For relapsed or refractory multiple myeloma, there are three available bispecific antibodies—two that target B-cell maturation antigen (BCMA) and one that targets G protein–coupled receptor class C group 5 member D (GPRC5D). Which is the preferred target? This question was addressed at the 2024 Debates and Didactics in Hematology and Oncology conference by two myeloma experts from Emory University Winship Cancer Center,1 which sponsors the annual event. Ajay K. Nooka, MD, MPH, Professor and Director of the Myeloma Program, and Nisha S. Joseph, MD, Associate Professor, both of the Department of Hematology and Medical Oncology at Emory, reviewed the data from pivotal trials that may inform clinicians in their treatment selection.
Ajay K. Nooka, MD, MPH
Nisha S. Joseph, MD
The Case for BCMA-Targeted Bispecific Antibodies
BCMA is expressed on the surface of nearly all myeloma cell lines, more in the malignant cells than normal plasma cells. Increased expression of BCMA has been associated with worse outcomes. The two BCMA-targeted bispecific antibodies are teclistamab-cqyv and elranatamab-bcmm.
In MajesTEC-1, findings after 30 months’ median follow-up (the longest for any bispecific in myeloma), the response rate to teclistamab was 63%, with 46% achieving complete responses or better.2 The undetectable measurable residual disease (MRD) rate was 86%, and median overall survival was 11 months overall and was not reached in patients with complete responses or better. A total of 30% of patients overall were progression-free, with the rate rising to 61% for complete and stringent complete responders. Similarly, in MagnetisMM-3, a 61% overall response rate was achieved with elranatamab, of which 35% were at least complete responses, and at 15 months, 51% of patients were progression-free.3
However, despite their strong efficacy, anti-BCMA bispecific antibodies carry a concerning risk for infection. “There is no doubt that infections need to be addressed with these agents,”
Dr. Nooka said.
In MajesTIC-1, infection was reported in 80% of patients, of which 55% were grade 3 or 4, primarily COVID-19 (21%) and respiratory infections (19%), with some viral, fungal, and gastrointestinal infections also observed.4 A total of 21 patients died of infections, with 18 being related to COVID-19. Also in that study, grade 3 infections occurred within the first year for about 25% of patients but diminished over time as patients switched to every-2-week dosing. Within 2 years, new-onset grade 3 infections were seen in about 5%,5 he noted.
In heavily pretreated patients, teclistamab impairs humoral immunity, but this can be partly reversed by supplementation with intravenous immunoglobulin (IVIG). “With IVIG and antimicrobial prophylaxis, we’ve seen grade 3 infections decline drastically,” Dr. Nooka said. “Continued monitoring throughout treatment is recommended, although improvements are expected with increased awareness and vigilance, new expert management guidelines, and additional strategies.”
Retreatment With an Alternative Anti-BCMA Agent
Of interest, serum BCMA levels drop sharply while patients respond to BCMA-targeted bispecific antibodies, but they return almost to baseline upon disease progression. Immune cell health is also maintained during treatment. For these reasons, retreatment with a different anti-BCMA agent may be effective, according to Dr. Nooka.
In MajesTIC-1, treatment with teclistamab resulted in responses in 55% of patients who had received prior belantamab mafodotin-blmf and in 53% after prior anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, with 71% still responding at 1 year.6 For patients treated with idecabtagene vicleucel CAR T-cell therapy after prior anti-BCMA therapy, the response rate was 74%, with responses more likely among patients with longer intervals between treatments.7
The Case for GPRC5D-Targeted Bispecific Antibodies
A newer therapeutic target in multiple myeloma, GPRC5D is highly expressed on malignant plasma cells as well as hair follicles, oral mucosa, skin, and nail beds. Unlike BCMA, with GPRC5D, there is little to no expression in normal B cells, T cells, or natural killer cells, which may be a factor in its lower risk for infection as compared with BCMA-targeted bispecific antibodies. The main toxicities associated with the GPRC5D-targeted agents are dysgeusia, weight loss, skin and nail changes, and rash, Dr. Joseph said.
“Even at the structural level, GPRC5D is designed to be a more effective therapeutic target,” she continued. The receptor’s short extracellular domain allows the exposed epitope for T-cell binding to be very close to the plasma cell membrane, thus tightening the T-cell binding and enhancing cytotoxicity. Next, as a seven-pass transmembrane receptor protein with a short extracellular N-terminal domain, GPRC5D is unlikely to be shed from target cells into the serum, which may reduce the risk of decreased efficacy related to target antigen shedding.
Efficacy of Talquetamab
The one available GPRC5D therapeutic, talquetamab, was approved based on findings from MonumenTAL-1, which showed a 74% response rate, of which 34% were complete responses or better.8 Although there is no direct head-to-head comparison with teclistamab, talquetamab showed an impressive depth of response (63% overall response rate) that was maintained across high-risk subsets, which was not universally seen in the subgroup analysis in MajesTEC-1 and the MagnetisMM studies, Dr. Joseph noted.
In patients with prior T-cell redirection therapy, the response rate was 63% after prior bispecific antibody therapy and 72% after CAR T-cell therapy, and the median duration of response was almost 13 months.9 “They are very active drugs in relapsed myeloma, including heavily pretreated, difficult-to-treat patients,” she added.
Infections Less Common With Talquetamab Than Teclistamab
The majority of adverse events with talquetamab are grade 1 or 2, with low rates of grade 3 or 4 toxicities: 17% with 0.4 mg/kg weekly and 12% with 0.8 mg/kg every 2 weeks. The rates of discontinuation of talquetamab in MonumenTAL-1 were 5% and 6%, respectively, with these dosing schedules. “We are getting better at managing toxicities and learning how to better dose the drug to mitigate adverse events,” explained Dr. Joseph.
In contrast to talquetamab, in the pivotal trial of teclistamab, infections occurred in 80% of patients, of which 55% were grade ≥ 3. “That’s a very big difference between drugs,” she noted. “What is better than mitigating infections is having them occur less frequently to begin with.”
Dose reductions of talquetamab at a median of 3 months in MonumenTAL-1 did not impair the drug’s efficacy, as response in patients with an initial response to the higher dose was maintained after dose reduction, and median progression-free survival was 14 months,10 stated Dr. Joseph. “For the most part, in the prospective cohort, the adverse events improved with the exception of weight loss. These adverse events may get better with awareness and less-frequent dosing,” she commented.
Looking Ahead for GPRC5D-Targeted Therapy
“It’s important to highlight that talquetamab is a good therapeutic partner with other antimyeloma drugs,” continued Dr. Joseph, noting there is preclinical evidence showing synergy between immunomodulatory drugs and T-cell engagers.
In MonumenTAL-2, the combination of talquetamab and pomalidomide led to a 94% response rate at 0.4 mg/kg weekly and an 84% response rate at 0.8 mg/kg every 2 weeks.11 These high response rates were consistent across subgroups. “Going forward, pomalidomide could be a good potential partner,” she maintained.
Although currently there are no GPRC5D-targeted CAR T-cell therapies, there are three under investigation. One is BMS-986393, which produced a 100% response rate in patients with prior anti-BCMA treatment in an early trial.12
DISCLOSURE: Dr. Nooka reported personal financial relationships with Aduro Biotech, Amgen, Arch Oncology, Bristol Myers Squibb, Cellectis, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharma, Merck, Pfizer, Takeda, Adaptive Biotechnologies, Amgen, BeyondSpring, Cellectar Biosciences, Oncopeptides, ONK Therapeutics, Sanofi, and Secura Bio. Dr. Joseph has served as a consultant to Janssen Oncology and has received honoraria from Bristol Myers Squibb.
REFERENCES
1. Nooka AK, Joseph NS: BCMA vs GPRC5D as targets for multiple myeloma. 2024 Debates & Didactics in Hematology and Oncology. Presented July 27, 2024.
2. Garfall AL, Nooka AK, van de Donk NWCJ, et al: Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. 2024 ASCO Annual Meeting. Abstract 7540. Presented June 3, 2024.
3. Lesokhin AM, Tomasson MH, Arnulf B, et al: Elranatamab in relapsed or refractory multiple myeloma: Phase 2 MagnetisMM-3 trial results. Nat Med 29:2259-2267, 2023.
4. Usmani SZ, Garfall AL, van de Donk NWCJ, et al: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): A multicentre, open-label, single-arm, phase 1 study. Lancet 398:665-674, 2021.
5. Nooka AK, Rodriguez C, Mateos MV, et al: Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study. Cancer 130:886-900, 2024.
6. Touzeau C, Krishnan AY, Moreau P, et al: Efficacy and safety of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma after exposure to other BCMA-targeted agents. 2022 ASCO Annual Meeting. Abstract 8013. Presented June 4, 2022.
7. Ferreri CJ, Hildebrandt MAT, Hashmi H, et al: Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy. Blood Cancer J 13:117, 2023.
8. Schinke CD, Touzeau C, Minnema MC, et al: Pivotal phase 2 MonumenTAL-1 results of talquetamab, a GPRC5D x CD3 bispecific antibody, for relapsed/refractory multiple myeloma. 2023 ASCO Annual Meeting. Abstract 8036. Presented June 5, 2023.
9. Jakubowiak AJ, Anguille S, Karlin L, et al: Updated results of talquetamab, a GPRC5D × CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma with prior exposure to T-cell redirecting therapies: Results of the phase 1/2 MonumenTAL-1 study. 2023 ASH Annual Meeting & Exposition. Abstract 3377. Presented December 10, 2023.
10. Touzeau C, Schinke C, Minnema M, et al: Pivotal phase 2 MonumenTAL-1 results of talquetamab, a GPRC5D x CD3 bispecific antibody, for relapsed/refractory multiple myeloma. European Hematology Association 2023 Congress. Abstract S191. Presented June 9, 2023.
11. Matous JV, Biran N, Perrot A, et al: Talquetamab + pomalidomide in patients with relapsed/refractory multiple myeloma: Safety and preliminary efficacy results from the phase 1b MonumenTAL-2 study. 2023 ASH Annual Meeting & Exposition. Abstract 1014. Presented December 11, 2023.
12. Bal S, Htut M, Nadeem O, et al: BMS-986393 (CC-95266), a G protein–coupled receptor class C group 5 member D (GPRC5D)-targeted chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma: Updated results from a phase 1 study. 2023 ASH Annual Meeting & Exposition. Abstract 219. Presented December 9, 2023.
