Ajay K. Nooka, MD, MPH
Insights on findings from the phase II MonumenTAL-1 trial1 were offered by Ajay K. Nooka, MD, MPH, Professor in the Department of Hematology and Medical Oncology, and Medical Director of the Winship Data and Technology Applications Shared Resource, Winship Cancer Institute, Emory University School of Medicine, Atlanta. According to Dr. Nooka, talquetamab answers several needs in the treatment of relapsed or refractory multiple myeloma and will have a notable impact in this disease.
Talquetamab is an off-the-shelf, T-cell–redirecting bispecific antibody that binds to CD3 and a novel target—G protein–coupled receptor family C group 5 member D (GPRC5D).2 “The exclusivity of GPRC5D to malignant plasma cells and hard, keratinized tissues, with minimal expression on normal tissues, makes it an ideal therapeutic target for treating myeloma,” he said.
The previous phase I MonumenTAL-1 study demonstrated “impressive” objective response rates of 64% in the dosing cohort treated with 405 μg/kg every week and 70% in the cohort receiving 800 μg/kg every other week.3 This led to further exploration of these two alternate doses of talquetamab in larger cohorts.
The study’s 288 patients with relapsed or refractory disease had received at least three prior lines of therapies (median of five), and were refractory to an immunomodulatory agent, proteasome inhibitor, and a CD38 monoclonal antibody (ie, were triple-refractory). There were 51 patients who had received prior B-cell maturation antigen (BCMA)-targeting therapies.
Responses were observed in 72.6% of patients treated weekly and in 71.0% of patients treated every 2 weeks. “The responses were deep and sustained, with rates of very good partial responses or better in 59.4% and 57.2%, respectively. Similar benefit extended to all subgroups of patients, including the penta-refractory patient population, where the response rates were 71.4% with weekly dosing and 70.6% with every-other-week dosing,” Dr. Nooka noted.
“Additionally, the responses were obtained quickly. The median time to first response was slightly over 1 month, and the median time to best response was less than 3 months for both dosing cohorts,” he added. Although the median duration of response for patients achieving a complete response or better has not been reached for either dosing cohort, for all responders, it was 9.3 months and 13 months, respectively, for weekly and every-other-week dosing cohorts.
How Do Results Compare?
How do these responses compare with responses to the existing approved agents? The objective response rate for single-agent daratumumab in the SIRIUS trial4 was close to 30%, leading to the conditional approval among patients with double-refractory disease. Subsequently, approvals were granted for selinexor and belantamab mafodotin-blmf, which yielded response rates of approximately 30% in the STORM5 and DREAMM-2 trials,6 respectively, in patients with triple-refractory disease.
In a similar patient population, approval was granted for the BCMA-targeting chimeric antigen receptor (CAR) T-cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel, based on response rates of 73% in KarMMAa7 and 98% in CARTITUDE-1,8 respectively. Additionally, the BCMA-directed bispecific antibody teclistamab-cqyv yielded a response rate of more than 60% in the MajesTEC-2 study.9
“Although we have several BCMA-targeting CAR T-cell therapies and bispecific antibodies, both as approved agents and agents available in clinical trials, there is a dearth of treatment options for patients who experience disease progression after receiving BCMA-targeting therapy. In this space, talquetamab has shown activity and will likely be a game-changer, given the easy availability as an off-the-shelf drug; simplicity of subcutaneous administration; and a not-too-constrained, every-other-week dosing schedule. More important, its safety is very appealing,” Dr. Nooka concluded.
The results from the cohort of patients who had received T-cell–redirected therapies were particularly encouraging, he said, though most of these patients received weekly dosing. “The impressive response rate of 62.7% among all patients, 72.2% for those who received prior CAR-T and 44.4% for those with prior T-cell–redirected therapies, provides a new benchmark of expected outcomes for this heavily refractory patient population with an unmet need.”
Safety Profile in MonumenTAL-1
Most grade 3 or 4 adverse events were cytopenias, which were generally limited to the first few cycles. Numerically, higher grades of anemia, neutropenia, thrombocytopenia, and lymphopenia were less frequent with the every-other-week dosing schedule, which, therefore, “will likely be a preferred option for the heavily pretreated patients,” he said.
Infections associated with bispecific antibodies have been of concern, and in this regard, the findings for talquetamab are reassuring. “So far, among the data presented on bispecific antibodies for treating relapsed or refractory multiple myeloma, talquetamab has the lowest reported rate of higher-grade infections, likely from the target selection as a non–BCMA-targeting agent,” Dr. Nooka said.
Infections occurred in 57.3% and 50.3% of patients treated with weekly and every-other-week schedules, respectively, with 16.8% and 11.7% being of higher grade. “Though, these numbers seem very high, they are relatively lower than those with other BCMA-targeting bispecific antibodies, where the higher-grade infectious toxicities are reported in more than 40% of patients,” he pointed out.10
Two deaths from COVID-19 infection, he added, “underscore the importance of adequate vaccinations and boosters to minimize this risk while receiving bispecific antibodies.” The 3% incidence of opportunistic infections speaks to the need to document baseline viral status and initiate infectious prophylaxis. Although 10% of patients received intravenous immunoglobulin (IVIG) in the study, Dr. Nooka foresees more use of IVIG in the future to minimize infectious complications.
Regarding nonhematologic adverse events, “three stand out,” he said. First, cytokine-release syndrome was seen in 79% of patients dosed weekly and 70% of patients dosed every other week and was mostly confined to step-up dosing and the first dose. The median time to onset was 2 days, and median duration was 2 days. Higher grades were infrequent and rarely led to treatment discontinuation. Second, immune effector cell–associated neurotoxicity syndrome events, reported in 10% of patients, were mostly grade 1 or 2 and were observed concurrently with cytokine-release syndrome; median time to onset was 2 to 3 days, and median duration was 1 to 2 days. Third, skin toxicity, nail changes, and dysgeusia were all low grade, managed with dose reductions or delays, and most likely related to the target expression in the hard, keratinized tissues.11,12
“Low rates of treatment discontinuation (approximately 6%) confirm that the drug can be safely administered over a long time. After the first full dose, the mean concentration time profiles were comparable between weekly and every-other-week dosing and were maintained at or over the maximum EC90 for the duration of administration,” he noted. “This suggests the every-other-week dosing schedule is effective, safe, and has a comparable pharmacokinetic profile. This may likely be the choice of dosing that could move forward.”
DISCLOSURE: Dr. Nooka has served on advisory boards and received honoraria from Takeda, Amgen, Janssen, Bristol Myers Squibb, GlaxoSmithKline, Sanofi, Karyopharm, Adaptive, Oncopeptides, SecuraBio, BeyondSpring, and Pfizer.
REFERENCES
1. Chari A, Touzeau C, Schinke C, et al: Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Phase 1/2 results from MonumenTAL-1. 2022 ASH Annual Meeting and Exposition. Abstract 157. Presented December 10, 2022.
2. Pillarisetti K, Edavettal S, Mendonça M, et al: A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Blood 135:1232-1243, 2020.
3. van de Donk N, Krishnan A, Oriol A, et al: OAB-025: Talquetamab, a G protein-coupled receptor family C group 5 member D × CD3 bispecific antibody, in relapsed/refractory multiple myeloma: Updated results of a phase 1, first-in-human study. Clin Lymphoma Myeloma Leuk 21:S16-S17, 2021.
4. Lonial S, Weiss BM, Usmani SZ, et al: Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. Lancet 387:1551-1560, 2016.
5. Chari A, Vogl DT, Gavriatopoulou M, et al: Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med 381:727-738, 2019.
6. Lonial S, Lee HC, Badros A, et al: Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol 21:207-221, 2020.
7. Munshi NC, Anderson Jr LD, Shah N, et al: Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384:705-716, 2021.
8. Berdeja JG, Madduri D, Usmani SZ, et al: Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet 398:314-324, 2021.
9. Moreau P, Garfall AL, van de Donk NWCJ, et al: Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med 387:495-505, 2022.
10. Nooka A, Moreau P, Usmani SZ, et al: Teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Updated efficacy and safety results from MajesTEC-1. 2022 ASCO Annual Meeting. Abstract 8007. Presented June 6, 2022.
11. Inoue S, Nambu T, Shimomura T: The RAIG family member, GPRC5D, is associated with hard-keratinized structures. J Invest Dermatol 122:565-573, 2004.
12. Goldsmith R, Cornax I, Ma JY, et al: P-095: Normal human tissue expression of G-protein coupled receptor 5D, a promising novel target for multiple myeloma, is restricted to plasma cells and hard keratinized tissues. Clin Lymphoma Myeloma Leuk 21:S91, 2021.
