Bispecific Antibodies in Multiple Myeloma

Bispecific Antibodies Linvoseltamab-REGN5458, Tecvayli, Talquetamab, ABBV-3883, Elranatamab) appear promising for treatment of advanced multiple myeloma; ASCO 2023 update.

Charles H. Weaver, MD
4–7 minutes
Home » Multiple Myeloma » Bispecific Antibodies in Multiple Myeloma

by Dr. C.H. Weaver M.D. 9/2023

Bispecific antibody constructs represent an innovative immunotherapy approach that helps the body’s immune system target cancer cells and appears very promising for the treatment of multiple myeloma. Bispecific antibodies or BiTE which is short for “bispecific T cell engager” are antibodies with two arms. One arm of the drug attaches to a specific protein on the cancer cell. The other arm of the BiTE activates immune cells in the patient to kill the cancer cells.1

There are several bispecific antibodies currently in development for the treatment of mulitple myeloma and clinical trial results were updated at the International Myeloma Society Annual Meeting and AACR.

Tecvayli (Teclistamab) 

Teclistamab is a bispecific antibody administered subcutaneously that targets both the B Cell maturation antigen (BCMA) present on multiple myeloma cellsBCMA and CD3. BCMA is expressed at high levels on multiple myeloma cells and teclistamab redirects CD3-positive T-cells to BCMA-expressing myeloma cells to kill the targeted cells.

Tecvauyli was evaluated in 165 refractory myeloma patients, many of whom were triple-class refractory (77%). Overall 63% of patients responded to treatment including a 6.7% complete response rate. Common side effects included infections (76%), cytokine release syndrome (CRS; 72.%), and neutropenia (71%).6

Linvoseltamab-REGN 5458

Linvoseltamab (REGN5458) and REGN5459 are BCMA x CD3 bispecific antibodies designed to bind to the BCMA present on multiple myeloma cells and the CD3 receptor on T-cells, bridging them together and activating T-cell killing of the cancerous myeloma cells. REGN5458 and REGN 5459 were invented using Regeneron’s next generation VelocImmune® “human antibody mouse” technology, together with its VelociBi™ platform. These allow for the creation of bispecific antibodies that closely resemble natural human antibodies with no linkers or artificial sequences.1

Initial results evaluating REGN5458 were presented at the American Society of Hematology Annual Meeting in December 2019 and were updated at the 2022 International Myeloma Society Annual Meeting.  Linvoseltamab elicited an objective response rate of 71% according to results from the phase 2 LINKER-MM1 study (NCT03761108) presented at the 2023 ASCO Annual Meeting. The probability of maintaining a response was 84% at 6 months and 80% at 12 months. 

  • Responses occurred rapidly, usually within the first month of treatment, and continue to deepen with longer treatment; the higher dose groups currently have substantially shorter follow up.

Cytokine release syndrome (CRS) was reported in 45% of patients, the majority of which were mild. The other most common side effects were fatigue, cough, fever, nausea, and anemia. Linvoseltamab is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.

REGN 5459

REGN5459 has slightly different binding characteristics than REGN 5458 and has been reported to induce fast onset, deep, and dose-dependent responses sustained over time, with a high frequency of manageable low-grade cytokine release syndrome (CRS) in patients with relapsed/refractory multiple myeloma, according to findings from a first-in-human phase 1/2 trial (NCT04083534) that were presented at the 2023 AACR Annual Meeting.9

At a median follow-up of 9 months (range, 1-32) an objective response rate was reported to be  65% in 43 individuals with relapsed/refractory multiple myeloma.  There was a complete response or better in 51% of patients receiving the treatment. 

Elranatamab

Elranatamab is also a BCMA x CD3 bispecific antibody designed to bind to BCMA on multiple myeloma cells and the CD3 receptor on T-cells. Examined in 94 myeloma patients who were overwhelmingly triple-class refractory, the overall response rate was 61%. The most common side effects were CRS (60%), infections (52%), and anemia (44%).

Talquetamab (JNJ-64407564)

Talquetamab is a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody therapy in development by Janssen. Study results suggest similar response rates and side effects to other bispecifics being developed in myeloma. 

ABBV-383

ABBV-383 is a BCMA × CD3 T-cell–engaging bispecific monoclonal IgG4 antibody.4,5 Among 58 evaluable patients in a dose-expansion and dose-escalation clinical trial the objective response rate was 60%. A very good partial response (VGPR) rate or better was reported for 43% of responders with a complete or stringent complete response (CR/sCR) reported among 29%. 

Cytokine release syndrome was observed in 72% of patients, with 48% of events being mile and 2% being grade 3 or higher. Serious CRS was documented in 16 patients. 

Cevostamab 

Cevostamab is a T-cell engaging bispecific antibody designed to target FcRH5 on myeloma cells and CD3 on T cells. FcRH5 is a unique and differentiated target, expressed on nearly all myeloma cells. Cevostamab has a structure similar to that of a natural human antibody in that it has two ‘Fab’ regions, but is different from naturally-occurring antibodies in that one ‘Fab’ region targets FcRH5 and the other ‘Fab’ region targets CD3. This dual targeting activates and re-directs a patient’s existing T cells to engage and eliminate target FcRH5-expressing myeloma cells by releasing cytotoxic proteins into the myeloma cells.

References:

  1. Leukemia; 2019; DOI:10.1038/s41375-019-0435-7
  2. https://www.prnewswire.com/news-releases/new-regn5458-bcmaxcd3-phase-1-data-show-75-response-rate-at-highest-dose-levels-studied-in-patients-with-heavily-pretreated-multiple-myeloma-301442629.html

  3. Zonder JA, Richter J, Bumma N, et al. Early, deep, and durable responses, and low rates of cytokine release syndrome with REGN5458, a BCMAxCD3 bispecific antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 19th Annual International Myeloma Society Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-056.

  4. Voorhees P, Shah N, D’Souza A, et al. Updated Results of a Phase 1, First-in-Human Study of ABBV-383, a BCMA × CD3 Bispecific T-Cell Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma. Presented at: 19th International Myeloma Society Annual Meeting. August 25-27, 2022; Los Angeles, CA. Abstract OAB-055 

  5. Buelow ,Choudry P, Clarke S, et al. Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma. J Clin Oncol. 2018;36(suppl 15):8034. doi:10.1200/JCO.2018.36.15_suppl.8034.

  6. Moreau P, Garfall AL, van de Donk NW, et al. Teclistamab in relapsed or refractory multiple myeloma.N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478.

  7. 1. Janssen announces US FDA breakthrough therapy designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. June 29, 2022. Accessed August 27, 2022. bit.ly/3AqKjZR

  8. Suvannasankha A, Kapoor P, Pianko MJ, et al. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMAxCD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT013.

  9. Lee HC, Bumma N, Richter JR, et al. LINKER-MM1 study: Linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8006. doi:10.1200/JCO.2023.41.16_suppl.8006

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