short (median, 1.2 months), and responses deepened over time. “Of note, although most subgroups benefited from teclistimab, a more pronounced benefit was seen among patients who had received fewer than three prior lines of therapy,” Dr. Nooka suggested. Cytokine-release syndrome was mostly confined to step-up and cycle 1 dosing (32.7% were ≥ grade 2), and just one transient grade 3 case was observed. Neurotoxicity was rare (12.7%) and did not lead to dose reductions or discontinuations.
As anticipated, more than two-thirds of patients had evidence of hypogammaglobulinemia, and a third received intravenous immunoglobulins (IVIG) per investigator’s discretion. “Given the increased incidence of hypogammaglobulinemia in BCMA-targeted bispecific antibodies, and a potential for increased risk of infections, administering monthly IVIG for the duration of treatment seems logical,” said Dr. Nooka.
In the ongoing phase I study of REGN5458,2 among 24 patients treated with 200 to 800 mg, the response rate was 75%, with 58% being very good partial responses or better. “With this agent, the rates of cytokine-release syndrome were much lower” than typically seen with these agents,” he noted. A total of 38% of patients developed any-grade cytokine-release syndrome, with all but 4% being grade 1. Neurotoxicity incidence was also low, with 4% being grade 2.
Elranatamab was given subcutaneously in a dose-escalation scheme in the MagnetisMM-1 study.3 Responses were observed in 69% of patients receiving 1,000 μg/kg weekly. “Of interest is the cohort with prior anti-BCMA exposure (21.8% of patients), 7 of 10 of whom (70%) achieved responses, all very good partial responses or better,” Dr. Nooka said. The dose of 1,000 μg/kg every 2 weeks achieved exposure associated with antimyeloma efficacy, which supports allowing responders to be dosed every 2 weeks after 6 months of treatment. At this dose, cytokine-release syndrome was seen in 87% of patients, but cases were mostly grade 1 or 2.
Lastly, TNB-383B (also known as ABBV-383) was studied in a dose-escalation schema. Among the 60 patients receiving at least 40 mg, the response rate was 60%, with very good partial responses or better seen in 40%.4 Cytokine-release syndrome of any grade occurred in 69%, all but 4% were grade 1 and all were resolved without treatment discontinuation. Neurotoxicity was also rare (4% grade 2).
Non–BCMA-Targeting Bispecific Antibodies
Other bispecific antibodies—including cevostamab and talquetamab—had non-BCMA targets. In the dose-escalation study of cevostamab, an FcRH5 x CD3 bispecific, one-third of patients had prior anti-BCMA treatment.5 Among 60 patients treated with 132 to 198 mg, the overall response rate was 56.7%, with 33.3% being very good partial responses or better. Cytokine-release syndrome was reported in 80.7% (1.2% grade 3), and cases were generally confined to cycle 1. The overall incidence of neurotoxicity was 14.3% (0.6% grade 3).
Talquetamab, a GPRC5D × CD3 bispecific, was evaluated at a weekly subcutaneous dose of 405 μg/kg (cohort 1) and an every-2-week dose of 800 μg/kg (cohort 2) in the MonumenTAL-1 trial.6 Previous treatment included anti-BCMA therapies in 27% and 16% of these dosing cohorts, respectively. In cohorts 1 and 2, respectively, responses were observed in 70.0% and 66.7%, with very good partial responses or better in 53.3% and 52.4%.
A “unique” toxicity—dysgeusia (abnormal taste)—was observed with talquetamab in 60% and 36%, respectively, mostly grade 1 or 2. Cytokine-release syndrome was observed in 76.7% and 72.0%, respectively, mostly mild and confined to cycle 1. “The 800-μg/kg every-2-week dose appeared to have comparable efficacy and safety to 405 μg/kg weekly, with no new safety signals, allowing for increasing the dosing interval,” Dr. Nooka commented.
Finally, talquetamab given in combination with fixed-dose daratumumab was active in the phase Ib TRIMM-2 trial, in which 55.2% of patients had prior anti-BCMA treatment.7 Responses ranged from 77.8% to 85.7% (according to the dose) and were improved over talquetamab monotherapy, without overlapping toxicity. Cytokine-release syndrome, mostly grade 1, occurred in 55.2% (17.2% grade 2) and was generally confined to cycle 1. Dysgeusia was observed in 48.3% and was mostly mild, with few dose adjustments required.
DISCLOSURE: Dr. Nooka has served as a consultant for BMS, Janssen, Takeda, Amgen, Adaptive, GlaxoSmithKline, Sanofi, Oncopeptides, Karyopharm, Secura Bio, and BeyondSpring.
REFERENCES
1. Moreau P, Usmani SZ, Garfall AL, et al: Updated results from MajesTEC-1: Phase 1/2 study of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 896. Presented December 13, 2021.
2. Zonder JA, Richter J, Bumma N, et al: Early, deep, and durable responses, and low rates of cytokine release syndrome with REGN5458, a BCMA x CD3 bispecific antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 160. Presented December 11, 2021.
3. Sebag M, Raje NS, Bahlis NJ, et al: Elranatamab (PF-06863135), a B-cell maturation antigen targeted CD3-engaging bispecific molecule, for patients with relapsed or refractory multiple myeloma: Results from MagnetisMM-1. 2021 ASH Annual Meeting & Exposition. Abstract 895. Presented December 13, 2021.
4. Kumar SK, D’Souza A, Shah N, et al: A phase I first-in-human study of TNB-383B, a BCMA x CD3 bispecific T-cell-redirecting antibody, in patients with relapsed/refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 900. Presented December 13, 2021.
5. Trudel S, Cohen AD, Krishnan AY, et al: Cevostamab monotherapy continues to show clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma: Updated results from an ongoing phase I study. 2021 ASH Annual Meeting & Exposition. Abstract 157. Presented December 11, 2021.
6. Krishnan AY, Minnema MC, Berdeja JG, et al: Updated phase 1 results from MonumenTAL-1: First-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 158. Presented December 11, 2021.
7. Chari A, Hari P, Bahlis NJ, et al: Phase 1b results for subcutaneous talquetamab plus daratumumab in patients with relapsed/refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 161. Presented December 11, 2021.
