Poor outcomes are observed in patients with myeloma who are refractory to multiple classes of therapies, with the average patient experiencing disease progression in up to 6 months and living no longer than 6 to 15 months. Patients often rapidly cycle through regimens that use less effective or less tolerable agents, without regaining sustained disease control. Multiple studies presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition suggest that bispecific antibodies may fill that treatment gap.
Talquetamab: Targeting GPRC5D
Talquetamab is a first-in-class antibody that binds to G-protein coupled receptor family C group 5 member D (GPRC5D) and CD3 receptors, mediating T-cell recruitment, activation, and subsequent lysis of GPRC5D-positive myeloma cells.
“Longer follow-up of the MonumenTAL-1 trial supports the encouraging efficacy of weekly or every-2-week schedules of talquetamab, with a 67% to 70% objective response rate across triple-class– and penta-drug–refractory patients,” said Amrita Krishnan, MD, FACP, of City of Hope in Duarte, California.1
Amrita Krishnan, MD, FACP
The ongoing phase I MonumenTAL-1 study enrolled patients with a median of six prior lines of treatment. Dr. Krishnan presented findings for cohorts receiving the recommended phase II weekly subcutaneous dose of 405 μg/kg weekly (n = 30) and 800 μg/kg every 2 weeks (n = 25), administered in a step-up dosing schema. In these cohorts, 27% and 16% of patients, respectively had received prior B-cell maturation antigen (BCMA)-targeted therapy, and 80% and 68%, respectively, were penta-drug–refractory.
“Talquetamab had a tolerable safety profile at both recommended phase II doses,” Dr. Krishnan reported. Skin- and nail-related toxicities occurred in 75% of patients. Cytokine-release syndrome occurred in 76.7% with the lower dose and 72.0% with the higher dose but was grade 3 in just one patient.
The objective response rates were 70.0% in the cohort treated weekly and 66.7% in those receiving 800 μg/kg every 2 weeks. Very good partial responses or better were observed in 53.3% and 52.4%, respectively. Responses were durable and deepened over time, and median duration of response was not reached.
Talquetamab Plus Daratumumab
Talquetamab given with daratumumab demonstrated a tolerable safety profile (with no overlapping toxicity) and induced responses in more than 75% of patients, according to findings from the phase Ib TRIMM-2 study presented by Ajai Chari, MD, of Mount Sinai Medicine.2 Daratumumab targets CD38, leading to T-cell expansion and enhanced T-cell cytotoxic potential. The combination of daratumumab and talquetamab could be clinically synergistic, he said.
Ajai Chari, MD
Of 29 patients enrolled, 65.5% were refractory to anti-CD38 therapy and 31.0% were penta-drug–refractory. Patients received talquetamab 400 μg/kg weekly, 400 μg/kg every 2 weeks, or 800 μg/kg every 2 weeks (all with step-up dosing), plus 1,800 mg daratumumab weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and monthly for cycles 7 and beyond.
After a median follow-up of 4.2 months, responses were observed in 80.0% of patients treated with 400 μg/kg every 2 weeks; 85.7% treated with the once-weekly 400-μg/kg dose; and 77.8% treated with 800 μg/kg every 2 weeks, with very good partial responses or better observed in 40.0%, 42.9%, and 55.6%, respectively.
Cytokine-release syndrome was seen in 55.2% of patients, with none higher than grade 2 and all resolving. Of interest, 65% of patients experienced skin- and nail-related toxicities, mostly skin exfoliation (27.6%). Rashes were primarily grade 1 or 2; in 10.3%, grade 3 rashes occurred but resolved, and the patients were successfully rechallenged with talquetamab.
“Objective response rates across all dose levels were improved, compared with the recommended phase II doses for talquetamab monotherapy,” Dr. Chari reported. “Responses were observed in both CD38-exposed and CD38-refractory patients, were durable, and appeared to deepen over time, with the majority of patients (88%) remaining on treatment after a median follow-up of 4.7 months.”
Teclistamab: Targeting BCMA and CD3
In the phase I/II MajesTEC-1 trial of teclistamab, the overall response rate was 62%, and responses were durable and deepened over time, according to the update presented by Philippe Moreau, MD, of University Hospital Hotel-Dieu in Nantes, France.3 Teclistamab binds to CD3 on T cells and BCMA on plasma cells to mediate T-cell activation and lysis of BCMA-expressing myeloma cells.
Philippe Moreau, MD
Dr. Moreau presented phase I/II data for 165 patients (70.3% penta-drug–refractory) treated at the recommended dose of 1.5 mg/kg, which they received weekly following step-up dosing. Almost half the patients had received at least 6 months of treatment.
At a median follow-up of 7.8 months, the objective response rate of 62.0% “represents a substantial benefit for patients with triple-class–exposed disease,” he said. The rate of measurable residual disease (MRD) negativity was 24.7% at 10–5 and rose to 41.9% in complete responders. “Responses were consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug–refractory.”
After at least 6 months of follow-up for 90% of patients, median duration of response has not been reached. The event-free rate for responders was 85.9%, the progression-free survival rate was 58.5%, and median overall survival was not reached. A total of 11 of 93 responders have experienced disease progression or died.Cytokine-release syndrome occurred in 71.5%; all were grade 1 or 2 except for one transient grade 3 event that resolved, and 97% were confined to cycle 1. The most common neurotoxicity was headache (8.5%).
REGN5458: Targeting BCMA and CD3
REGN5458 is a BCMA × CD3 bispecific antibody that targets T-cell effector function to induce cytotoxicity of BCMA-expressing myeloma cells. In a phase I dose-escalation study, early, deep, and durable responses have been observed in patients with relapsed or refractory myeloma. For those treated at the higher dose levels, the estimated duration of response has not been reached, according to an update presented by Jeffrey A. Zonder, MD, of Karmanos Cancer Institute, Detroit.4
Jeffrey A. Zonder, MD
The study enrolled 73 patients, 38% of whom were penta-drug–refractory. Patients were treated with REGN5458 monotherapy in a dose-escalation schedule that consisted of 16 weekly infusions, followed by every-2-week dosing until disease progression.
“Although one might not expect a significant number of responses in heavily pretreated patients, in fact we saw responses across all dose levels,” Dr. Zonder reported. The overall response rate was 51% for the entire study, rising to 75% with doses of 200 to 800 mg; 58% had very good partial responses or better at these higher dose levels. Across all dose levels, responses were mostly deep and tended to deepen over time: 86% of responding patients achieved very good partial responses or better, and 43% had complete responses. Among 10 complete responders with available data, 4 achieved MRD negativity.
“Dose-limiting toxicity was observed in two patients (at 24 mg and 96 mg). The maximum tolerated dose was not reached,” Dr. Zonder said. Cytokine-release syndrome was observed in 38% of patients, all but 4% were grade 1, and almost all occurred within 24 hours of administration.
Most responders are still on treatment, and median duration of response has not been reached. The 8-month progression-free survival rate was estimated at more than 90%.
Elranatamab: Targeting BCMA and CD3
Elranatamab, which targets BCMA and CD3, led to promising response rates and was well tolerated in the phase I MagnetisMM-1 trial, reported Michael Sebag, MD, PhD, of Cedars Cancer Center of McGill University Health Centre, Montreal.5
Michael Sebag, MD, PhD
Patients had a median of six prior therapies (90.9% triple-class–refractory), and 21.8% had received prior BCMA-targeting therapies. Patients received elranatamab subcutaneously in a dose-escalation cohort (80–1,000 μg/kg weekly), a priming cohort (single dose of 600 μg/kg followed 1 week later by 1,000 μg/kg given weekly or every 2 weeks), and an expansion cohort (single priming dose of 44 mg followed 1 week later by 76 mg weekly). There were 55 patients who received elranatamab monotherapy at efficacious dose levels of at least 215 μg/kg.
At the recommended dose of 1,000 μg/kg or a 76-mg fixed dose, cytokine-release syndrome (87.3%) was limited to grade 1 or 2. “One-step priming and premedication reduced the overall incidence of this by one third,” Dr. Sebag said. “Based on this, a two-step priming regimen has been implemented within the MagnetisMM program to further mitigate its incidence and duration.”
The objective response rate was 69% at the recommended dose of 1,000 μg/kg weekly. Of 10 patients with prior BCMA-directed therapy, 70% achieved a response. Virtually all patients evaluable for MRD attained MRD negativity.
“Elranatamab at 1,000 μg/kg every 2 weeks achieved exposure in the range associated with antimyeloma efficacy, supporting the transition for responding patients to every-2-week dosing after 6 months of therapy,” he said. “These results, including both clinical and molecular responses, support the continued development of elranatamab.”
TNB-383B: Targeting BCMA and CD3
“An objective response rate of 81% was observed with TNB-383B (also known as ABBV-383) at doses of 40 mg and higher,” Shaji K. Kumar, MD, of the Mayo Clinic, Rochester, reported as part of the updated findings of a phase I trial.6
Shaji K. Kumar, MD
TNB-383B targets BCMA and CD3 and is specifically designed to evade systemic T-cell activation to minimize cytokine-release syndrome. It recruits CD3-positive cells to BCMA-positive myeloma cells and induces tumor cell death in cell lines and mouse models.
The phase I dose-escalation and -expansion study of TNB-383B evaluated 118 patients with at least three prior lines, of whom 61% were triple-class–refractory. Patients were treated intravenously with doses ranging from 0.025 to 120 mg; in the dose-expansion phase, they received 60 mg. Treatment is ongoing for about half the patients.
At a median follow-up of 8.0 months, 81% of the dose-escalation cohort had responded to TNB-383B at ≥ 40 mg, with 69% being very good partial responses or better. After 4.3 months of median follow-up, 53% of the patients with triple-class–refractory disease responded, with 35% being very good partial responses or better. Median duration of response was not reached; estimated overall survival is 72.1% at 12 months.
Treatment-emergent adverse events leading to discontinuation of TNB-383B were rare. Cytokine-release syndrome occurred in 54% but was grade ≥ 3 in just 3 of these 64 patients. “Patients recovered quickly with standard supportive measures or tocilizumab,” Dr. Kumar reported. Pharmacokinetic data support dosing every 3 weeks, which further studies of TNB-383B will explore.
Cevostamab: Targeting FcRH5 and CD3
Cevostamab, which targets Fc receptor-homolog-5 (FcRH5) and CD3 on T cells, showed clinically meaningful activity in heavily pretreated patients, yielding an overall response rate of 56.7% at higher doses and a median duration of response of 11.5 months in a phase I study, presented by Suzanne Trudel, MD, of Princess Margaret Cancer Centre and University of Toronto.7
Suzanne Trudel, MD
The dose-finding study enrolled 161 patients for whom prior treatment with chimeric antigen receptor T-cell therapy, antibody-drug conjugates, and other bispecific antibodies was allowed. Patients received a median of six prior lines, and 68% of patients were penta-drug–refractory. Cevostamab was given intravenously every 3 weeks for 17 cycles in a single- and double-step-up dosing schema.
“Responses were observed at the 20-mg target dose and higher. Overall response and depth of response increased with the target dose, and responses deepened with time,” Dr. Trudel reported.
At doses of 20 to 90 mg, the response rate was 36.1%, with 20.5% achieving a very good partial response or better; at doses of 132 to 198 mg, these rates rose to 56.7% and 33.3%, respectively. Of 10 evaluable patients who achieved very good partial responses or better, 7 were MRD-negative at < 10–5. Median duration of response in the single-step-up cohort with the longer follow-up was 11.5 months. Six patients in this cohort have continued in response for at least 6 months after stopping treatment.
“Step dosing provided effective mitigation of cytokine-release syndrome,” she said. Although it occurred in 80.7% of patients, it was grade 3 in just 1.2% and resolved within 48 hours in 85%. Cytokine-release syndrome was less likely with double vs single step-up dosing, (79.5% vs 88.4%), as were grade 1 events with fever and grade 2 events (52.3% vs 73.3%).
DISCLOSURE: Dr. Krishnan disclosed financial relationships with Magenta, BMS, Janssen, Regeneron, Sanofi, GSK, and Amgen. Dr. Chari reported relationships with BMS/Celgene, Amgen, Secura Bio, Shattuck Labs, Antengene, Millennium/Takeda, Genentech, Oncopeptides, Novartis, AbbVie, Seattle Genetics, Sanofi Genzyme, GlaxoSmithKline, Janssen, Takeda, and Karyopharm. Dr. Moreau has served on advisory boards for Celgene, Janssen, Amgen, Sanofi, AbbVie, Oncopeptides, and GSK. Dr. Zonder has served as a consultant to Alnylam, Amgen, BMS, Caelum Biosciences, Intellia, Janssen, Regeneron, and Takeda and has served on the board of directors of Takeda. Dr. Sebag has served as a consultant to or received honoraria from Takeda, Amgen, Novartis, Karyopharm, Sanofi, Janssen, and BMS. Dr. Kumar has served as a consultant to BMS, AbbVie, Amgen, Takeda, BeiGene, Oncopeptides, Antengene, Janssen, KITE, AstraZeneca, Roche-Genentech, and bluebird bio. Dr. Trudel reported relationships with Amgen, GlaxoSmithKline, Roche, Pfizer, BMS/Celgene, Janssen, Sanofi, and Genentech.
REFERENCES
1. Krishnan AY, et al: Updated phase 1 results from MonumenTAL-1. 2021 ASH Annual Meeting & Exposition. Abstract 158. Presented December 11, 2021.
2. Chari A, 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.
3. Moreau P, et al: Updated results from MajesTEC-1. 2021 ASH Annual Meeting & Exposition. Abstract 896. Presented December 13, 2021.
4. Zonder JA, 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.
5. Sebag M, et al: Elranatamab (PF-06863135), a B-cell maturation antigen targeted CD3-engaging bispecific molecule, for patients with relapsed or refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 895. Presented December 13, 2021.
6. Kumar SK, 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.
7. Trudel S, et al: Cevostamab monotherapy continues to show clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 157. Presented December 11, 2021.
