T-Cell–Redirecting Strategies Emerge in Myeloma From 2025 ASCO, EHA, and IMS

Recent advances and novel approaches in immunotherapies for multiple myeloma (MM), including T-cell–redirecting antibodies, chimeric antigen receptor (CAR) T cells, and novel targeted agents, were presented at the 2025 European Hematology Association (EHA), American Society of Clinical Oncology (ASCO), and International Myeloma Society (IMS) conferences. These exciting data with bispecific and trispecific antibodies have the potential to transform the approach to treatment of first-line and relapsed MM.

At present, there are 4 bispecific T-cell–engaging antibodies approved for MM, with 3 targeting B-cell maturation antigen (BCMA) and 1 targeting GPRC5D: teclistamab (Tecvayli), elranatamab (Elrexfio), linvoseltamab (Lynozyfic), and talquetamab (Talvey), respectively. All are approved after at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. Data for their use in newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM) were covered across the major conferences this year.

Bispecific Advancement in NDMM

Marc S. Raab, MD, PhD, and colleagues presented initial phase 2 data from MajesTEC-5 (NCT05695508), a study looking primarily at adverse outcomes with teclistamab combined with either daratumumab (Darzalex) and lenalidomide (Revlimid [Tec-DR]) or daratumumab, bortezomib (Velcade), and lenalidomide (Tec-DVR) in transplant-eligible NDMM.¹ Among 46 evaluable patients who received at least 1 dose of teclistamab, the overall response rate (ORR) was 100% after cycle 6 of induction, with 100% minimal residual disease (MRD) negativity by next-generation sequencing (10^-6). Ninety percent of patients had grade 3/4 adverse events (AEs), with hematologic AEs being the most common; there were no deaths or study discontinuations. Cytokine release syndrome (CRS) occurred in 65%, and all were grade 1/2. There were no immune effector cell–associated neurotoxicity syndrome (ICANS) events reported.

During all 3 conferences, we saw the early results of part 1 of the phase 3 MagnetisMM-6 study (NCT05623020), examining elranatamab with DR (Elra-DR) or Elra-R compared with DR with dexamethasone.^2-4 Thirty-seven patients with transplant-ineligible NDMM treated with Elra-DR had an ORR of 92% (95% very good partial response [VGPR] or better) at a median follow-up of 4.6 months. CRS was reported in 62% of patients, all grade 2 or lower, with only 1 grade 2 ICANS event.

Targeting FcRH5 With Cevostamab in RRMM

Cevostamab, a novel bispecific antibody that targets FcRH5 on MM plasma cells and is not yet FDA approved, was studied in combination with pomalidomide (Pomalyst) in the CAMMA 1 study (NCT04910568). The findings were presented at the 22nd IMS Annual Meeting and Exposition.⁵ In this phase 1 study, low- or high-dose cevostamab was combined with pomalidomide in 32 patients with RRMM who had a median of 2 to 3 prior lines of therapy. The median follow-up was 8.9 in the low-dose group, with an ORR of up to 94% (81% VGPR or better). Most of the 69% of grade 3 or higher AEs were related to myelosuppression and infections, with 81% CRS (all grade 2 or lower).

Additionally at the IMS meeting, Adam D. Cohen, MD, and colleagues presented phase 2 data from the STEM trial (NCT05801939) exploring consolidation with fixed-dose duration cevostamab for 8 cycles following anti-BCMA CAR T-cell therapy.⁶ Twenty-seven patients with RRMM with a median of 4 prior lines of therapy and most with high-risk disease (74%) were treated with either idecabtagene vicleucel (Abecma) or ciltacabtagene autoleucel (Carvykti), achieving 65% complete response (CR)/stringent CR (sCR), followed by cevostamab starting 10 to 12 weeks later. In 22 evaluable patients, 81% were in sCR, with 91% MRD negative at 10^-6. There was a 15% rate of CRS events, but no ICANS events were seen.

Linvoseltamab Combos Boost RRMM Responses

Data using linvoseltamab, a recently FDA-approved anti-BCMA bispecific antibody, in combination with proteasome inhibitors (either bortezomib⁷ or carfilzomib [Kyprolis]) were presented at the 2025 ASCO Annual Meeting.^8,9 Paula Rodríguez-Otero, MD, PhD, and colleagues presented data from the phase 1 LINKER-MM2 trial (NCT05137054) using linvoseltamab/bortezomib in 22 patients with RRMM with a median of 3 prior lines of therapy. The ORR was reported to be 79%, with 79% of patients progression free at the 6-month follow-up. Fifty-five percent had CRS, all grade 2 or lower, and 4 patients had low-grade ICANS.

At the ASCO and EHA meetings, Salomon Manier, MD, PhD, presented data from this same phase 1 study combining linvoseltamab/carfilzomib. Data from 18 patients with RRMM and a median of 3 prior lines of treatment showed an ORR of 91%, with 73% progression free at 6 months. In this cohort, 61% of patients had grade 2 or lower CRS, and 1 patient had grade 1 ICANS. Of note, 44% had grade 3 or higher infections.

The Rise of Trispecific Antibodies

Novel trispecific antibodies are emerging in clinical trials aimed at targeting 2 antigens highly expressed on MM plasma cells. One of these, JNJ-5322, targets both BCMA and GPRC5D. First-in-human data in patients with RRMM were presented at this year's ASCO and EHA meetings.^10,11 At ASCO, Niels van de Donk, MD, PhD, presented phase 1 dose escalation data in 126 patients with RRMM and a median of 4 prior lines of therapy at a median follow-up of 8.2 months. The ORR was 82% at the recommended phase 2 dose and 100% among patients naive to anti-BCMA and anti-GPRC5D therapies. The median time to response was 1 to 2 months. Fifty-nine percent of patients had CRS, all grade 2 or less, and 2% had grade 1 ICANS. There were 28% of patients with grade 3/4 infections, and 56% had grade 1/2 nail or taste AEs, consistent with targeting GPRC5D.

Lastly, Eben Lichtman, MD, and colleagues also presented data at ASCO on ISB 2001, an anti-BCMA and anti-CD38 trispecific antibody evaluated in the phase 1 dose-escalation TRIgnite-1 study (NCT05862012), which included 24 patients with RRMM and a median of 6 prior lines of treatment.¹² The ORR was 75% across all doses, and the median time to response was 1 to 2 months. Seventy-one percent of patients had low-grade CRS; no neurotoxicities or grade 5 AEs were reported. At IMS, Hang Quach, MBBS(Hons), presented additional data from this trial of ISB 2001 in a total of 35 patients with RRMM.¹³ Similarly, the ORR was 74% across doses, and 1 patient had a grade 1 ICANS event.

Conclusions

Taken together, these emerging data suggest that bispecific T-cell–redirecting strategies have the potential to enhance responses when used in combination with established antimyeloma agents. In addition, trispecific antibodies may facilitate improved efficacy by dual targeting highly specific plasma cell antigens, potentially reducing the risk of resistance. While we await longer-term follow-up of these studies, patients should be encouraged to enroll in clinical trials involving T-cell–engaging antibodies that have demonstrated substantial efficacy as single agents in heavily pretreated patients and remarkable depth of response in NDMM, often using steroid-sparing approaches.

_References

_{1. Raab MS, Weinhold M, Kortüm KM, et al. Post-induction outcomes and updated minimal residual disease analysis from GMMG-HD10/DSMM-XX (MajesTEC-5): a study of teclistamab-based induction regimens in newly diagnosed multiple myeloma (NDMM). Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-13.}

_{2. Quach H, Pour L, Grosicki S, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: initial results from MagnetisMM-6 part 1. J Clin Oncol. 2025;43(suppl 16):7504. doi:10.1200/JCO.2025.43.16_suppl.7504}

_{3. Dimopoulos MA, Pour L, Grosicki S, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: initial results from MagnetisMM-6 part 1. Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S206.}

_{4. Trudel S, Quach H, Pour L, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: initial results from MagnetisMM-6 part 1. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-07.}

_{5. Trudel S, Quach H, Pour L, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: initial results from MagnetisMM-6 part 1. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-07.}

_{6. Trudel S, Quach H, Pour L, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: initial results from MagnetisMM-6 part 1. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-07.}

_{7. Rodriguez-Otero P, Delimpasi S, Oriol A, et a. Linvoseltamab (LINVO) + bortezomib (BTZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): first results from the LINKER-MM2 trial. J Clin Oncol. 2025;43(suppl 16):7510. doi:10.1200/JCO.2025.43.16_suppl.7510}

_{8. Manier S, Ocio EM, Martinez-Chamorro C, et al. Linvoseltamab (LINVO) + carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): initial results from the LINKER-MM2 trial. J Clin Oncol. 2025;43(suppl 16):7513. doi:10.1200/JCO.2025.43.16_suppl.7513}

_{9. Manier S, Ocio EM, Martínez-Chamorro, et al. Linvoseltamab (LINVO) + carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): initial results from the LINKER-MM2 trial. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract PA-064.}

_{10. van de Donk NWCJ, Vega G, Perrot A, et al. First-in-human study of JNJ-79635322 (JNJ-5322), a novel, next-generation trispecific antibody (TsAb), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): initial phase 1 results. J Clin Oncol. 2025;43(suppl 16):7505. doi:10.1200/JCO.2025.43.16_suppl.7505}

_{11. Popat R, Touzeau C, Perrot A, et al. First-in-human study of JNJ-79635322 (JNJ-5322), a novel, next-generation trispecific antibody, in patients with relapsed/refractory multiple myeloma: initial phase 1 results. Abstract presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S100.}

_{12. Lichtman E, Khot A, Augustson B, et al. Phase 1, first-in-human study of ISB 2001: a BCMAxCD38xCD3-targeting trispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—dose escalation (DE) results. J Clin Oncol. 2025;43(suppl 16):7514. doi:10.1200/JCO.2025.43.16_suppl.7514}

_{13. Quach H, Augustson B, Levitz D, et al. TRIgnite-1 study: phase 1, first-in-human study of ISB 2001: a BCMAxCD38xCD3-targeting tri-specific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—dose escalation (DE) results. Clin Lymphoma Myeloma Leuk. 2025;25(2):S23-S24. doi:10.1016/S2152-2650(25)03439-1}