For the challenging population of patients with multiple myeloma who have become refractory to essentially all current treatments, new approaches are much needed. Early clinical trials data suggest bispecific antibodies may help meet this need, as suggested by studies presented at the 2021 ASCO Annual Meeting for talquetamab,1 teclistamab,2 and elranatamab.3 Teclistamab and elranatamab target B-cell maturation antigen (BCMA)—known for its highly selective expression in malignant plasma cells—whereas talquetamab targets the novel GPRC5D receptor, which is highly expressed in myeloma cells.
MonumenTAL-1: Talquetamab
Talquetamab is a first-in-human antibody that binds to CD3 and GPRC5D (G protein–coupled receptor class C group 5 member D) to redirect T cells to kill myeloma cells. At the recommended phase II dose of 405 µg/kg weekly, talquetamab led to responses in 70% of patients overall, in 65% of patients with triple-class–refractory disease, and 83% of patients with penta-refractory disease, in an updated analysis of the phase I MonumenTAL-1 trial presented by Jesus G. Berdeja, MD, Director of Myeloma Research at Sarah Cannon Research Institute, Nashville.1
Jesus G. Berdeja, MD
“Talquetamab is an off-the-shelf T-cell–redirecting agent that requires limited steroid use and has a manageable safety profile. The drug showed encouraging efficacy in heavily pretreated patients,” Dr. Berdeja said. “Additional patients and longer follow-up of the study support the recommended phase II dose.”
The current analysis of the ongoing phase I first-in-human study of 184 patients was based on 30 patients who received the recommended phase II dose of 405 µg/kg weekly by subcutaneous delivery and were followed for a median of 6.3 months. Patients underwent two step-up doses of 10 µg/kg and 60 µg/kg, followed by the first full dose of 405 µg/kg on day 1 of cycle 1. Talquetamab was given weekly for 3 weeks, with repeating cycles. Premedication was limited to step-up doses and the first full dose, with no steroid requirement thereafter.
Patients had received a median of six prior lines of therapy. All were refractory to anti-CD38 antibodies, 77% were triple-class–refractory, 20% were penta-refractory, and 87% were refractory to their last line of treatment.
Six patients across the entire study (including intravenous and subcutaneous treatments) were evaluable for minimal residual disease (MRD) negativity; four had MRD-negative complete or stringent complete responses at 10-6, including one patient given the recommended dose. “MRD negativity was sustained 7 months after complete response in one evaluable patient,” he said.
“Responses were durable and deepened over time,” Dr. Berdeja said. At the recommended phase II dose, the median duration of response was not reached. After a median of 6.3 months, 81% of patients are still on treatment. Responses were more mature for the intravenous cohort; “even at subtherapeutic doses,” some responses are ongoing at 22-plus months in the intravenous cohort. “We hope this translates to the subcutaneous cohort as well,” he said.
At the recommended dose, cytopenias were mostly confined to patients who received step-up doses or treatment in the first two cycles. Neutropenia occurred in 67% overall, with 60% being grade 3; it was also limited to cycles 1 and 2 and resolved within a week.
Cytokine-release syndrome of any grade was observed in 73% of patients (one grade 3) and was confined to the step-up and first full doses, and 7% experienced grade 1 or 2 neurotoxicity. Skin-related adverse effects, mostly mild, were observed in 77% of patients and nail disorders, in 27%. This was not unexpected since GPRC5D is expressed in keratinized tissue, he added.
A phase II expansion study of talquetamab at the recommended phase II dose is under way.
MajesTEC-1: Teclistamab
Teclistamab is a novel steroid-sparing off-the-shelf, full-sized bispecific antibody that redirects T cells to myeloma cells expressing BCMA. It is being studied in the first-in-human phase I MajesTEC-1 trial of 157 heavily pretreated patients. A total of 40 patients have received the recommended phase II dose of 1,500 µg/kg given subcutaneously once weekly, with step-up doses of 60 µg/kg and 300 µg/kg used to mitigate the risk for severe cytokine-release syndrome.
Patients receiving the recommended dose had a median of five prior lines of treatment; 83% of patients were triple-class–refractory; 38% were penta-refractory; and 83% were refractory to the last regimen. Patients were not allowed to have prior BCMA-targeted treatment.
In this dose cohort, response rates were encouraging; complete or partial responses were reported in 65% and 61% of triple-class–refractory patients, respectively; very good partial responses or better, in 58%; and complete response or better, in 40%. These findings were reported by Amrita Y. Krishnan, MD, of City of Hope Comprehensive Cancer Center, Duarte, California.2
Amrita Y. Krishnan, MD
The median duration of response was not reached. Of 26 patients responding to the recommended phase II dose, 22 (85%) were alive and still on treatment with teclistamab after a median follow-up of 7.1 months.
“We showed that teclistamab was well tolerated…and response rates to teclistamab were high, with durable responses that deepened over time,” Dr. Krishnan said. “Our results with longer follow-up support the recommended phase II dose of teclistamab.”
Of six evaluable patients as of data cutoff, all achieved MRD negativity with complete or stringent complete responses. Two evaluable patients with complete responses lasting at least 12 months had sustained MRD negativity, she said.
The most common grade 3 or 4 adverse events were neutropenia (40%), anemia (28%), thrombocytopenia (20%), and leukopenia (18%). Dr. Krishnan commented: “This is not surprising, given these patients were heavily pretreated…. Of note, their onset was generally confined to the step-up dosing in cycles 1 and 2.”
Grade 3 or 4 infections were observed in 23%. Cytokine-release syndrome occurred in 70% of those who received the recommended dose. However, all events were grade 1 or 2 and were generally confined to the step-up and first full doses, she added.
An international open-label phase II expansion study of teclistamab evaluating weekly subcutaneous 1,500 µg/kg is under way. Future studies will evaluate the drug in earlier lines and in combination with other agents, Dr. Krishnan noted.
Elranatamab
“Elranatamab is a bispecific antibody that targets BCMA on myeloma cells and CD3 on T cells. Engagement of BCMA and CD3 by elranatamab induces the formation of immunologic synapses and activation of cytotoxic T cells,” explained Nizar J. Bahlis, MD, of the Arnie Charbonneau Cancer Institute at the University of Calgary, Canada, who presented the dose-escalation study results.3
The current study examined weekly subcutaneous dosing in 30 patients, with a median of eight prior lines of therapy; 87% were triple-class–refractory.
At doses higher than 215 µg/kg, 70% of patients responded, with complete and stringent complete responses achieved by 30%. In patients who received the recommended phase II dose of 1,000 µg/kg, 83% of patients responded. The median duration of response has not been reached, and the probability of responders being event-free at 6 months was estimated to be 92.3%, Dr. Bahlis reported.
“Three of four patients with prior BCMA-directed therapy achieved a response, including two very good partial responses and one stringent complete response,” he added. “Three assessed patients achieved MRD negativity.”
Doses up to 1,000 µg/kg weekly were associated with a manageable safety profile, according to Dr. Bahlis. Cytokine-release syndrome was seen in 73% of patients, but all were reported to be limited to grade 1 or 2. “Premedication as well as priming and step-up dosing will be explored to mitigate cytokine-release syndrome,” he added. “These results support further development of elranatamab both as monotherapy and in combination with other agents,” Dr. Bahlis commented.
DISCLOSURE: Dr. Berdeja has served as an institutional consultant or advisor to Bluebird Bio, Bristol Myers Squibb, Celgene, CRISPR Therapeutics, Janssen, Karyopharm Therapeutics, Kite Pharma, Legend Biotech, SecuraBio, Servier, and Takeda; and has received institutional research funding from AbbVie, Acetylon, Amgen, Bluebird Bio, Bristol Myers Squibb, Celgene, Cellularity, Constellation, CRISPR Therapeutics, Curis, EMD Serono, Genentech/Roche, Glenmark, Ichnos, Janssen, Kesios, Lilly, Novartis, Poseida Therapeutics, Sanofi, Takeda, Teva, and Vivolux. Dr. Krishnan has served in a leadership role for Sutro; holds stock or other ownership interests in Bristol Myers Squibb; has served as a consultant or advisor to Celgene, GSK, Janssen Oncology, Oncopeptides, Pfizer, and Regeneron; has participated in a speakers bureau for Amgen, Celgene, and Takeda; and has received institutional research funding from Janssen Oncology. Dr. Bahlis has received honoraria from AbbVie, Amgen, Celgene, Genentech/Roche, GSK, Janssen, Karyopharm Therapeutics, Sanofi Canada, and Takeda; has served as a consultant or advisor to Amgen, Celgene, Janssen, Karyopharm Therapeutics, Pfizer, Sanofi Canada, and Takeda; and has received institutional research funding from Celgene and Janssen.
REFERENCES
1. Berdeja JG, Krishnan AY, Oriol A, et al: Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. 2021 ASCO Annual Meeting. Abstract 8008. Presented June 8, 2021.
2. Krishnan AY, Garfall AL, Mateos MV, et al: Updated phase 1 results of teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in relapsed/refractory multiple myeloma. 2021 ASCO Annual Meeting. Abstract 8007. Presented June 8, 2021.
3. Bahlis NJ, Raje NS, Costello C, et al: Efficacy and safety of elranatamab (PF-06863135), a B-cell maturation antigen-CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma. 2021 ASCO Annual Meeting. Abstract 8006. Presented June 8, 2021.
